compound or pharmaceutically acceptable salt thereof, pharmaceutical composition, use of the compoun

专利摘要:
  It is a class of new aryl-phosphorus-oxygen compounds as shown in Formula (I), as EGFR kinase inhibitors, and pharmaceutically acceptable salts thereof.
公开号:BR112020001124A2
申请号:R112020001124-0
申请日:2018-07-19
公开日:2020-09-01
发明作者:Lingyun Wu；Ning Zhao；Jun Zhao；Xile LIU；Charles Z. Ding；Shuhui Chen；Lihong Hu；Lele ZHAO；Wei Pan；Guoping Hu；Jian Li
申请人:Chia Tai Tianqing Pharmaceutical Group Co., Ltd.；
IPC主号:

专利说明:

[001] [001] This application claims the following priority for: CN201710592778.X, date of application 2017, 07.19; CN201711277584.7, date of application 2017, 12.06; CN201810130633.2, order date 2018, 02.08; and CN201810355614.X, order date 2018, 04.19. FIELD OF THE INVENTION
[002] [002] The present application relates to an aryl-phosphine-oxygen compound as an EGFR kinase inhibitor, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. BACKGROUND OF THE INVENTION
[003] [003] Lung cancer is one of the most common malignant tumors. There will be about 1.6 million new cases of lung cancer each year worldwide, and there will be 1.4 million lung cancer deaths annually. Among them, non-small cell lung cancer (NSCLC) accounts for about 80% to 85% of all lung cancers (the 10th Lung Cancer Summit Forum).
[004] [004] EGFR (epidermal growth factor receptor) -TKI (tyrosine kinase inhibitor), as a small molecule inhibitor, competitively binds to
[005] [005] Osimertinib (AZD9291) is a targeted drug for third generation EGFR-TKI. Although they have greater responsiveness to drug resistance caused by the T790M mutation, patients also develop drug resistance (Clin Cancer Res; 21 (17), 2015). In 2015, drug resistance analysis in 15 patients with AZD9291 was first reported in Nature Medicine, 21, 560-562, 2015, in which the third mutation obtained, that is, EGFR C797S mutation, was one of the mechanisms that lead Osimertinib drug resistance, accounting for about 40%. At the same time, AZD9291 drug resistance has also been reported in several conferences, and among these, 2015 WCLC, Oxnard GR reported the drug resistance analysis of 67 patients, of whom C797S accounted for about 22%; 2017 ASCO, Piotrowska also reported 23 cases, and C797S also accounted for about 22%; and 2017 ASCO, Zhou Caicun et al reported the analysis of drug resistance mechanisms in 99 patients, of which C797S accounted for about 22%. Therefore, it is of great significance for the study to overcome AZD9291 resistance to the C797S mutation and to provide patients with an inhibitor of
[006] [006] In 2016, "Nature, 534, 129-132, 2016" reported the compound EAI045 with the ability to overcome Osimertinib drug resistance to C797S. EAI045 belongs to an allosteric inhibitor that shows a better tumor inhibition effect in the in vivo pharmacodynamic model of mice with L858R / T790M / C797S mutations when combined with EGFR monoclonal antibody such as cetuximab; but that compound failed to enter clinical studies. In 2017, Nature Communications, 8: 14768, 2017 reported that Brigatinibe (AP26113) in combination with the EGFR monoclonal antibody (such as cetuximab) can overcome the drug resistance of the third generation targeting drug Osimertinib caused by the C797S mutation. Both combinations of Brigatinib with panitumumab or cetuximab have been shown to exhibit satisfactory antitumor efficacy from the results in the PC9 mouse pharmacodynamic model (EGFR-C797S / T790M / del19).
[007] [007] The document WO2012051587A1 reveals the
[008] [008] Comparative Example 1 SUMMARY OF THE INVENTION
[009] [009] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, where,
[010] [010] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, C5-7 cycloalkenyl and C5-7 cycloalkyl, being said phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, C5-7 cycloalkenyl and C5-7 cycloalkyl are optionally substituted by R6;
[011] [011] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, wherein said C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[012] [012] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkenyl, phenyl and heterocyclic group with 3 to 14 members are optionally substituted by groups 1, 2 or 3 R;
[013] [013] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) NRR, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, - O (CH2) nNRaRb, C1-6 alkyl, C3-6 cycloalkyl and 5 or 6 membered heterocyclic group containing 1, 2 or 3 N or O atoms, said C1-6 alkyl, C3-6 cycloalkyl,
[014] [014] n is selected from 0, 1, 2, 3 or 4;
[015] [015] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and wherein said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[016] [016] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[017] [017] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and heterocyclic group with 5 to 6 members, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[018] [018] or alternatively, R4 and R5 are linked together to form a 5-6 membered ring containing 1, 2, or 3 atoms independently selected from N, S or O, where the 5-6 membered ring is optionally replaced by groups 1, 2 or 3 R;
[019] [019] each R6 is independently selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[020] [020] R7 and R8 are each independently selected from H or C1-6 alkyl;
[021] [021] or alternatively R7 and R8 are joined together to form the 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[022] [022] R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl, and heteroaryl with 5 to 6 members, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkynyl , C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl, and heteroaryl with 5 to 6 members are optionally substituted by groups 1, 2 or 3 R ';
[023] [023] R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CF3, CHF2 and CH2F;
[024] [024] "hetero" represents a hetero atom or a group of hetero atoms, and each "hetero" group in said 5- to 6-membered heterocyclic group, 5- to 6-membered heterocyclic ring, 5- to 7-membered heterocycloalkyl, 3-to-heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members or heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, -
[025] [025] in either case, as described above, the number of the heteroatom or group of hetero atoms is each independently selected from 1, 2, or 3.
[026] [026] In some embodiments of the present application, the above R is selected from F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, (CH3) 2N,,, , , and .
[027] [027] In some embodiments of the present application, the above R1 is selected from H, halogen, C1-3 alkyl and C1-3 heteroalkyl, C2-5 alkenyloxy, and C4-6 cycloalkyloxy, with said C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy and C4-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R, and R is as defined in the present application.
[028] [028] In some embodiments of the present application, the above R1 is selected from H, F, Cl, Br, I, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O, (CH3) 2CHO, and, said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,
[029] [029] In some embodiments of the present application, the above R2 is selected from H, halogen, CN, OH, NO2, NH2, C3-12 cycloalkyl, and heterocycloalkyl with 3 to 12 members, the said NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members are optionally substituted by groups 1, 2 or 3 R, and R is as defined in this application.
[030] [030] In some embodiments of the present application, the above R2 is selected from H, halogen, CN, OH, NH 2, NO 2, -NHR, -N (R) 2,,,,, and, and R complies defined this application.
[031] [031] In some embodiments of the present application, the above R2 is selected from H, F, Cl, Br, CN, OH, NH2, NO2,,,,,,,,,,
[032] [032] In some embodiments of the present application, the above R6 is selected from H, F, Cl, Br, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, = S and = O.
[033] [033] In some embodiments of the present application, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl, and pyrrolyl, the so-called phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl , cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6, and R6 is as defined in this application.
[034] [034] In some embodiments of this application, the structural unit is selected from,,,,,,, and.
[035] [035] In some embodiments of the present application, the Ra and Rb above are each independently selected from H, CH3, CH3CH2, and -S (= O) 2CH3, the said CH3,
[036] [036] In some embodiments of the present application, the Ra and Rb above are each independently selected from H,, and -S (= O) 2CH3.
[037] [037] In some embodiments of the present application, the above R3 is selected from, and.
[038] [038] In some embodiments of the present application, the above R3 is selected from H, F, Cl, Br, CH3, CH3CH2, (CH3) 2CH, and.
[039] [039] In some embodiments of the present application, the R5 above is selected from H, F, Cl, Br, I, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,, and, being said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,, and are optionally substituted by groups 1, 2 or 3 R, and R is as defined in this application.
[040] [040] In some embodiments of the present application, the above R5 is selected from H, Cl, Br, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, ， ， ， ， ， ， ， e.
[041] [041] In some embodiments of this application, the structural unit is selected from,,,,,,,, and.
[042] [042] In some embodiments of the present application, the R7 and R8 above are each independently selected from H or CH3.
[043] [043] In some embodiments of the present application, the above R is selected from F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, (CH3) 2N,,, ,,
[044] [044] In some embodiments of the present application, the above R1 is selected from H, halogen, C1-3 alkyl and C1-3 heteroalkyl, C2-5 alkenyloxy, and C4-6 cycloalkyloxy, with said C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy and C4-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R, and R and other variables are as defined above.
[045] [045] In some embodiments of the present application, the above R1 is selected from H, F, Cl, Br, I, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O, (CH3) 2CHO, and, said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O, (CH3) 2CHO, and are optionally substituted by groups 1, 2 or 3 R, and R and other variables are as defined above.
[046] [046] In some embodiments of the present application, the above R2 is selected from H, halogen, CN, OH, NO2, NH2, C3-12 cycloalkyl, and heterocycloalkyl with 3 to 12 members, the said NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members are optionally substituted by groups 1, 2 or 3 R, and R and other variables are as defined above.
[047] [047] In some embodiments of the present application, the above R2 is selected from H, halogen, CN, OH, NH 2, NO 2, -NHR, -N (R) 2,,,,, and, and R and others variables are as defined above.
[048] [048] In some embodiments of the present application, the above R2 is selected from H, F, Cl, Br, CN, OH, NH2, NO2,,,,,,,,,, -NHCH2CH3, -NHCH3, -N (CH3) 2 e, and other variables are as defined above.
[049] [049] In some embodiments of the present application, the above R6 is selected from H, F, Cl, Br, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, = S e = O, and other variables are as defined above.
[050] [050] In some embodiments of this application, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl,
[051] [051] In some embodiments of the present application, the structural unit above is selected from ,,,,,,,, and, and other variables are as defined above.
[052] [052] In some embodiments of the present application, the Ra and Rb above are each independently selected from H, CH3, CH3CH2, and -S (= O) 2CH3, the said CH3, CH3CH2, and -S ( = O) 2CH3 are optionally substituted by groups 1, 2 or 3 R, and R and other variables are as defined above.
[053] [053] In some embodiments of the present application, the Ra and Rb above are each independently selected from H,, and -S (= O) 2CH3, and other variables are as defined above.
[054] [054] In some embodiments of the present application, the R3 above is selected from, and, and other variables are as defined above.
[055] [055] In some embodiments of the present application, the R3 above is selected from H, F, Cl, Br, CH3, CH3CH2, (CH3) 2CH, and, and other variables are as defined above.
[056] [056] In some embodiments of the present application, the above R5 is selected from H, F, Cl, Br, I, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,, and, being said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,, and are optionally substituted by groups 1, 2 or 3 R, and R and other variables are as defined above.
[057] [057] In some embodiments of the present application, the above R5 is selected from H, Cl, Br, CN, CH3, CH3CH2,
[058] [058] In some embodiments of the present application, the structural unit above is selected from,,,,, N N
[059] [059] In some embodiments of the present application, the R7 and R8 above are each independently selected from H or CH3, and other variables are as defined above.
[060] [060] In some embodiments of the present application, the above compound or the pharmaceutically acceptable salt thereof is selected from among
[061] [061],
[062] [062] where, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above.
[063] [063] In some embodiments of the present application, the above compound or the pharmaceutically acceptable salt thereof is selected from,,
[064] [064] where R1, R3, R4, R5, R7, R8, R and R 'are as defined above.
[065] [065] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein,
[066] [066] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, where C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and group C3-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[067] [067] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkenyl, phenyl and heterocyclic group with 3 to 14 members are optionally substituted by groups 1, 2 or 3 R;
[068] [068] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) N ( R) 2, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, -O (CH2) nNRaRb, C1-6 alkyl, C3-6 cycloalkyl and heterocyclic group with 5 or 6 members containing 1, 2 or 3 atoms of N or O, said C1-6 alkyl, C3-6 cycloalkyl, and a 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms are optionally substituted by groups 1, 2 or 3 R;
[069] [069] n is selected from 0, 1, 2, 3 or 4;
[070] [070] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and wherein said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[071] [071] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[072] [072] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and a 5- to 6-membered heterocyclic group, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[073] [073] or alternatively, R4 and R5 are linked together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S and O, where the 5-6 membered ring containing 1 , 2 or 3 atoms independently selected from N, S or O is optionally substituted by groups 1, 2 or 3 R;
[074] [074] R9 and R10 are linked together to form ring A, and the structural unit is not selected from:;
[075] [075] or alternatively, R10 and R11 are linked together to form ring A;
[076] [076] or alternatively, R11 and R12 are linked together to form ring A;
[077] [077] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl, being said phenyl,
[078] [078] R6 is selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[079] [079] R7 and R8 are each independently selected from H or C1-6 alkyl;
[080] [080] or alternatively R7 and R8 are joined together to form the 5- to 6-membered heterocyclic ring, wherein said 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[081] [081] R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl, and heteroaryl with 5 to 6 members, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkynyl , C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl, and heteroaryl with 5 to 6 members are optionally substituted by groups 1, 2 or 3 R ';
[082] [082] R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CF3, CHF2 or CH2F;
[083] [083] "hetero" represents a hetero atom or a group of hetero atoms, and each "hetero" group in said 5- to 6-membered heterocyclic group, 5- to 6-membered heterocyclic ring, 5- to 7-membered heterocyclic alkyl, 3-to-heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members and heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, - S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH -, -O-, -S-, -C (= O) O-, - C (= O) -, -C (= S) -, -S (= O) -, -S (= O) 2 - or -N (R) C (= O) N (R) -;
[084] [084] in either case, as described above, the number of the heteroatom or group of hetero atoms is independently selected from 1, 2, or
[085] [085] In some embodiments of the present application, the above compound represented by formula (I ') or the pharmaceutically acceptable salt thereof is selected from formula (I), wherein,
[086] [086] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl, being said phenyl,
[087] [087] and the structural unit is not selected from:;
[088] [088] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, where C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3 -6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[089] [089] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkenyl, phenyl and heterocyclic group with 3 to 14 members are optionally substituted by groups 1, 2 or 3 R;
[090] [090] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy or C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) NRR, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, -
[091] [091] n is selected from 0, 1, 2 and 3;
[092] [092] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and wherein said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[093] [093] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[094] [094] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and 5- to 6-membered heterocyclic group, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[095] [095] or alternatively, R4 and R5 are bonded together to form a 5-6 membered ring containing 1, 2, or 3 atoms independently selected from N, S or O, where the 5-6 membered ring is optionally replaced by groups 1, 2 or 3 R;
[096] [096] each R6 is independently selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[097] [097] R7 and R8 are each independently selected from H or C1-6 alkyl;
[098] [098] or alternatively R7 and R8 are linked together to form a 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[099] [099] R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, C3-6 heterocycloalkyl, phenyl, and heteroaryl with 5 to 6 members, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl , C4-6 cycloalkynyl, C1-6 heteroalkyl, 3 to 6 membered heterocycloalkyl, C3-6 heterocycloalkyl, phenyl, and 5 to 6 membered heteroaryl are optionally substituted by groups 1, 2 or 3 R ';
[100] [100] R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CF3, CF2H and CFH2;
[101] [101] "hetero" represents a heteroatom or a group of hetero atoms, and each "hetero" group in said 5 to 6 membered heterocyclic group, 5 to 6 membered heterocyclic ring, 5 to 7 membered heterocycloalkyl, 3 to heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members or heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, - S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH -, -O-, -S-, -C (= O) O-, - C (= O) -, -C (= S) -, -S (= O) -, -S (= O) 2 - or -N (R) C (= O) N (R) -;
[102] [102] in either case, as described above, the number of the heteroatom or group of hetero atoms is each independently selected from 1, 2, or 3.
[103] [103] In some embodiments of the present application, the compound represented by formula (I ') or the pharmaceutically acceptable salt thereof is selected from formula (Ia),
[104] [104]
[105] [105] where,
[106] [106] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl, being said phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl are optionally substituted by R6;
[107] [107] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, where C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3 -6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[108] [108] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkenyl, phenyl and heterocyclic group with 3 to 14 members are optionally substituted by groups 1, 2 or 3 R;
[109] [109] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) N ( R) 2, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, -O (CH2) nNRaRb, C1-6 alkyl, C3-6 cycloalkyl and heterocyclic group with 5 or 6 members containing 1, 2 or 3 atoms of N or O, said C1-6 alkyl, C3-6 cycloalkyl, and a 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms are optionally substituted by groups 1, 2 or 3 R;
[110] [110] n is selected from 0, 1, 2, 3 or 4;
[111] [111] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and wherein said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[112] [112] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[113] [113] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and a 5- to 6-membered heterocyclic group, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[114] [114] or alternatively R4 and R5 are linked together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O, where the 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O is optionally substituted by groups 1, 2 or 3 R;
[115] [115] R6 is selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[116] [116] R7 and R8 are each independently selected from H or C1-6 alkyl;
[117] [117] or alternatively R7 and R8 are linked together to form a 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[118] [118] R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl, and heteroaryl with 5 to 6 members, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkynyl , C1-6 heteroalkyl, C3-6 heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are optionally substituted by groups 1, 2 or 3 R ';
[119] [119] R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CF3, CHF2 or CH2F;
[120] [120] "hetero" represents a heteroatom or a group of hetero atoms, and each "hetero" group in said 5- to 6-membered heterocyclic group, 5- to 6-membered heterocyclic ring, 5- to 7-membered heterocycloalkyl, 3-to-heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members or heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, - S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH -, -O-, -S-, -C (= O) O-, - C (= O) -, -C (= S) -, -S (= O) -, -S (= O) 2 - and -N (R) C (= O) N (R) -;
[121] [121] in either case, as described above, the number of the heteroatom or group of hetero atoms is each independently selected from 1, 2, or 3.
[122] [122] In some embodiments of the present application, the compound represented by the formula (I ') above or the pharmaceutically acceptable salt thereof is selected from the formula (Ib), where,
[123] [123] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl, being said phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl are optionally substituted by R6;
[124] [124] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, where C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3 -6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[125] [125] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkenyl, phenyl and heterocyclic group with 3 to 14 members are optionally substituted by groups 1, 2 or 3 R;
[126] [126] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) N ( R) 2, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, -O (CH2) nNRaRb, C1-6 alkyl, C3-6 cycloalkyl and heterocyclic group with 5 or 6 members containing 1, 2 or 3 atoms of N or O, said C1-6 alkyl, C3-6 cycloalkyl, and a 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms are optionally substituted by groups 1, 2 or 3 R;
[127] [127] n is selected from 0, 1, 2, 3 or 4;
[128] [128] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and wherein said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[129] [129] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[130] [130] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and a 5- to 6-membered heterocyclic group, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[131] [131] or alternatively R4 and R5 are linked together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O, where the 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O is optionally substituted by groups 1, 2 or 3 R;
[132] [132] R6 is selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[133] [133] R7 and R8 are each independently selected from H or C1-6 alkyl;
[134] [134] or alternatively R7 and R8 are linked together to form a 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[135] [135] R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl, and heteroaryl with 5 to 6 members, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkynyl , C1-6 heteroalkyl, C3-6 heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are optionally substituted by groups 1, 2 or 3 R ';
[136] [136] R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CF3, CHF2 or CH2F;
[137] [137] "hetero" represents a heteroatom or a group of heteroatoms, and each "hetero" group in said 5 to 6 membered heterocyclic group, 5 to 6 membered heterocyclic ring, 5 to 7 membered heterocycloalkyl, 3 to heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members or heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, - S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH -, -O-, -S-, -C (= O) O-, - C (= O) -, -C (= S) -, -S (= O) -, -S (= O) 2 - and -N (R) C (= O) N (R) -;
[138] [138] in either case, as described above, the number of the heteroatom or group of hetero atoms is each independently selected from 1, 2, or 3.
[139] [139] In some embodiments of the present application, in the formula (I '), the above R is selected from F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, (CH3) 2N,,,,, or.
[140] [140] In some embodiments of the present application, in formula (I '), the above R1 is selected from H, halogen, C1-3 alkyl and C1-3 heteroalkyl, C2-5 alkenyloxy or C4-6 cycloalkyloxy, with said C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy and C4-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R.
[141] [141] In some embodiments of the present application, in formula (I '), the above R1 is selected from H, F, Cl, Br, I, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O, (CH3) 2CHO, and, said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O, (CH3) 2CHO, and are optionally substituted by groups 1, 2 or 3 R.
[142] [142] In some embodiments of the present application, in the formula (I '), the above R2 is selected from H, halogen, CN, OH, NO2, NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members, with the said NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members are optionally substituted by groups 1, 2 or 3 R.
[143] [143] In some embodiments of the present application, in the formula (I '), R2 is selected from H, halogen, CN, OH, NH2, NO2, -NHR, -N (R) 2,,,,, and.
[144] [144] In some embodiments of the present application, in formula (I '), the R2 above is selected from H, F, Cl, Br,
[145] [145] In some embodiments of the present application, in formula (I '), the R6 above is selected from H, F, Cl, Br, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, = S and = O.
[146] [146] In some embodiments of the present application, in formula (I '), when R9 and R10 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, and said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6.
[147] [147] In some embodiments of this application,
[148] [148] In some embodiments of the present application, in formula (I '), when R10 and R11 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, and said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6.
[149] [149] In some embodiments of the present application, in formula (I '), when R10 and R11 are linked together to form ring A, the structural unit is selected from,,,,,
[150] [150] In some embodiments of the present application, in formula (I '), when R11 and R12 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, and said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6.
[151] [151] In some embodiments of the present application, in formula (I '), when R11 and R12 are linked together to form ring A, the structural unit is selected from among
[152] [152] In some embodiments of this application, in formula (I '), the Ra and Rb above are each
[153] [153] In some embodiments of the present application, in formula (I '), the Ra and Rb above are each independently selected from H,, and - S (= O) 2CH3.
[154] [154] In some embodiments of the present application, in formula (I '), the R3 above is selected from, and.
[155] [155] In some embodiments of the present application, in formula (I '), the R3 above is selected from H, F, Cl, Br, CH3, CH3CH2 and.
[156] [156] In some embodiments of the present application, in formula (I '), the R5 above is selected from H, F, Cl, Br,
[157] [157] In some embodiments of the present application, in formula (I '), the above R5 is selected from H, Cl, Br, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,,,, and .
[158] [158] In some embodiments of the present application, in formula (I '), the structural unit above is selected from among.
[159] [159] In some embodiments of the present application, in formula (I '), the R7 and R8 above are each independently selected from H or CH3.
[160] [160] In some embodiments of the present application, in formula (I '), the R above is selected from F, Cl, Br, I,
[161] [161] In some embodiments of the present application, in formula (I '), the above R1 is selected from H, halogen, C1-3 alkyl and C1-3 heteroalkyl, C2-5 alkenyloxy and C4-6 cycloalkyloxy, with said C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy, and C4-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R, and other variables are as defined above.
[162] [162] In some embodiments of the present application, in formula (I '), the above R1 is selected from H, F, Cl, Br, I, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O, (CH3) 2CHO, and, being said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O, (CH3) 2CHO, and are optionally substituted by groups 1, 2 or 3 R, and other variables are as defined above.
[163] [163] In some embodiments of the present application, in the formula (I '), the R2 above is selected from H, halogen, CN, OH, NO2, NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members, with the said NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members are optionally substituted by groups 1, 2 or 3 R, and other variables are as defined above.
[164] [164] In some embodiments of the present application, in the formula (I '), the above R2 is selected from H, halogen, CN, OH, NH2, NO2, -NHR, -N (R) 2,,,,, and , and other variables are as defined above.
[165] [165] In some embodiments of the present application, in the formula (I '), the above R2 is selected from H, F, Cl, Br, CN, OH, NH2, NO2,,,,,,,
[166] [166] In some embodiments of the present application, in formula (I '), the above R6 is selected from H, F, Cl, Br, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, = S and = O, and other variables are as defined above.
[167] [167] In some embodiments of the present application, in formula (I '), when R9 and R10 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6, and other variables are as defined above.
[168] [168] In some embodiments of the present application, in formula (I '), when R9 and R10 are linked together to form ring A, the structural unit is selected from among
[169] [169] In some embodiments of the present application, in formula (I '), when R10 and R11 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6, and other variables are as defined above.
[170] [170] In some embodiments of the present application, in formula (I '), when R10 and R11 are linked together to form ring A, the structural unit is selected from,,,,,
[171] [171] In some embodiments of the present application, in formula (I '), when R11 and R12 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl , isothiazolyl and pyrrolyl, said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, imidazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6, and other variables are as defined above.
[172] [172] In some embodiments of the present application, in formula (I '), when R11 and R12 are linked together to form ring A, the structural unit is selected from among
[173] [173] In some embodiments of the present application, in formula (I '), the Ra and Rb above are each independently selected from H, CH3, CH3CH2, and - S (= O) 2CH3, the said CH3 , CH3CH2, and -S (= O) 2CH3 are optionally substituted by groups 1, 2 or 3 R, and other variables are as defined above.
[174] [174] In some embodiments of the present application, in formula (I '), the Ra and Rb above are each independently selected from H,, and - S (= O) 2CH3, and other variables are as defined above.
[175] [175] In some embodiments of this application, in formula (I '), the R3 above is selected from, and, and other variables are as defined above.
[176] [176] In some embodiments of the present application, in formula (I '), the R3 above is selected from H, F, Cl, Br,
[177] [177] In some embodiments of the present application, in formula (I '), the above R5 is selected from H, F, Cl, Br, I, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,, , and, said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,, and are optionally substituted by groups 1, 2 or 3 R, and other variables are as defined above.
[178] [178] In some embodiments of the present application, in formula (I '), the above R5 is selected from H, Cl, Br, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,,,, and , and other variables are as defined above.
[179] [179] In some embodiments of the present application, in formula (I '), the structural unit above is selected from, and other variables are as defined above.
[180] [180] In some embodiments of the present application, in formula (I '), the R7 and R8 above are each independently selected from H or CH3, and other variables are as defined above.
[181] [181] In some embodiments of the present application, in formula (I '), the above compound or the pharmaceutically acceptable salt thereof is selected from among
[182] [182],,,
[183] [183] where R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above.
[184] [184] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
[185] [185]
[186] [186] (I '')
[187] [187] where,
[188] [188] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, where C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3 -6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[189] [189] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkenyl, phenyl and heterocyclic group with 3 to 14 members are optionally substituted by groups 1, 2 or 3 R;
[190] [190] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) N ( R) 2, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, -O (CH2) nNRaRb, C1-6 alkyl and 5- or 6-membered heterocyclic group containing 1 , 2 or 3 N or O atoms, said C1-6 alkyl and 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms are optionally substituted by groups 1, 2 or 3 R;
[191] [191] n is selected from 0, 1, 2, 3 or 4;
[192] [192] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and wherein said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[193] [193] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[194] [194] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and a 5- to 6-membered heterocyclic group, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[195] [195] or alternatively R4 and R5 are linked together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O, where the 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O is optionally substituted by groups 1, 2 or 3 R;
[196] [196] R9 and R10 are linked together to form ring A;
[197] [197] or alternatively, R10 and R11 are linked together to form ring A;
[198] [198] or alternatively, R11 and R12 are linked together to form ring A;
[199] [199] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl, being said phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl are optionally substituted by R6;
[200] [200] R6 is selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[201] [201] R7 and R8 are each independently selected from H or C1-6 alkyl;
[202] [202] or alternatively R7 and R8 are linked together to form a 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[203] [203] R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl, and heteroaryl with 5 to 6 members, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkynyl , C1-6 heteroalkyl, C3-6 heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are optionally substituted by groups 1, 2 or 3 R ';
[204] [204] R 'is selected from among H, F, Cl, Br, I,
[205] [205] "hetero" represents a heteroatom or a group of hetero atoms, and each "hetero" group in said 5- to 6-membered heterocyclic group, 5- to 6-membered heterocyclic ring, 5- to 7-membered heterocyclic alkyl, 3-to-heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members or heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, - S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH -, -O-, -S-, -C (= O) O-, - C (= O) -, -C (= S) -, -S (= O) -, -S (= O) 2 - and -N (R) C (= O) N (R) -;
[206] [206] in either case, as described above, the number of the heteroatom or group of hetero atoms is each independently selected from 1, 2, or 3.
[207] [207] In some embodiments of the present application, the compound represented by the formula (I '') above or the pharmaceutically acceptable salt thereof is selected from formula (I),
[208] [208] where,
[209] [209] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl, being said phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl are optionally substituted by R6;
[210] [210] and the structural unit is not selected from:;
[211] [211] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, wherein said C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[212] [212] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkenyl, phenyl and heterocyclic group with 3 to 14 members are optionally substituted by groups 1, 2 or 3 R;
[213] [213] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) NRR, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, - O (CH2) nNRaRb, C1-6 alkyl and 5- or 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms, said C1-6 alkyl and 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms are optionally substituted by groups 1, 2 or 3 R;
[214] [214] n is selected from 0, 1, 2 or 3;
[215] [215] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and wherein said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[216] [216] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[217] [217] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and a 5- to 6-membered heterocyclic group, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[218] [218] or alternatively, R4 and R5 are linked together to form a 5- to 6-membered ring containing 1, 2, or 3 atoms independently selected from N, S or O,
[219] [219] each R6 is independently selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[220] [220] R7 and R8 are each independently selected from H or C1-6 alkyl;
[221] [221] or alternatively R7 and R8 are linked together to form a 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[222] [222] R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, C3-6 heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, C1- 6 heteroalkyl, C3-6 heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are optionally substituted by groups 1, 2 or 3 R ';
[223] [223] R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, CH3O, CF3, CF2H and CFH2;
[224] [224] "hetero" represents a heteroatom or a group of hetero atoms, and each "hetero" group in said 5 to 6 membered heterocyclic group, 5 to 6 membered heterocyclic ring, 5 to 7 membered heterocycloalkyl, 3 to heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members or heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, - S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH -, -O-, -S-, -C (= O) O-, - C (= O) -, -C (= S) -, -S (= O) -, -S (= O) 2 - and -N (R) C (= O) N (R) -;
[225] [225] in either case, as described above, the number of the heteroatom or group of hetero atoms is independently selected from 1, 2, or
[226] [226] In some embodiments of the present application, the compound represented by the formula (I '') above or the pharmaceutically acceptable salt thereof is selected from the formula (Ia),
[227] [227] where,
[228] [228] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl, being said phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl are optionally substituted by R6;
[229] [229] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, where C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3 -6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[230] [230] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkenyl, phenyl and heterocyclic group with 3 to 14 members are optionally substituted by groups 1, 2 or 3 R;
[231] [231] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) N ( R) 2, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, -O (CH2) nNRaRb, C1-6 alkyl and 5- or 6-membered heterocyclic group containing 1 , 2 or 3 N or O atoms, said C1-6 alkyl and 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms are optionally substituted by groups 1, 2 or 3 R;
[232] [232] n is selected from 0, 1, 2, 3 or 4;
[233] [233] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[234] [234] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[235] [235] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and 5- to 6-membered heterocyclic group, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[236] [236] or alternatively, R4 and R5 are linked together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O, where the 5-6 membered ring containing 1 , 2 or 3 atoms independently selected from N, S or O is optionally substituted by groups 1, 2 or 3 R;
[237] [237] R6 is selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[238] [238] R7 and R8 are each independently selected from H or C1-6 alkyl;
[239] [239] or alternatively R7 and R8 are joined together to form the 5- to 6-membered heterocyclic ring, wherein said 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[240] [240] R is selected from halogen, CN, OH,
[241] [241] R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, CH3O, CF3, CHF2 and CH2F;
[242] [242] "hetero" represents a hetero atom or a group of hetero atoms, and each "hetero" group in said 5- to 6-membered heterocyclic group, 5- to 6-membered heterocyclic ring, 5- to 7-membered heterocycloalkyl, 3-to-heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members or heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, - S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH -, -O-, -S-, -C (= O) O-, - C (= O) -, -C (= S) -, -S (= O) -, -S (= O) 2 - and -N (R) C (= O) N (R) -;
[243] [243] in either case, as described above, the number of the heteroatom or group of hetero atoms is each independently selected from 1, 2, or 3.
[244] [244] In some embodiments of this application,
[245] [245] where,
[246] [246] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl, being said phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, and C5-7 cycloalkyl are optionally substituted by R6;
[247] [247] R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, where C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3 -6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
[248] [248] R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, phenyl , and 3 to 14 membered heterocyclic group, said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl,
[249] [249] R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, - OC (= O) NHR, -OC (= O) N ( R) 2, -NRC (= O) OR, -NHC (= O) OR, -NHC (= O) OH, -O (CH2) nNRaRb, C1-6 alkyl and 5- or 6-membered heterocyclic group containing 1 , 2 or 3 N or O atoms, said C1-6 alkyl and 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms are optionally substituted by groups 1, 2 or 3 R;
[250] [250] n is selected from 0, 1, 2, 3 or 4;
[251] [251] Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and wherein said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R;
[252] [252] or alternatively, Ra and Rb are linked together to form a 5- to 6-membered heterocyclic ring;
[253] [253] R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl, and a 5- to 6-membered heterocyclic group, with said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
[254] [254] or alternatively R4 and R5 are linked together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O, where the 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O is optionally substituted by groups 1, 2 or 3 R;
[255] [255] R6 is selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S;
[256] [256] R7 and R8 are each independently selected from H or C1-6 alkyl;
[257] [257] or alternatively R7 and R8 are linked together to form a 5- to 6-membered heterocyclic ring, wherein the 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R;
[258] [258] R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl, and heteroaryl with 5 to 6 members, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkynyl , C1-6 heteroalkyl, C3-6 heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are optionally substituted by groups 1, 2 or 3 R ';
[259] [259] R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, CH3O, CF3, CHF2 and CH2F;
[260] [260] "hetero" represents a heteroatom or a group of heteroatoms, and each "hetero" group in said 5 to 6 membered heterocyclic group, 5 to 6 membered heterocyclic ring, 5 to 7 membered heterocyclic alkyl, 3 to heterocyclic group to 14 members, C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members or heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, - S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH -, -O-, -S-, -C (= O) O-, - C (= O) -, -C (= S) -, -S (= O) -, -S (= O) 2 - and -N (R) C (= O) N (R) -;
[261] [261] in either case, as described above, the number of the heteroatom or group of hetero atoms is each independently selected from 1, 2, or 3.
[262] [262] In some embodiments of the present application, in the formula (I ''), the above R is selected from F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, CH3O , (CH3) 2N,,,,, and.
[263] [263] In some embodiments of the present application, in formula (I ''), the above R1 is selected from H, halogen, C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy, and C4-6 cycloalkyloxy, being whereas said C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy and C4-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R.
[264] [264] In some embodiments of the present application, in the formula (I ''), the R1 above is selected from H, F, Cl, Br, I, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, CH3O, CH3CH2O, CH3CH2CH2O , (CH3) 2CH2O, e.g.
[265] [265] In some embodiments of the present application, in the formula (I ''), the R2 above is selected from H, halogen, CN, OH, NO2, NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members, with said NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members are optionally substituted by groups 1, 2 or 3 R.
[266] [266] In some embodiments of the present application, in the formula (I ''), the above R2 is selected from H, halogen, CN, OH, NH2, NO2, -NHR, -N (R) 2,,,,, and .
[267] [267] In some modalities of the present application, in the formula (I ''), the R2 above is selected from H, F, Cl, Br,
[268] [268] In some embodiments of the present application, in the formula (I ''), the above R6 is selected from H, F, Cl, Br, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, CH3O , = S and = O.
[269] [269] In some embodiments of the present application, in formula (I '), when R9 and R10 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, and said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6.
[270] [270] In some embodiments of this application,
[271] [271] In some embodiments of the present application, in formula (I '), when R10 and R11 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, and said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6.
[272] [272] In some embodiments of the present application, in formula (I '), when R10 and R11 are linked together to form ring A, the structural unit above is selected from,,,,,
[273] [273] In some embodiments of the present application, in formula (I '), when R11 and R12 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, and said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6.
[274] [274] In some embodiments of the present application, in formula (I '), when R11 and R12 are linked together to form ring A, the structural unit is selected from,,,,,,,,, and.
[275] [275] In some embodiments of the present application, in formula (I '), the Ra and Rb above are each independently selected from H, CH3, CH3CH2, and -
[276] [276] In some embodiments of this application, in formula (I '), the Ra and Rb above are each independently selected from H,, and - S (= O) 2CH3.
[277] [277] In some embodiments of the present application, in formula (I '), the R3 above is selected from, and.
[278] [278] In some embodiments of the present application, in formula (I '), the R3 above is selected from H, F, Cl, Br, CH3, CH3CH2 and.
[279] [279] In some embodiments of the present application, in formula (I '), the R5 above is selected from H, F, Cl, Br,
[280] [280] In some embodiments of the present application, in formula (I '), the above R5 is selected from H, Cl, Br, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2,,,,,,,, and .
[281] [281] In some embodiments of the present application, in the formula (I '), the structural unit above is selected from among.
[282] [282] In some embodiments of the present application, in formula (I '), the R7 and R8 above are each independently selected from H or CH3.
[283] [283] In some embodiments of the present application, in formula (I '), the R above is selected from F, Cl, Br, I,
[284] [284] In some embodiments of the present application, in formula (I '), the R1 above is selected from H, halogen, C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy and C4-6 cycloalkyloxy, with said C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy, and C4-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R, and other variables are as defined above.
[285] [285] In some embodiments of the present application, in the formula (I ''), the R1 above is selected from H, F, Cl, Br, I, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, CH3O, CH3CH2O, CH3CH2CH2O , (CH3) 2CH2O, e, and other variables are as defined above.
[286] [286] In some embodiments of the present application, in the formula (I '), the above R2 is selected from H, halogen, CN, OH, NO2, NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members, with the said NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members are optionally substituted by groups 1, 2 or 3 R, and other variables are as defined above.
[287] [287] In some embodiments of the present application, in the formula (I '), the above R2 is selected from H, halogen, CN, OH, NH2, NO2, -NHR, -N (R) 2,,,,, and , and other variables are as defined above.
[288] [288] In some embodiments of the present application, in the formula (I '), the above R2 is selected from H, F, Cl, Br, CN, OH, NH2, NO2,,,,,,,,,,, , -NHCH2CH3, -NHCH3, -N (CH3) 2 and
[289] [289] In some embodiments of the present application, in the formula (I ''), the above R6 is selected from H, F, Cl, Br, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, CH3O , = S and = O, and other variables are as defined above.
[290] [290] In some embodiments of the present application, in formula (I ''), when R9 and R10 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl , thiazolyl, isothiazolyl and pyrrolyl, said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6, and other variables are as defined above.
[291] [291] In some embodiments of the present application, in formula (I ''), when R9 and R10 are linked together to form ring A, the structural unit is selected from,,,,,
[292] [292] In some embodiments of the present application, in formula (I ''), when R10 and R11 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl , thiazolyl, isothiazolyl and pyrrolyl, said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6, and other variables are as defined above.
[293] [293] In some embodiments of the present application, in formula (I ''), when R10 and R11 are linked together to form ring A, the structural unit is selected from,,,,,,,, and, and other variables are as defined above.
[294] [294] In some embodiments of the present application, in formula (I ''), when R11 and R12 are linked together to form ring A, ring A is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl , thiazolyl, isothiazolyl and pyrrolyl, said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6, and other variables are as defined above.
[295] [295] In some embodiments of the present application, in formula (I ''), when R11 and R12 are linked together to form an A ring, the structural unit above is selected from,,,,,,,,, and, and other variables are as defined above.
[296] [296] In some modalities of the present application, in the formula (I ''), the Ra and Rb above are each independently selected from H, CH3, CH3CH2, and - S (= O) 2CH3, the said CH3, CH3CH2, and -S (= O) 2CH3 are optionally substituted by groups 1, 2 or 3 R, and other variables are as defined above.
[297] [297] In some modalities of the present application, in the formula (I ''), the Ra and Rb above are each independently selected from H, ， and - S (= O) 2CH3, and other variables are as defined above .
[298] [298] In some embodiments of the present application, in formula (I '), the R3 above is selected from, and, and other variables are as defined above.
[299] [299] In some embodiments of the present application, in the formula (I ''), the R3 above is selected from H, F, Cl, Br, CH3, CH3CH2 and, and other variables are as defined above.
[300] [300] In some embodiments of the present application, in formula (I ''), the R5 above is selected from H, F, Cl, Br,
[301] [301] In some embodiments of the present application, in the formula (I ''), the above R5 is selected from H, Cl, Br, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2,,,,,,, and, and other variables are as defined above.
[302] [302] In some embodiments of the present application, in the formula (I ''), the structural unit above is selected from, and other variables are as defined above.
[303] [303] In some embodiments of the present application, in formula (I ''), the R7 and R8 above are each independently selected from H or CH3, and other variables are as defined above.
[304] [304] In some embodiments of the present application, in formula (I ''), the above compound or the pharmaceutically acceptable salt thereof is selected from among
[305] [305],,,,,
[306] [306] where R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above.
[307] [307] The present application provides a compound represented by the formula (I '' '') or a pharmaceutically acceptable salt thereof,
[308] [308]
[309] [309] (I '' ')
[310] [310] where,
[311] [311] ring A is selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, or C5-7 cycloalkyl, which is optionally substituted by R6;
[312] [312] and the structural unit is not selected from:
[313] [313] R1 is selected from H or halogen, or selected from C1-6 alkyl, C1-6 heteroalkyl, C3-6 alkenyloxy or C3-6 cycloalkoxy group, which is optionally substituted by groups 1, 2 or 3 R;
[314] [314] R2 is selected from: H, halogen, CN, OH, or NO2, or selected from NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4 -6 cycloalkynyl, phenyl, or 3 to 14 membered heterocyclic group, which is optionally substituted by groups 1, 2 or 3 R;
[315] [315] R3 is selected from H, halogen, C1-6 alkoxy, C3-6 alkenyloxy or C3-6 cycloalkyloxy, -OC (= O) NH2, -OC (= O) NHR, -OC (= O) NRR, -NRC (= O) OR, -NHC (= O) OR, or -NHC (= O) OH, or selected from C1-6 alkyl, or 5- to 6-membered heterocyclic group containing 1, 2 or 3 atoms N or O, which is optionally substituted by groups 1, 2 or 3 R;
[316] [316] R4 is selected from: H or NH2;
[317] [317] R5 is selected from H or halogen, or selected from NH2, C1-4 alkyl, C1-4 heteroalkyl, phenyl or 5- to 6-membered heterocyclic group, which is optionally substituted by groups 1, 2 or 3 R;
[318] [318] or alternatively, R4 and R5 are linked together to form a 5- to 6-membered ring containing 1, 2, or 3 heteroatoms independently selected from N, S or O, which is optionally substituted by groups 1, 2 or 3 R;
[319] [319] R6 is independently selected from: H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O, or = S;
[320] [320] R7 and R8 are each independently selected from H, C1-6 alkyl;
[321] [321] R is selected from halogen, CN, OH, or NH2, or selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1 -6 heteroalkyl, C3-6 heterocycloalkyl, phenyl or 5- to 6-membered heteroaryl, which is optionally substituted by groups 1, 2 or 3 R ';
[322] [322] R 'is selected from: H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, or CH3O;
[323] [323] "hetero" represents a heteroatom or a group of hetero atoms, and each "hetero" group in said 5 to 6 membered heterocyclic group, C1-6 heteroalkyl, 3 to 14 membered heterocyclic group, C1-4 heteroalkyl, C1 -6 heteroalkyl, C3-6 heterocycloalkyl, or heteroaryl with 5 to
[324] [324] in either case, as described above, the number of the heteroatom or group of hetero atoms is each independently selected from 1, 2, or 3.
[325] [325] In some embodiments of the present application, in the formula (I '' '), the R above is selected from: F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2 , or CH3O.
[326] [326] In some embodiments of the present application, in the formula (I '' '), the R1 above is selected from: H, F, Cl, Br, I, C1-6 alkyl, or C1-6 heteroalkyl.
[327] [327] In some modalities of this application, in the formula (I '' '), the R1 above is selected from:.
[328] [328] In some embodiments of the present application, in the formula (I '' '), the R2 above is selected from: H, halogen, CN, OH, or NO2, or selected from C3-14 cycloalkyl, or heterocyclic group with 3 to 14 members, which is optionally substituted by groups 1, 2 or 3 R.
[329] [329] In some embodiments of the present application, in the formula (I '' '), the R2 above is selected from: H,
[330] [330] In some embodiments of the present application, in the formula (I '' '), the R2 above is selected from:,, or.
[331] [331] In some embodiments of the present application, in formula (I '' '), ring A above is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, or cyclopentanonyl, which is optionally substituted by R6.
[332] [332] In some embodiments of the present application, in the formula (I '' '), the structural unit above is
[333] [333] In some modalities of the present application, in the formula (I '' '), the R3 above is selected from: H, Cl and CH3.
[334] [334] In some embodiments of the present application, in formula (I '' '), the R4 above is selected from: H.
[335] [335] In some embodiments of the present application, in the formula (I '' '), the R5 above is selected from: H, or Cl.
[336] [336] In some embodiments of the present application, in the formula (I '' '), the R6 above is selected from: H, or CH3.
[337] [337] In some modalities of this application, in the formula (I '' '), the R7 and R8 above are each independently selected from: CH3.
[338] [338] In some embodiments of the present application, in the formula (I '' '), the above R is selected from F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH2, or CH3O, and other variables are as defined above.
[339] [339] In some embodiments of the present application, in the formula (I ′ ′ ′), the R1 above is selected from: H, F, Cl, Br, I, C1-6 alkyl, or C1-6 heteroalkyl, and other variables are as defined above.
[340] [340] In some embodiments of this application,
[341] [341] In some embodiments of the present application, in the formula (I '' '), the R2 above is selected from: H, halogen, CN, OH, or NO2, or selected from C3-14 cycloalkyl or heterocyclic group with 3 to 14 members optionally replaced by groups 1, 2 or 3 R, and other variables are as defined above.
[342] [342] In some embodiments of the present application, in the formula (I '' '), the R2 above is selected from: H, halogen, CN, OH, NH2, NO2, -NHR, -NRR,,,,,, or , and other variables are as defined above.
[343] [343] In some modalities of this application, in the formula (I '' '), the R2 above is selected from:,,
[344] [344] In some embodiments of the present application, in formula (I '' '), ring A above is selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, or cyclopentanonyl, which is optionally substituted by R6, and other variables are as defined above.
[345] [345] In some embodiments of the present application, in formula (I '' '), the structural unit above is
[346] [346] In some embodiments of the present application, in the formula (I '' '), the R3 above is selected from H, Cl, or CH3, and other variables are as defined above.
[347] [347] In some embodiments of the present application, in the formula (I '' '), the R4 above is selected from H, and other variables are as defined above.
[348] [348] In some embodiments of the present application, in formula (I '' '), the R5 above is selected from H, or Cl, and other variables are as defined above.
[349] [349] In some embodiments of the present application, in Formula (I '' '), the R6 above is selected from H, or CH3, and other variables are as defined above.
[350] [350] In some embodiments of the present application, in formula (I '' '), the R7 and R8 above are each independently selected from CH3, and other variables are as defined above.
[351] [351] In some embodiments of the present application, in formula (I '' '), the above compound or the pharmaceutically acceptable salt thereof is selected from,,,,
[352] [352] where R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above.
[353] [353] The present application also provides the following compounds or pharmaceutically acceptable salts thereof
[354] [354] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[355] [355] The present application also provides for the use of the above compound or the pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the manufacture of a medicament for the treatment of cancer.
[356] [356] The present application also provides for the use of the above compound or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition above for the treatment of cancer.
[357] [357] The application also provides a method for the treatment of cancer, which comprises administering to a subject a therapeutically effective amount of the above compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof.
[358] [358] The present application also provides for the use of the above compound or the pharmaceutically acceptable salt thereof in combination with the monoclonal antibody of EGFR in the manufacture of a medicament for the treatment of cancer.
[359] [359] The application also provides a method for the treatment of cancer, which comprises administering to a subject a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof, and a monoclonal antibody to EGFR.
[360] [360] In some embodiments of the present application, the EGFR monoclonal antibody above is cetuximab.
[361] [361] The application also provides a method for the treatment of cancer, which comprises administering to a subject a therapeutically effective amount of the above compound or the pharmaceutically acceptable salt thereof or its pharmaceutical composition, and a MEK inhibitor.
[362] [362] In some embodiments of the present application, cancer is lung cancer.
[363] [363] In the present application, yet other modalities are derived from any combination of the above variables. Technical effect
[364] [364] The compounds of the present application show excellent antiproliferative activity in the EGFR Ba / F3 cell with three mutations (Δ19del / T790M / C797S) and phosphorylation activity in the EGFR Ba / F3 cell model with three mutations (Δ19del / T790M / C797S) .
[365] [365] The compound in this application exhibits unexpected inhibitory activity compared to Comparative Example 1. Definitions and Introductions
[366] [366] Unless otherwise stated, the following terms and phrases as used in this document are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be interpreted as its common meanings. When a mark appears in this document, it is intended to refer to the corresponding commodity or active ingredient therein. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that fall within the scope of sound clinical opinion, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, proportional to a reasonable benefit / risk ratio.
[367] [367] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present application, which is prepared from a compound that has a specific substituent found in the present application and a relatively non-toxic acid or base. When the compound of the present application contains a relatively acidic functional group, the base addition salt thereof can be obtained by contacting that compound in neutral form with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compound of the present application contains a relatively basic functional group, the acid addition salt thereof can be obtained by contacting that compound in neutral form with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition salt include salts of inorganic acid, salts of organic acid, ammonium salts, and salts of organic acids such as glucuronic acid. Certain specific compounds in the application contain basic and acidic functional groups, which can be converted to base or acid addition salt.
[368] [368] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains an acidic chemical portion or a basic chemical portion by conventional chemical methods. In general, that salt is prepared by reacting the free base acid form of the compound with a stoichiometric amount of a suitable acid or base in the water or an organic solvent or a mixture thereof. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
[369] [369] In addition to the salt form, the compound provided in this document also exists as a prodrug. The prodrug of the compound described in this document is the compound that undergoes chemical change promptly under physiological condition, to be converted into the compound of the application. Furthermore,
[370] [370] Certain compounds in the application may exist in an unsolvated form or a solvated form, including a hydrated form. In general, the solvated form is equivalent to the unsolvated form, and both are covered by the scope of the application.
[371] [371] The compounds of the present application can exist in specific or stereoisomeric forms. All of these compounds provided by the present invention include cis and trans isomers, (-) - and (+) - enantiomeric pairs, (R) - and (S) -enantiomers, diastereoisomers, (D) -isomers, (L) - isomers, and racemic mixtures thereof, and other mixtures thereof, such as mixtures enriched with enantiomers or diastereomers, all of which fall within the scope of this application. Other asymmetric carbon atoms may be present in the substituents such as alkyl. All of these isomers and their mixtures are included in the scope of this application.
[372] [372] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
[373] [373] Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of carbon atoms in the ring to rotate freely.
[374] [374] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers in which the molecules have two or more chiral centers and are not mirror images of each other.
[375] [375] Unless otherwise indicated, "(D)" or "(+)" means dextrorotation, "(L)" or "(-)" means levorotation, "(DL)" or "(±)" means racemization .
[376] [376] Unless otherwise stated, the absolute configuration of a stereogenic center is represented by a solid wedge bond () and the dashed wedge bond (), and the relative configuration of a stereogenic center is represented by a solid straight bond () and a straight dashed link (). A wavy line () represents a solid wedge bond () or a dashed wedge bond (), or represents a solid straight bond () and a straight dashed bond ().
[377] [377] The compounds of the present application may be present in particular. Unless otherwise indicated, the terms "tautomer" or "tautomeric form" refer to the fact that different functional isomers are in dynamic equilibrium at room temperature and can be quickly converted to one another. If tautomers are possible (as in the solution ), the chemical balance of tautomers can be achieved. For example, proton tautomers (also known as prototopic tautomers) include proton transfer interconversions such as keto-enol isometrization and imine-enamine isomerization. mutual transformation of some bonding electrons A specific example of keto-enol tautomerization is the interconversion between two pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
[378] [378] Unless otherwise indicated, the term "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enriched in an enantiomer" refers to the content of one of the isomers or enantiomers being less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97 % or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99 , 9% or more.
[379] [379] Unless otherwise indicated, the term "excess of isomer" or "excess of enantiomer" refers to the difference between the relative percentages of the two isomers or enantiomers. For example, where, the content of one of the isomers or enantiomers is 90%, and the other is 10%, then the excess isomer or enantiomeric (ee value) is 80%.
[380] [380] Optically active (R) - and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a given compound of the present application is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, in which the resulting diastereometric mixture is separated and the ancillary group is cleaved to provide the desired pure enantiomers. Alternatively, when a molecule contains a basic functional group (such as an amino) or an acidic functional group (such as a carboxyl), it also forms a diastereomer salt with a suitable optically active acid or base, and then a diastereomer resolution it is carried out by a conventional method well known in the art, followed by recovery to generate the pure enantiomer. In addition, the separation of enantiomers and diastereomers is generally accomplished by using chromatography that adopts a chiral stationary phase, and optionally in combination with a chemical derivatization method (for example, the formation of amine carbamates). The compounds of the present application may contain unnatural proportions of atomic isotopes in one or more atoms that make up the compound. For example, the compound can be labeled with a radioisotope, such as tritium (3H), iodine-125 (125I) or C-14 (14C). Any transformations in the isotopic composition of the application compound, whether they are radioactive or not, are included in the scope of this application.
[381] [381] The term "pharmaceutically acceptable carrier" refers to any carrier formulation or medium capable of delivering an effective amount of an active substance in this application, without interfering with the biological activity of the active substance and which has no toxic side effects. in the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspensions, stickiness enhancers, transdermal enhancers, etc. Its formulations are well known to those skilled in the field of cosmetic or topical drug techniques.
[382] [382] The term "excipient" generally refers to the carrier, diluent and / or medium that is necessary to formulate an effective pharmaceutical composition.
[383] [383] The term "effective amount" or "therapeutically effective amount" in relation to drugs or pharmacologically active agents refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. oral dosage in the present application, the "effective amount" of an active substance in a composition means the amount necessary to achieve the desired effect when used in combination with another active substance in the composition. Determination of the effective amount will vary with each individual age and general condition of the individual, as well as the specific active substance, the appropriate effective amount in each case can be determined by the person skilled in the art according to a routine experiment.
[384] [384] The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that can effectively treat a target disorder, disease or condition.
[385] [385] "Optional" or "optionally" means that the subsequently described event or situation may, but is not necessary to, occur, and the description includes cases in which the event or situation occurs and cases in which the event or situation does not occur.
[386] [386] The term "substituted" means that any one or more of the hydrogen atoms in a specific atom are replaced by a substituent (which may include heavy hydrogen and hydrogen variants), provided that the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxygen (ie, = O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur in an aromatic group. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified; the type and number of the substituent can be arbitrary as long as it is chemically achievable.
[387] [387] When any variable (for example, R) appears more than once in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is replaced by 0-2 R, that group can optionally be replaced by a maximum of two R's, and R in each case has an independent option. In addition, the combination of substituents and / or variants thereof is permissible only if that combination results in stable compounds.
[388] [388] When the number of a link group is 0, such as - (CRR) 0-, it means that the link group is a single link.
[389] [389] When one of the variables is selected from the single link, it means that the two groups linked by the single link are directly connected. For example, when L in A-L-Z represents the single bond, the structure of A-L-Z is really A-Z.
[390] [390] When a substituent is empty, it means that the substituent does not exist. For example, when X is empty in A-X, the structure is actually A. When a substituent can be attached to more than one atom in a ring, the substituent can be attached to any atom in the ring. For example, the structural unit or means that the substituent R can occur in any position in cyclohexyl or cyclohexadiene. When the substituents listed are not indicated by which atom is attached to the substituted group, that substituent can be attached via any of its atoms, for example, pyridyl as a substituent can be attached to the substituted group via any of the carbon atoms in pyridine ring. When the enumerative liaison group does not indicate the direction to call, the direction to call is arbitrary. For example, the linking group L in is -MW-, so -MW- can link ring A and ring B to form in the direction equal to the reading order from left to right, and form in the opposite direction to the order of reading from left to right. Combinations of the linker groups, substituents and / or variants thereof are permissible only if those combinations result in stable compounds.
[391] [391] Unless otherwise specified, the term "hetero" refers to a heteroatom or heteroatomic group (that is, an atomic group containing a heteroatom), including the atom in addition to carbon (C) and hydrogen (H) , and the atomic group containing these heteroatoms, including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, = O, = S, - C (= O) O-, -C (= O) -, -C (= S) -, -S (= O), -S (= O) 2-, and -C (= O) N (H) -, -N (H) -, -C (= NH) -, -S (= O) 2N (H) - or -S (= O ) N (H) -, each of which is optionally substituted.
[392] [392] Unless otherwise specified, the "ring" refers to a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkylyl, heterocycloalquinyl, aryl or heteroaryl. The so-called ring includes a single ring, a bicyclic ring, a spiral ring, a cast ring or a bridged ring. The number of the atom in the ring is generally defined as the number of members of the ring. For example, "5- to 7-membered ring" means that 5-7 atoms are arranged in a ring. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatom. Therefore, a "5- to 7-membered ring" includes, for example, phenyl, pyridine and piperidinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but excludes phenyl. The term "ring" also includes a ring system that contains at least one ring, with each "ring" independently meeting the above definition.
[393] [393] Unless otherwise specified, the term "heterocycle" or "heterocyclyl" refers to a stable monocyclic, bicyclic or tricyclic ring that contains a heteroatom or group of heteroatoms, which can be saturated, partially unsaturated or unsaturated (aromatic) , and may contain carbon atoms and 1, 2, 3 or 4 ring hetero atoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatom can be optionally oxidized (ie NO and S (O) p, p is 1 or 2). The nitrogen atom can be substituted or unsubstituted (that is, N or NR, where R is H or other substituents as already defined in this document). The heterocycle can be attached to the pendant groups of any heteroatom or carbon atom to form a stable structure.
[394] [394] Unless otherwise specified, the term "hydrocarbyl" or its hyponymy (eg, alkyl, alkenyl, alkynyl, aryl, etc.), alone or as part of another substituent, refers to a hydrocarbon radical cyclic, branched chain, straight or a combination thereof, they can be completely saturated (like alkyl), mono- or polyunsaturated (for example, alkenyl, alkynyl and aryl), can be mono- or poly-substituted, and can be monovalent (for example, methyl), divalent (for example, methylene) or multivalent (for example, methylene), can include a divalent or multivalent group, have a specified number of carbon atoms (for example, C1-C12 represents 1 to 12 carbon atoms, C1-12 is selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12; C3-12 is selected from C3, C4, C5, C6, C7, C8, C9, C10, C11 and C12). "Hydrocarbyl" includes, without limitation, aliphatic hydrocarbyl and aromatic hydrocarbyl, aliphatic hydrocarbyl includes cyclic and linear hydrocarbyl, specifically includes, without limitation, alkyl, alkenyl and alkynyl, and aromatic hydrocarbyl includes, without limitation, aromatic hydrocarbyl with 6 to 12 members, such as phenyl, naphthyl and the like In some embodiments, the term "hydrocarbyl" means a branched or straight group or a combination thereof, which can be completely saturated, mono- or polyunsaturated, and can include a divalent radical Examples of the saturated hydrocarbyl radical include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and the homologue or isomer of n-pentyl, n-hexyl, n-heptyl, n-octyl and the like The unsaturated hydrocarbyl group has one or more double or triple bonds, and examples thereof include, without limitation, vin ila, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and more superior counterparts and isomers.
[395] [395] Unless otherwise specified, the term "heterohydrocarbyl" or its hyponymy (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), alone or in combination with another term, denotes a cyclic, branched or straight hydrocarbon radical stable or any combination thereof, which have a specified number of carbon atoms and at least one hetero atom.
[396] [396] Unless otherwise specified, the term "heteroalkyl" alone or in combination with another term denotes a stable straight chain, branched hydrocarbon radical or a combination thereof, which has a specified number of carbon atoms and at least least one heteroatom. In a specific modality, a heteroatom is selected from B, O, N, and S, where nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroatom or group of heteroatoms can be located at any internal position of a heterohydrocarbyl, including the position where the hydrocarbyl is attached to the remainder of the molecule. But the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) belong to the usual expression, which denotes an alkyl that is attached to the remainder of the molecule by means of an oxygen atom, an amino or a sulfur atom , respectively. Examples of "heteroalkyl" include, without limitation, -OCH 3, -OCH2CH3, -OCH2CH2CH3, -OCH (CH3) 2, -N (CH3) 2, -CH2-CH2-O-CH3, -CH2-CH2-NH -CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S (O) - CH3, -S (O) 2-CH3, -CH2-CH2 -S (O) 2-CH3, -CH = CH-O-CH3, -CH2-CH = N-OCH3 and -CH = CH-N (CH3) -CH3. Up to two heteroatoms can be continuous, such as -CH2-NH-OCH3.
[397] [397] Unless otherwise specified, the term "cyclohydrocarbyl", "heterocyclohydrocarbyl" or its hyponymy (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl,
[398] [398] Unless otherwise specified, the term "alkyl" refers to a branched or straight saturated hydrocarbon group, which may be mono- (for example, -CH2F) or poly-substituted (for example, -CF3), and it can be monovalent (for example, methyl), divalent (for example, methylene) or multivalent (for example, methylenyl). Examples of alkyl include methyl (Me), ethyl (Et), propyl (like, n-propyl and isopropyl), butyl (like n-butyl, isobutyl, s-butyl, t-butyl), pentyl (like n-pentyl , isopentyl, neopentyl) and the like.
[399] [399] Unless otherwise specified,
[400] [400] Unless otherwise specified, "alkynyl" refers to an alkyl group that has one or more carbon-carbon triple bonds at any position in the chain, which may be mono-substituted or poly-substituted, and may be monovalent , divalent or multivalent. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl and the like.
[401] [401] Unless otherwise specified, "cycloalkyl" includes any stable cyclic or polycyclic hydrocarbyl, and any carbon atom is saturated, which may be mono-substituted or poly-substituted, and may be monovalent, divalent or multivalent. Examples of such a cycloalkyl include, without limitation, cyclopropyl, norbornanil, [2.2.2] bicyclooctane, [4.4.0] bicyclodecanyl and the like. However, the term "cycloalkyloxy" refers to the cycloalkyl group that are each attached to the remainder of the molecule via an oxygen atom, examples of which include, without limitation,,,,.
[402] [402] Unless otherwise specified, "cycloalkenyl" includes any stable cyclic or polycyclic hydrocarbyl that contains one or more unsaturated carbon-carbon double bonds in any position of the ring, which may be mono-substituted or poly-substituted, and be monovalent, divalent or multivalent. Examples of such a cycloalkenyl include, without limitation, cyclopentenyl, cyclohexenyl and the like.
[403] [403] Unless otherwise specified, "cycloalkynyl" includes any stable cyclic or polycyclic hydrocarbyl that contains one or more carbon-carbon triple bonds at any position on the ring, which can be mono-substituted or poly-substituted, and can be monovalent, divalent or multivalent.
[404] [404] Unless otherwise specified, the term "halo" or "halogen", alone or as part of another substituent, refers to a fluorine, chlorine, bromine or iodine atom. In addition, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo (C1-C4) alkyl" is intended to include, without limitation, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like. Unless otherwise specified, examples of haloalkyl include, without limitation,
[405] [405] "Aloxy" represents any alkyl defined above that has a specific number of carbon atoms attached by an oxygen bridge. Unless otherwise specified, C1-6 alkoxy includes C1, C2, C3, C4, C5 and C6 alkoxy. Examples of alkoxy include, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentyloxy.
[406] [406] Unless otherwise specified, the term "aryl" refers to a polyunsaturated aromatic substituent, may be mono- or poly-substituted, may be monovalent, divalent or polyvalent, may be a single ring or multiple rings (for example , 1 to 3 rings; where one ring is aromatic), which are fused together or connected covalently.
[407] [407] Unless otherwise specified, the term "heteroaryl" refers to an aryl (or ring) that contains one to four heteroatoms. In an illustrative example, the heteroatom is selected from B, N, O and S, where nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl can be attached to the remaining part of a molecule by means of a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isoxazolyl, thiazolyl,
[408] [408] Unless otherwise specified, when combined with other terms (such as aryloxy, arylthio, aralkyl), the aryl includes the aryl and heteroaryl rings as defined above. Therefore, the term "aralkyl" is intended to include groups (for example, benzyl, phenethyl, pyridylmethyl, etc.) in which an aryl is attached to an alkyl, including an alkyl in which the carbon atom (for example, methylene ) has been replaced by an atom such as oxygen, for example, phenoxymethyl, 2-pyridyloxymethyl 3- (1-naphthyloxy) propyl and the like.
[409] [409] The term "leaving group" refers to an atom or functional group that can be replaced by another atom or functional group through a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine and iodine; sulfonate, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy, such as acetoxy, trifluoroacetoxy and the like.
[410] [410] The term "protection group" includes, without limitation, "amino protection group", "hydroxy protection group" or "thiol protection group". The term "amino protecting group" refers to a suitable protecting group to prevent side reactions at the nitrogen position at the amino. Representative amino protecting groups include, without limitation, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, like, tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, like benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, like benzyl (Bn), trityl (Tr) (4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protection group" refers to a protection group suitable for use in preventing hydroxyl side reactions. Hydroxy protecting groups include, without limitation, alkyl, such as methyl, ethyl and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM);
[411] [411] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the following exemplified modalities, the modalities formed by combining them with other methods of chemical synthesis, and equivalent alternatives known to those skilled in the art. Preferred embodiments include, without limitation, the examples of the present invention.
[412] [412] The solvents used in the present application are commercially available. The present application uses the following abbreviations: aq stands for aqua; eq represents equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; BOC represents t-butyl carbonyl, which is an amine protecting group; HOAc represents acetic acid; Na (OAc) 3BH represents sodium borohydride acetate; THF represents tetrahydrofuran; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; Cu (acac) 2 represents copper acetylacetonate; DIEA stands for diisopropylethylamine; Xantphos represents 9,9-dimethyl-4,5-bisdiphenylphosphene xanthene; Pd (OAc) 2 represents palladium acetate; Pd (dppf) Cl2 represents [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride; K3PO4 represents potassium phosphate; K2CO3 represents potassium carbonate; NaHCO3 represents sodium hydrogencarbonate; Na2CO3 represents sodium carbonate; HCl represents hydrogen chloride; Pd / C represents palladium carbon; ICl represents iodine chloride; NaH represents sodium hydride; DMAP represents 4-dimethyl aminopyridine; DIPEA / DIEA represents N, N'-diisopropylethylamine; DPPF represents 1,1'-bis (diphenylphosphino) ferrocene; DCE represents 1,2-dichloroethane; DME represents dimethoxyethane.
[413] [413] Compounds are named manually or by ChemDraw® software, and commercially available compounds use their vendor directory names. DETAILED DESCRIPTION
[414] [414] The request is described in detail below with the following examples, but it does not mean any limitation adverse to the request. This application has been specified in this document, in which the particulars of this application are disclosed. Various variations and modifications will be made to the modalities of this application without departing from the spirit and scope of this application, which would be evident to the individual skilled in the art. Example 1 Compound 1A:
[415] [415] Under the protection of nitrogen gas, 5-bromobenzothiophene (10 g, 46.93 mmol), K3PO4 (9.96 g, 46.93 mmol) and Cu (acac) 2 (644 mg, 1.16 mmol, 0.05 eq.) Were dissolved in the DMF solution in liquid ammonia (2M, 50 ml). The reaction solution was reacted in a high pressure reactor at 100 ° C for 12 hours. The reaction solution was filtered and the filtrate was concentrated to generate a crude product. The crude product was purified by column chromatography to obtain compound 1A. 1H NMR (400MHz, CDCl3) δ = 7.65 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 5.3 Hz, 1H), 7.16 (d, J = 5 , 3 Hz, 1H), 7.11 (s, 1H), 6.79 (dd, J = 1.8, 8.5 Hz, 1H), 3.67 (ls, 2H). Compound 1B:
[416] [416] Compound 1A (3.8 g, 25.47 mmol) and NaHCO3 (4.28 g, 50.93 mmol) were dissolved in 50 ml of DCM and then added in drops with iodine chloride (4 , 96 g, 30.56 mmol, 1.56 ml), and the reaction solution was reacted at 20 ° C for 1 hour. After the reaction was completed, the reaction solution was added with 100 ml of DCM and washed with water and saturated brine respectively. The organic phases were combined, dried and concentrated to generate compound 1B. Compound 1C:
[417] [417] Compound 1B (0.6 g, 2.18 mmol), dimethylphosphine oxide (364.76 mg, 3.27 mmol), Xantphos (126.19 mg, 218.10 μmol), Pd (OAc) 2 (48.96 mg, 218.10 μmol) and K3PO4 (694.41 mg, 3.27 mmol) were dissolved in 10 ml of DMF and 2 ml of H2O, and the reaction was carried out at 120 ° C under the protection nitrogen gas for 24 hours. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography to obtain compound 1C. Compound 1D:
[418] [418] Compound 1C (0.3 g, 1.33 mmol) was dissolved in 5 ml of EtOH, and 2,4,5-trichloropyrimidine (488.59 mg, 2.66 mmol, 303.47 μl) and DIEA (688.54 mg, 5.33 mmol, 927.95 μl) was added to it. The reaction solution was refluxed under the protection of nitrogen gas for 24 hours. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography to obtain compound 1D. Compound 1E:
[419] [419] The compounds of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane were dissolved in 30 ml of DMF, and then K2CO3 (5.04 g, 36.48 mmol) was added. The reaction was carried out at 60 ° C under nitrogen protection for 8 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound 1E. 1H NMR (400MHz, CDCl3) δ = 8.05 (s, 1H), 6.57 (s, 1H), 3.96 (s, 3H), 3.19-3.11 (m, 4H), 2 , 42 (m, 4H), 2.31 (s, 3H), 1.71-1.67 (m, 4H), 1.65-1.61 (m, 4H). Compound 1F:
[420] [420] Compound 1E (3.1 g, 8.76 mmol) was dissolved in 30 ml of EtOH, and iron powder (2.94 g, 52.57 mmol) and an aqueous solution of ammonium chloride (4 , 69 g of ammonium chloride dissolved in 10 ml of water) were added. Under the protection of nitrogen gas, the reaction was carried out at 90 ° C for 2 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to obtain compound 1F. 1H NMR (400MHz, DMSO-d6) δ = 6.71 (s, 1H), 6.66 (s, 1H), 4.73 (s, 2H), 3.77 (s, 3H), 3.25 (m, 2H), 3.06 (m, 2H), 2.81 (m, 4H), 2.74 (s, 3H), 1.89 (m, 2H), 1.74 (m, 2H) , 1.60 (m, 2H), 1.49 (m, 2H). Compound 1:
[421] [421] Compound 1D (100 mg, 268.67 μmol) and compound 1F (87.01 mg, 268.67 μmol) were dissolved in 4 ml of tert-butanol, and added with methylsulfonic acid (103.28 mg, 1.07 mmol, 76.50 μl). The reaction was carried out at 90 ° C for 12 hours. After the reaction was completed, the reaction solution was concentrated, adjusted to a pH of about 9 with saturated NaHCO3, and extracted three times with DCM. The organic phases were collected, dried and concentrated to generate a crude product. The crude product was purified by preparative HPLC to obtain compound 1 (40.16 mg, 63.98 μmol). 1H NMR (400MHz, MeOD) δ = 8.54 (sl, 1H), 8.17 (d, J = 9.0 Hz, 1H), 8.09 (s, 1H), 8.02 (d, J = 5.6 Hz, 1H), 7.91 -7.80 (m, 3H), 6.74 (s, 1H), 3.88 (s, 3H), 3.30-3.16 (m, 4H), 2.96-2.88 (m, 4H), 2.84 (s, 3H), 1.99 (s, 3H)), 1.95 (s, 3H), 1.83 (s, 3H), 1.73 (bs, 4H). Example 2 Compound 2A:
[422] [422] Except for the separate substitution of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 1-fluoro-5- methoxy-2-methyl-4-nitrobenzene and 2-methyl-2,7-diazaspiro [3,5] nonane, compound 2A was prepared according to the method for preparing compound 1E. Compound 2B:
[423] [423] Except for the replacement of compound 1E by compound 2A, compound 2B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CDCl3) δ = 6.57 (s, 1H), 6.53 (s, 1H), 4.64 (s, 1H), 3.86 -3.82 (m, 1H), 3 , 91-3.79 (m, 1H), 3.37 (s, 4H), 2.78-2.69 (m, 4H), 2.58-2.49 (m, 3H), 2.19 (d, J = 15.8 Hz, 3H), 1.97-1.89 (m, 4H). Compound 2:
[424] [424] Except for the replacement of compound 1F with compound 2B, compound 2 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ = 8.54 (sl, 1H), 8, 17 (d, J = 9.0 Hz, 1H), 8.09 (s, 1H), 8.02 (d, J = 5.6 Hz, 1H), 7.91-7.80 (m, 3H ), 6.74 (s, 1H), 3.88 (s, 3H), 3.30-3.16 (m, 4H), 2.96-2.88 (m, 4H), 2.84 ( s, 3H), 1.99 (s, 3H), 1.95 (s, 3H), 1.83 (ls, 3H), 1.73 (ls, 4H). Example 3 Compound 3A:
[425] [425] The tert-butyl 4-oxopiperidine-1-carboxylate compounds (20 g, 100.38 mmol) and 1-methylpiperazine (12.06 g, 120.45 mmol, 13.36 ml) were dissolved in 200 ml of ethanol, and added with AcOH (6.03 g, 100.38 mmol, 5.74 ml) and NaBH (OAc) 3 (42.55 g, 200.76 mmol). The reaction was carried out at 20 ° C for 12 hours. After the reaction was completed, the reaction was quenched by adding methanol (10 ml) and water (10 ml) and then extracted with ethyl acetate (500 ml). The organic phase was collected, dried and concentrated to generate compound 3A. Compound 3B:
[426] [426] Compound 3A (16 g, 56.46 mmol) was dissolved in HCl / MeOH (50 ml, 4M) and reacted at 0 ° C for 12 hours. After the reaction was completed, the reaction solution was concentrated to generate compound 3B. Compound 3C:
[427] [427] Except for the separate substitution of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 4-fluoro-2- methoxy-1-nitrobenzene and 1-methyl-4- (4-piperidinyl) piperazine, compound 3C was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CDCl3) δ = 8.02-7.88 (m, 1H), 6.40 (dd, J = 2.5, 9.5 Hz, 1H), 6.29 (d, J = 2.5 Hz, 1H), 3.99-3.84 (m, 5H), 3.26-2.86 (m, 4H), 2.65-2.41 (m, 8H), 2.29 (s, 3H), 2.00-1.92 (m, 2H), 1.59 (dq, J = 4.0, 12.0 Hz, 2H). 3D compound:
[428] [428] Except for the replacement of compound 1E by compound 3C, compound 3D was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CDCl3) δ = 6.56 (d, J = 8.3 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.34 (dd, J = 2 , 4, 8.6 Hz, 1H), 3.76 (s, 3H), 3.45 (dl, J = 12.2 Hz, 3H), 2.75-2.47 (m, 7H), 2 , 46-2.36 (m, 3H), 2.31-2.20 (m, 5H), 1.85 (dl, J = 12.5 Hz, 2H), 1.64 (dq, J = 3 , 8, 12.0 Hz, 2H). Compound 3:
[429] [429] Except for the substitution of compound 1F for compound 3D, compound 3 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.14 (d, J = 8.8 Hz , 1H), 8.04-7.87 (m, 4H), 7.36 (dl, J = 8.6 Hz, 1H), 6.59 (d, J = 2.2 Hz, 1H), 5 , 98 (dl, J = 8.1 Hz, 1H), 3.83 (s, 3H), 3.64-3.57 (m, 3H), 2.96-2.56 (m, 10H), 2.47 (s, 4H), 2.02 (dl, J = 12.5 Hz, 2H), 1.95 (s, 3H), 1.91 (s, 3H), 1.71-1.60 (m, 2H). Example 4 Compound 4A:
[430] [430] Under the protection of nitrogen gas, naphthalene-2-amine (4 g, 27.94 mmol) was dissolved in a mixed solution of 120 ml of DCM and 40 ml of MeOH, and added with benzyltrimethylammonium dichloriodide (9, 72 g, 27.94 mmol). The reaction solution was reacted at 20 ° C for 0.5 hour. After the reaction was completed, the reaction solution was washed with sodium bicarbonate solution, and the organic phase was collected and concentrated to obtain a crude product. The crude product was purified by column chromatography to generate compound 4A. 1H NMR (400MHz, CDCl3) δ = 8.00 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.3, 17.6 Hz, 2H), 7.54 (ddd , J = 1.2, 7.2, 8.4 Hz, 1H), 7.37-7.29 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4, 47 (bs, 2H). Compound 4B:
[431] [431] Except for the replacement of compound 1B by compound 4A, compound 4B was prepared according to the method for preparing compound 1C. 1H NMR (400MHz, CDCl3) δ = 7.66 (d, J = 8.8 Hz, 2H), 7.51-7.45 (m, 1H), 7.45-7.37 (m, 1H) , 7.25-7.17 (m, 1H), 6.76 (dd, J = 3.6, 8.8 Hz, 1H), 6.51 (ls, 2H), 2.05 (s, 3H ), 2.01 (s, 2H); LC-MS (ESI): m / z: 220.1 [M + 1]. Compound 4C:
[432] [432] Except for the replacement of compound 1C with compound 4B, compound 4C was prepared according to the method for preparing compound 1D. 1H NMR (400MHz, CDCl3) δ = 13.05 (s, 1H), 8.62 (dd, J = 4.0, 9.2 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J = 9.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.56 (dd , J = 7.2, 7.2 Hz, 1H), 7.48 (dd, J = 7.2, 7.2 Hz, 1H), 2.18 (s, 3H), 2.14 (s, 3H). Compound 4:
[433] [433] Except for the replacement of compound 1D with compound 4C, compound 4 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, MeOD) δ = 8.45 (s, 1H), 8.24 -8.17 (m, 2H), 8.11 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.63 (ddd, J = 1.2, 7.2, 7.2 Hz, 1H), 7.53 (dd, J = 7.2, 7.2 Hz , 1H), 6.75 (s, 1H), 3.89 (s, 3H), 3.32-3.12 (m, 4H), 2.98-2.90 (m,
[434] [434] Except for respectively replacing compounds 1D and 1F with compounds 4C and 2B, compound 5 was prepared according to the method to prepare compound 1. 1H NMR (400MHz, CD3OD) δ = 8.56 (sl, 1H ), 8.30-8.21 (m, 2H), 8.06 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 8, 0 Hz, 1H), 7.67-7.61 (m, 1H), 7.61-7.53 (m, 2H), 6.62 (d, J = 2.0 Hz, 1H), 6, 11 (d, J = 8.8 Hz, 1H), 3.87 (s, 4H), 3.84 (s, 3H), 3.09-2.97 (m, 4H), 2.88 (s , 3H), 2.10 (s, 3H), 2.07 (s, 3H), 2.04-1.94 (m, 4H); LCMS (ESI): m / z: 591.1 [M + 1]. Example 6 Compound 6:
[435] [435] Except for respectively replacing compounds 1D and 1F with compounds 4C and 3D, compound 6 was prepared according to the method to prepare compound 1. 1H NMR (400MHz, CD3OD) δ = 8.54 (sl, 1H ), 8.30-8.22 (m, 2H), 8.06 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 8, 0 Hz, 1H), 7.67-7.62 (m, 1H), 7.60-7.49 (m, 2H), 6.63 (d, J = 2.4 Hz, 1H), 6, 13 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.63 (d, J = 12.4 Hz, 2H), 2.79 (ls, 6H), 2, 71-2.61 (m, 3H), 2.61-2.38 (m, 5H), 2.11 (s, 3H), 2.07 (s, 3H), 2.02 (dl, J = 12.8 Hz, 2H), 1.72-1.61 (m, 2H); LCMS (ESI): m / z: 634.1 [M + 1]. Example 7 Compound 7A:
[436] [436] 7-Nitroquinoline (7 g, 40.19 mmol) was dissolved in 120 ml of methanol, and added with Pd / C (10%, 1 g) under a nitrogen atmosphere. After being purged with hydrogen 3 times, the reaction solution was stirred at 20 ° C under a hydrogen atmosphere for 12 hours. After the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated to generate compound 7A. 1H NMR (400MHz, CDCl3) δ = 8.75 (dd, J = 1.8, 4.3 Hz, 1H), 7.98 (dd, J = 0.8, 8.0 Hz, 1H), 7 , 61 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 4.4, 8.2 Hz, 1H) , 6.98 (dd, J = 2.3, 8.5 Hz, 1H), 3.98 (ls, 2H). Compound 7B:
[437] [437] Compound 7A (2.5 g, 17.34 mmol) was dissolved in 75 ml of AcOH, and ICl (3.10 g, 19.07 mmol, 973.85 μl) was dissolved in 25 ml of acid acetic acid, which was added in drops to the reaction solution. The reaction was stirred at 20 ° C for 1 hour. After the reaction was completed, the reaction solution was subjected to rotary evaporation to remove acetic acid, and the residue was extracted with ethyl acetate and diluted, and then washed consecutively with water and saturated brine. The organic phase was collected, dried and concentrated to generate a crude product. The crude product was purified by column chromatography to generate compound 7B. 1H NMR (400MHz, CDCl3) δ = 8.88 (dd, J = 1.5, 4.3 Hz, 1H), 7.95 (dd, J = 1.5, 8.0 Hz, 1H), 7 , 58 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 4.3, 8.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H) , 5.10-4.63 (m, 2H).
[438] [438] Except for the replacement of compound 1B with compound 7B, compound 7C was prepared according to the method for preparing compound 1C. 1H NMR (400MHz, CDCl3) δ = 8.63 (dd, J = 1.8, 4.3 Hz, 1H), 7.88 (td, J = 1.5, 7.9 Hz, 1H), 7 , 61 (d, J = 9.0 Hz, 1H), 7.10 (dd, J = 4.4, 8.1 Hz, 1H), 6.80 (dd, J = 3.9, 8.8 Hz, 1H), 6.73-6.23 (m, 1H), 2.07 (s, 3H), 2.03 (s, 3H). Compound 7D:
[439] [439] Except for the replacement of compound 1C with compound 7C, compound 7D was prepared according to the method for preparing compound 1D. 1H NMR (400MHz, CDCl3) δ = 13.31 (s, 1H), 8.93 (dd, J = 3.9, 9.2 Hz, 1H), 8.82 (dd, J = 1.8, 4.3 Hz, 1H), 8.27 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 9.3 Hz, 1H), 7 , 38 (dd, J = 4.3, 8.3 Hz, 1H), 2.19 (s, 3H), 2.15 (s, 3H). Compound 7:
[440] [440] Except for the replacement of compound 3D with compound 7D, compound 7 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.92-8.79 (m, 2H) , 8.50 (ls, 1H), 8.23 (dl, J = 8.3 Hz, 1H), 8.07 (s, 1H), 7.90 (d, J = 9.3 Hz, 1H) , 7.69 (d, J = 8.6 Hz, 1H), 7.43 (dd, J = 4.3, 8.2 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 2.4, 8.8 Hz, 1H), 3.85 (s, 3H), 3.74 (dl, J = 12.2 Hz, 2H), 2, 99 -2.65 (m, 10H), 2.62-2.56 (m, 1H), 2.55 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H) , 2.04 (dl, J = 12.5 Hz, 2H), 1.76-1.65 (m, 2H). Example 8 Compound 8A:
[441] [441] 4-Nitrobenzene-1,2-diamine (10 g, 65.30 mmol) was dissolved in 100 ml of ethanol and added with glyoxal (4.55 g, 78.36 mmol, 4.10 ml), with stirring at 80 ° C for 15 hours. After the reaction was completed, the mixture was filtered and the filter cake was dried to generate compound 10A. 1H NMR (400MHz, DMSO-d6) δ = 9.18 (s, 2H), 8.93 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 2.4, 9, 2 Hz, 1H), 8.36 (d, J = 9.2 Hz, 1H); LC-MS (ESI) (5-95AB): m / z: 176.1 [M + 1]. Compound 8B:
[442] [442] Except for the replacement of compound 1E with compound 8A, compound 8B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 1.6 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.24 (dd, J = 2.4, 9.2 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.08 (s , 2H). LC-MS (ESI) (5-95AB): m / z: 146.2 [M + 1]. Compound 8C:
[443] [443] Except for the replacement of compound 7A with compound 8B, compound 8C was prepared according to the method for preparing compound 7B. 1H NMR (400MHz, DMSO-d6) δ = 8.76 (d, J = 1.6 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 9.2 Hz, 1H), 6.38 (ls, 2H). LC-MS (ESI) (5-95AB): m / z: 271.9 [M + 1]. Compound 8D:
[444] [444] Except for the replacement of compound 1B with compound 8C, compound 8D was prepared according to the method for preparing compound 1C. 1H NMR (400MHz, DMSO-d6) δ = 8.61 (d, J = 1.6 Hz, 1H), 8.49 (d, J = 1.6 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 6.38 (ls, 2H), 1.89 (s, 3H), 1.85 (s, 3H ). LC-MS (ESI) (5-95AB): m / z: 222.1 [M + 1]. Compound 8E:
[445] [445] Except for the replacement of compound 1C with compound 8D, compound 8E was prepared according to the method for preparing compound 1D. 1H NMR (400MHz, CDCl3) δ = 13.20 (s, 1H), 9.12 (dd, J = 4.0, 9.6 Hz, 1H), 8.75 (s, 1H), 8.68 (s, 1H), 8.23 (s, 1H), 8.21 (d, J = 9.6 Hz, 1H), 2.08 (s, 3H), 2.05 (s, 3H); LC-MS (ESI): m / z: 367.9 [M + 1]. Compound 8:
[446] [446] Except for respectively replacing compounds 1D and 1F with compounds 8E and 2B, compound 8 was prepared according to the method to prepare compound 1. 1H NMR (400MHz, DMSO-d6) δ = 12.90 (s , 1H), 9.09-8.96 (m, 1H), 8.87 (dd, J = 2.0, 7.6 Hz, 2H), 8.31-8.24 (m, 2H), 8.20 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.37 (s, 1H), 6.74 (s, 1H), 3.78 (s, 3H ), 3.10 (s, 4H), 2.77 (t, J = 5.2 Hz, 4H), 2.33 (s, 3H), 2.12 (s, 3H), 2.05 (s , 3H), 2.02 (s, 3H), 1.84 (t, J = 5.2 Hz, 4H); LC-MS (ESI): m / z: 607.1 [M + 1]. Example 9 Compound 9:
[447] [447] Except for respectively replacing compounds 1D and 1F with compounds 4C and 2B, compound 9 was prepared according to the method to prepare compound 1. 1H NMR (400MHz, CD3OD) δ = 8.57 (s, 1H ), 8.27 (d, J = 8.8 Hz, 1H), 8.24-8.19 (m, 1H), 8.08 (s, 1H), 8.00 (d, J = 9, 1 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.68-7.53 (m, 3H), 6.65 (s, 1H), 3.84 (s, 3H), 3.58-3.50 (m, 4H), 2.79-2.71 (m, 4H), 2.66 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 1.98-1.90 (m, 4H), 1.79 (s, 3H). Example 10 Compound 10:
[448] [448] Except for the replacement of compound 1D with compound 7D, compound 10 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.83 (dd, J = 1.7, 4.4 Hz, 1H), 8.71 (dd, J = 3.7, 9.0 Hz, 1H), 8.49 (ls, 1H), 8.20 (dl, J = 8.1 Hz, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 8.00 (d, J = 9.3 Hz, 1H), 7.43 (dd, J = 4.3, 8 , 2 Hz, 1H), 6.78 (s, 1H), 3.89 (s, 3H), 3.24 (ls, 4H), 3.04-2.92 (m, 4H), 2.86 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H), 1.93-1.59 (m,
[449] [449] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5,5] undecane compounds for 1-chloro-2- fluoro-4-methoxy-5-nitrobenzene and 1-methyl-4- (piperidin-4-yl) piperazine, compound 11A was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CD3OD) δ = 6.79 (s, 1H), 6.68 (s, 1H), 3.84 (s, 3H), 3.24-2.76 (m, 8H), 2 , 72 (bs, 1H), 2.71-2.65 (m, 2H), 2.02 (dl, J = 10.8 Hz, 2H), 1.89-1.71 (m, 2H). Compound 11B:
[450] [450] Except for the replacement of compound 1E by compound 11A, compound 11B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CDCl3) δ = 8.04 (s, 1H), 6.56 (s, 1H), 4.02-3.91 (m, 3H), 3.65 (dl, J = 12, 1 Hz, 2H), 2.81-2.73 (m, 2H), 2.66 (ls, 4H), 2.56-2.37 (m, 5H), 2.31 (s, 3H), 1.98 (dl, J = 12.2 Hz, 2H), 1.84-1.71 (m, 2H). Compound 11:
[451] [451] Except for replacing compounds 1D and 1F separately with compounds 4C and 11B, compound 11 was prepared according to the method to prepare compound 1. 1H NMR (400MHz, CD3OD) δ = 8.23 (dl, J = 8.7 Hz, 2H), 8.16 - 8.10 (m, 1H), 8.02 (dl, J = 8.1 Hz, 1H), 7.76-7.55 (m, 3H) , 6.85 (s, 1H), 4.01 (s, 2H), 3.92 (s, 5H), 3.73 (s, 3H), 3.69-3.56 (m, 2H), 3.50 (dl, J = 10.1 Hz, 2H), 3.08 (s, 3H), 2.86 (tl, J = 11.5 Hz, 2H), 2.36 (dl, J = 11 , 5 Hz, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 2.11-2.02 (m, 2H). Example 12
[452] [452] Except for respectively replacing compounds 1D and 1F with compounds 2B and 7D, compound 12 was prepared according to the method to prepare compound 1. 1H NMR (400MHz, CD3OD) δ = 8.84 (dl, J = 2.7 Hz, 1H), 8.79 (d ld, J = 3.7, 9.0 Hz, 1H), 8.50 (ls, 1H), 8.22 (dl, J = 8.1 Hz, 1H), 8.08 (s, 1H), 7.90 (dl, J = 9.0 Hz, 1H), 7.74 (s, 1H), 7.44 (dd, J = 4.3 , 8.2 Hz, 1H), 6.71 (s, 1H), 4.01 (s, 4H), 3.84 (s, 3H), 2.95 (s, 3H), 2.82 (s , 4H), 2.16 (s, 3H), 2.13 (s, 3H), 2.08 (s, 3H), 2.03 (s, 4H). Example 13 Compound 13A:
[453] [453] 6-Nitro-1H-indazole (25 g, 153.25 mmol) was dissolved in 200 ml of DMF, NaH (6.74 g, 168.57 mmol, 60% purity) was added in portions at 0 ° C, and then MeI (23.93 g, 168.57 mmol, 10.49 ml) was added in portions at 0 ° C. The reaction was carried out at 25 ° C for 1 hour. After the reaction was completed, the reaction solution was poured into 500 ml of water and extracted with EtOAc. The organic phase was collected and washed consecutively with 20 ml of water and 20 ml of saturated brine. The organic phase was collected, dried and concentrated to generate a crude product. The crude product was purified by column chromatography to generate compound 13A. 1H NMR (400MHz, DMSO-d6) δ = 8.71 (d, J = 0.7 Hz, 1H), 8.29 (d, J = 0.7 Hz, 1H), 8.03-7.97 (m, 1H), 7.96-7.92 (m, 1H), 4.19 (s, 3H). Compound 13B:
[454] [454] Except for the replacement of compound 1E by compound 13A, compound 13B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, DMSO-d6) δ = 7.68 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 6.50 (dd, J = 2.0, 8, 6 Hz, 1H), 6.45 (s, 1H), 5.32 (s, 2H), 3.81 (s, 3H). Compound 13C:
[455] [455] Except for the replacement of compound 7A with compound 13B, compound 13C was prepared according to the method for preparing compound 7B. 1H NMR (400MHz, CDCl3) δ = 7.76 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 4.38 (s, 3H).
[456] [456] Except for the replacement of compound 1B with compound 13C, compound 10D was prepared according to the method for preparing compound 1C. 1H NMR (400MHz, DMSO-d6) δ = 7.81 (d, J = 1.7 Hz, 1H), 7.50 (dd, J = 1.1, 8.7 Hz, 1H), 6.55 (dd, J = 3.2, 8.8 Hz, 1H), 6.50 (s, 2H), 4.05 (s, 3H), 1.93 (s, 3H), 1.89 (s, 3H). Compound 13E:
[457] [457] Except for the replacement of compound 1C with compound 13D, compound 13E was prepared according to the method for preparing compound 1D. 1H NMR (400MHz, DMSO-d6) δ = 10.38 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 8.00 (dl, J = 8.6 Hz , 1H), 7.24 (dd, J = 2.8, 8.4 Hz, 1H), 4.41 (s, 3H), 1.88 (s, 3H), 1.84 (s, 3H) . Compound 13:
[458] [458] Except for replacing compound 1D with compound 13E and replacing compound 1F with compound 2B, compound 13 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, DMSO-d6) δ = 9, 56 (sl, 1H), 8.33 (s, 1H), 8.19 (d, J = 1.5 Hz, 1H), 8.11 (s, 1H), 7.96 (dd, J = 1 , 1, 8.4 Hz, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 7.18 (dd, J = 2.9, 8.6 Hz, 1H), 6 , 53 (s, 1H), 4.37 (s, 3H), 3.72 (s, 3H), 3.21 (s, 4H), 2.57 (s, 4H), 2.39 (s, 3H), 1.79 (s, 3H), 1.76 (s, 7H). Example 14 Compound 14A:
[459] [459] 2,3-Dihydro-1H-indene-1-one (10 g, 75.67 mmol, 9.09 ml) was dissolved in 100 ml of concentrated sulfuric acid, and KNO3 (8.03 g, 79, 45 mmol) was added thereto at 0 ° C. The reaction was carried out at 0 to 5 ° C for 1.5 hours. After the reaction was completed, the reaction solution was poured into 300 ml of water. After filtration, the filter cake was dissolved in EtOAc, dried and then concentrated to generate a crude product. The crude product was purified by column chromatography to generate compound 14A. 1H NMR (400MHz, DMSO-d6) δ = 8.60 (d, J = 2.0 Hz, 1H), 8.48 (dd, J = 2.3, 8.5 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 3.34-3.27 (m, 2H), 2.90-2.83 (m, 2H). Compound 14B:
[460] [460] Except for the replacement of compound 1E with compound 14A, compound 14B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, DMSO-d6) δ = 7.29-7.25 (m, 1H), 7.02 (s, 1H), 6.98 (dl, J = 8.3 Hz, 1H), 3 , 81 (bs, 2H), 3.09-3.00 (m, 2H), 2.74-2.66 (m, 2H); LCMS (ESI) m / z: 147.9 [M + 1]. Compound 14C:
[461] [461] Except for the replacement of compound 7A with compound 14B, compound 14C was prepared according to the method for preparing compound 7B. 1H NMR (400MHz, CDCl3) δ = 7.26 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 5.49 (s, 2H), 2.86-2.81 (m, 2H), 2.65 -2.60 (m, 2H); LCMS (ESI) m / z: 273.9 [M + 1].
[462] [462] Except for the replacement of compound 1B with compound 14C, compound 14D was prepared according to the method for preparing compound 1C. LCMS (ESI) m / z: 223.9 [M + 1]. Compound 14E:
[463] [463] Except for the replacement of compound 1C with compound 14D, compound 14E was prepared according to the method for preparing compound 1D. 1H NMR (400MHz, DMSO-d6) δ = 13.09 (s, 1H), 8.84 (dd, J = 3.5, 8.8 Hz, 1H), 8.24 (s, 1H), 7 , 71 (d, J = 8.3 Hz, 1H), 3.21-3.16 (m, 2H), 2.80-2.75 (m, 2H), 2.08 (s, 3H), 2.04 (s, 3H); LC-MS (ESI) m / z: 369.9 [M + 1]. Compound 14:
[464] [464] Except for the replacement of compound 1D with compound 14E, compound 14 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, DMSO-d6) δ = 12.60 (s, 1H), 8 , 61 (dl, J = 6.6 Hz, 1H), 8.30 (ls, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.75 (s, 1H) , 7.63 (dl, J = 8.6 Hz, 1H), 6.87 (s, 1H), 3.84 (s, 3H), 3.08-3.01 (m, 2H), 2, 93 (m, 4H), 2.74-2.67 (m, 2H), 2.60 (m, 4H), 2.36 (s, 3H), 1.93 (s, 3H), 1.90 (s, 3H), 1.60 (m, 8H); LCMS (ESI) m / z: 657.0 [M + 1]. Example 15 Compound 15A:
[465] [465] DMAP (376 mg, 3.08 mmol) was added to a solution of 5-nitro-1H-indole (10 g, 61.6 mmol) and Boc2O (14.1 g, 64.7 mmol, 14, 9 ml) in tetrahydrofuran (100 ml) at room temperature, and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated and pasted with petroleum ether to generate compound 15A. 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (d, J = 1.88 Hz, 1 H), 8.17-8.35 (m, 2 H), 7.76 (d, J = 3 , 76 Hz, 1 H), 7.28 (s, 1 H), 6.74 (d, J = 3.64 Hz, 1 H), 1.72 (s, 9 H), 1.59 (s , 7 H). Compound 15B:
[466] [466] Except for the replacement of compound 15A by the compound of 7-nitroquinoline, compound 15B was prepared according to the method of preparation of compound 7A. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 13 H), 3.41 (s, 1 H), 3.52 (s, 2 H), 6.32 (d, J = 3, 67 Hz, 1 H), 6.64 (dd, J = 8.68, 2.20 Hz, 1 H), 6.77 (d, J = 2.20 Hz, 1 H), 7.19 (s , 1 H), 7.36-7.51 (m, 1 H), 7.74-7.93 (m, 1 H). Compound 15C:
[467] [467] Except for the replacement of compound 15B by compound 1A, compound 15C was prepared according to the method of preparing compound 1B. 1H NMR (400 MHz, CDCl3) δ 1.58 (s, 9 H), 6.34 (d, J = 3.67 Hz, 1 H), 6.69 (d, J = 8.68 Hz, 1 H), 7.19 (s, 1 H), 7.43-7.56 (m, 1 H), 7.83 (dl, J = 8.44 Hz, 1 H). Compound 15D:
[468] [468] Except for the replacement of compound 1B with compound 15C, compound 15D was prepared according to the method of preparing compound 1C. 1H NMR (400 MHz, m) δ ppm 1.57 (s, 9 H), 2.88 (s, 3 H), 3.01 (s, 3 H), 6.47-6.56 (m, 1H), 6.59 (d, J = 3.91 Hz, 1 H), 6.75 (dd, J = 9.05, 4.16 Hz, 4 H). Compound 15E:
[469] [469] Except for the replacement of compound 1C with compound 15D, compound 15E was prepared according to the method of preparing compound 1D. Compound 15F:
[470] [470] Compound 15E (1.5 g, 3.29 mmol) was dissolved in 20 ml of DCM, and TFA (3.76 g, 32.9 mmol, 2.44 ml) was added thereto. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the organic phase was concentrated and purified by preparative HPLC to generate compound 15F. 1H NMR (400 MHz, CDCl3) δ ppm 11.88 (s, 1H), 8.45 (d, J = 8.8Hz, 1H), 7.65 (d, J = 8.8Hz, 1H), 7 , 28 (s, 1H), 6.41 (s, 1H), 2.07 (s, 3H), 2.03 (s, 3H). 15G Compound:
[471] [471] Sodium-hydrogen (59.9 mg, 1.49 mmol, 60% purity) and methyl iodide (211 mg, 1.49 mmol, 92.9 μl) were added to a 15F compound solution (0 , 53 g, 1.49 mmol) in DMF (10 ml), and the solution was cooled to 0 ° C and reacted for 1 hour. After the reaction was completed, it was quenched by adding water, extracted with ethyl acetate, and the organic phase was washed with saturation solution, subjected to drying over anhydrous sodium sulfate, concentrated and purified by layer chromatography. fine preparation to generate 15G compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.52-8.49 (m, 1H), 8.21 (s, 1H), 7.61-7.59 (m, 1H), 7.20 (s , 1H), 6.31 (s, 1H), 3.87 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H). Compound 15:
[472] [472] Except for replacing compound 1D with compound 15G and replacing compound 1F with compound 2B, compound 15 was prepared according to the method of preparing compound 1. 1H NMR (400 MHz, CDCl3) δ ppm 11.31 (s, 1 H), 8.59 (s, 1 H), 8.41 (dd, J = 9.16, 3.76 Hz, 1 H), 7.51 (d, J = 9.29 Hz , 1 H), 7.37 (s, 1 H), 7.28 (s, 1 H), 6.34 (d, J = 3.01 Hz, 1 H), 3.86 (m, 8 H ), 3.72 (s, 3H), 2.76 (m, 7H), 2.11 (s, 3H), 2.03-1.98 (m, 9H). Example 16 Compound 16A:
[473] [473] Except for the substitution of compound 1A with 2,3-dihydro-1H-inden-5-amine compound, compound 16A was prepared according to the method for preparing compound 1B. 1H NMR (400MHz, CDCl3) δ = 7.26 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 2.96-2.96 (m , 4H), 2.76-2.73 (m, 2H). Compound 16B:
[474] [474] Except for the replacement of compound 1B with compound 16A, compound 16B was prepared according to the method for preparing compound 1C. Except for the replacement of compound 1B by compound 16A, compound 16B was prepared according to the method for preparing compound 1C. 1H NMR (400MHz, CDCl3) δ = 7.11 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 2.84-2.76 (m , 4H), 2.08-2.06 (m, 2H), 1.84 (s, 3H), 1.81 (s, 3H). Compound 16C:
[475] [475] Except for the replacement of compound 1C with compound 16B, compound 16C was prepared according to the method for preparing compound 1D. 1H NMR (400MHz, CDCl3) δ = 12.18 (s, 1H), 8.41 (dd, J = 3.9, 8.4 Hz, 1H), 8.19 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 2.93 (t, J = 7.4 Hz, 4H), 2.15 (qμμin, J = 7.3 Hz, 2H), 1.93 (s , 3H), 1.89 (s, 3H). Compound 16:
[476] [476] Except for replacing compound 1D with compound 16C and replacing compound 1F with compound 2B, compound 16 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, DMSO-d6) δ = 11, 50 (s, 1H), 8.33 (ls, 1H), 8.09 (d ld, J = 3.2, 8.1 Hz, 1H), 8.06 (s, 1H), 7.86 ( s, 1H), 7.47 (s, 1H), 7.26 (d, J = 8.3 Hz, 1H), 6.68 (s, 1H), 3.77 (s, 3H), 3, 45 (sl, 3H), 2.97 (tl, J = 7.1 Hz, 2H), 2.80 (tl, J = 7.3 Hz, 2H), 2.73 (ls, 4H), 2, 56-2.52 (m, 4H), 2.07 (s, 3H), 2.05-1.97 (m, 2H), 1.87 (ls, 4H), 1.80 (s, 3H) , 1.76 (s, 3H). Example 17 Compound 17A:
[477] [477] Except for the substitution of the 2,4,5-trichloropyrimidine compound for the 2,4-dichloro-5-methoxypyrimidine compound and replacement of the 1C compound by
[478] [478] Compound 17A (0.94 g, 2.60 mmol) was dissolved in 25 ml DCE, and added with BBr3 (6.51 g, 25.9 mmol, 2.50 ml). After being purged with nitrogen gas 3 to 5 times, the mixture was stirred at an ambient temperature of about 25 ° C for 2 hours, and stirred at 80 ° C for 1 hour. The reaction solution was cooled to 0 ° C and adjusted to pH 7 to 8 by adding saturated NaHCO3 solution. After filtration, the filtrate was extracted with DCM, and the organic phase was dried and concentrated to generate compound 17B. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (s, 3 H), 2.08 (s, 3 H), 6.54 (s, 1 H), 7.47-7.53 ( m, 1 H), 7.60 (ddd, J = 8.50, 6.91, 1.47 Hz, 1 H), 7.78 (s, 1 H), 7.92-8.04 (m , 2 H), 8.13 (d, J = 9.54 Hz, 1 H), 8.64 (dd, J = 9.41, 3.55 Hz, 1 H), 12.73 (sl, 1 H). LCMS (ESI): m / z: 348.0 [M + 1]. Compound 17C:
[479] [479] Compound 17B (0.2 g, 575 μmol) and N, N-dimethylcarbamoyl chloride (92.7 mg, 862 μmol, 79.3 μl) were dissolved in 4 ml of DMF, added with K2CO3 (158 mg, 1.15 mmol), and stirred at 25 ° C for 2 hours.
[480] [480] Except for replacing compound 1D with compound 7C and replacing compound 1F with compound 2B, compound 17 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 , 85 (ls, 4 H), 2.03 (s, 3 H), 2.07 (dl, J = 10.03 Hz, 6 H), 2.40 (s, 3 H), 2.75 ( bs, 4 H), 2.92 (s, 3 H), 3.12-3.18 (m, 4 H), 3.22 (s, 4 H), 3.80 (s, 3 H), 6.71 (s, 1 H), 7.43-7.51 (m, 1 H), 7.52-7.66 (m, 2 H), 7.80 (s, 1 H), 7, 86-8.03 (m, 4 H), 8.33 (s, 1 H), 8.71 (dl, J = 5.87 Hz, 1 H), 12.52 (s, 1 H). LCMS (ESI): m / z: 658.1 [M + 1]. Example 18 Compound 18A:
[481] [481] 4-Methoxy-3-nitrophenol compounds
[482] [482] Compound 18A (1.95 g, 6.88 mmol) was dissolved in THF (30 ml), and a hydrochloric acid solution (0.5 M, 223.80 ml) was added, followed by stirring at 70 ° C for 12 hours. The reaction was quenched by adding 10 ml of water, and extracted three times with 100 ml of ethyl acetate. The organic phases were combined, washed twice with saturated brine, dried and concentrated to generate compound 18B. (400 MHz, CDCl3) δ ppm: 3.95 (s, 3 H), 4.65 (s, 2 H), 7.09 (m, 1 H), 7.25 (d, J = 9.2 Hz, 1H), 7.46 (s, 1H), 9.86 (s, 1H).
[483] [483] At 25 ° C, compound 18B (200 mg, 947 μmol) was dissolved in 10 ml of a mixed solution of DCE, followed by the consecutive addition of pyrazin-2-ylmethylamine (206 mg, 1.89 mmol), acetic acid (113 mg, 1.89 mmol, 108 μl) and sodium borohydride acetate (602 mg, 2.84 mmol) and stirring at room temperature for 12 hours. After the reaction was completed, an aqueous solution of saturated NaHCO3 was added to the reaction solution to adjust the pH to about 9, and extracted three times with DCM. The organic phase was subjected to drying over anhydrous Na2SO4, concentrated and purified by thin layer chromatography to generate compound 18C. 1H NMR (400 MHz, CDCl3) δ ppm 8.64 (s, 1H), 8.38–8.40 (m, 3H), 7.24- 7.42 (m, 1 H), 6.93- 7.21 (m, 2 H), 4.03-4.30 (m, 4 H), 3.91 (s, 3 H), 3.01-3.18 (m, 2 H). Compound 18D:
[484] [484] Except for the replacement of compound 1E with compound 18C, compound 18D was prepared according to the method for preparing compound 1F. 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (s, 1 H), 8.54-8.57 (m, 1 H), 8.49 (d, J = 2.38 Hz, 1 H) , 6.70 (d, J = 8.78 Hz, 1 H), 6.37 (d, J = 2.89 Hz, 1 H), 6.27 (dd, J = 8.78, 2.89 Hz, 1 H), 4.03-4.10 (m, 4 H), 3.82 (s, 3 H), 3.06 (t, J = 5.21 Hz, 2 H). Compound 18:
[485] [485] Except for replacing compound 1F with compound 18D and replacing compound 1D with compound 4C, compound 18 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 2.05 -2.19 (m, 7 H), 2.79 (ls, 2 H), 3.61 - 3.75 (m, 2 H), 3.86 (s, 3 H),
[486] [486] Except for the substitution of the compound pyrazin-2-ylmethylamine for the compound pyridin-3-ylmethylamine, compound 19A was prepared according to the method for preparing compound 18A. Compound 19B:
[487] [487] Except for the replacement of compound 1E by compound 19A, compound 19B was prepared according to the method for preparing compound 1F. Compound 19:
[488] [488] Except for replacing compound 1F with compound 19B and replacing compound 1D with compound 4C, compound 19 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.60- 8.42 (m, 3H), 8.29 (dd, J = 3.9, 9.0 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 8.17 (s , 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.85-7.79 (m, 2H), 7 , 62 (ddd, J = 1.5, 6.9, 8.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.48-7.43 (m, 1H ), 6.89 (d, J = 8.8 Hz, 1H), 6.54 (dd, J = 3.2, 8.8 Hz, 1H), 3.89-3.84 (m, 5H) , 3.74-3.55 (m, 2H), 2.67 (tl, J = 5.0 Hz, 2H), 2.19-2.06 (m, 7H). Example 20 Compound 20A:
[489] [489] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 1-fluoro-5- methoxy-2-methyl-4-nitrobenzene and 2,7-diazaspiro [3,5] non-tert-butyl non-2-carboxylate, compound 20A was prepared according to the method for preparing compound 1E. 1H NMR (400 MHz, CDCl3) δ ppm: 1.48 (s, 9 H), 1.90-1.98 (m, 4 H), 2.26 (s, 3 H), 2.91 - 2 , 95 (m, 4 H), 3.73 (s, 4 H), 3.96 (s, 3 H), 6.54 (s, 1 H), 7.82-7.86 (m, 1 H). Compound 20B:
[490] [490] Compound 20A (2.14 g, 5.47 mmol) was dissolved in DCM (15 ml), TFA (6.23 g, 54.67 mmol, 4.05 ml) was added thereto, and The mixture was stirred at 25 ° C for 1 hour. The reaction solution was concentrated under reduced pressure to generate compound 20B. 1H NMR (400 MHz, CD3OD) δ ppm 2.05-2.09 (m, 4 H), 2.28 (s, 3 H), 2.98-3.02 (m, 4 H), 3, 33 (s, 4 H), 3.94 (s, 3 H), 6.74 (s, 1 H), 7.78 (s, 1 H). Compound 20C:
[491] [491] Compound 20B and 2-chloroacetaldehyde compound were dissolved in 5 ml of DCM, and added with acetic acid (43.19 microliters) and sodium borohydride acetate (218.2 mg, 1.03 mmol). The reaction was carried out at 20 ° C for 2 hours. The reaction was quenched with water and extracted with ethyl acetate to generate an organic phase. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by a preparative thin layer chromatography plate to generate compound 20A. 1H NMR (400 MHz, CD3OD) δ ppm 7.77 (s, 1 H), 6.72 (s, 1 H), 3.93-3.95 (m, 3 H), 3.60-3, 64 (m, 2 H), 3.41 (s, 4 H), 3.04 (t, J = 6.15 Hz, 2 H), 2.95-2.99 (m, 4 H), 2 , 26 (s, 3 H), 2.03 (s, 2 H), 1.97-2.00 (m, 4 H).
[492] [492] Compound 20C was dissolved in 5 ml of EtOH and added with a solution of dimethylamine in ethanol (2 M, 10.8 ml). The mixture was heated to 90 ° C and reacted for 12 hours. After the reaction was completed, the reaction solution was concentrated to generate compound 20D. Compound 20E:
[493] [493] Except for the replacement of compound 1E with compound 20D, compound 20E was prepared according to the method for preparing compound 1F. 1H NMR (400 MHz, CD3OD) δ ppm 1.94-1.97 (m, 3 H), 2.16 (s, 3 H), 2.41-2.46 (m, 6 H),
[494] [494] Except for replacing compound 1F with compound 20E and replacing compound 1D with compound 4C, compound 20 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, DMSO-d6) δ ppm = 12.48 (ls, 1H), 8.38 (dl, J = 5.9 Hz, 1H), 8.28 (ls, 2H), 8.14 (s, 1H), 8.05 (dl, J = 8.6 Hz, 1H), 7.98-7.94 (m, 2H), 7.91 (dl, J = 10.0 Hz, 2H), 7.59 (tl, J = 7.3 Hz , 1H), 7.52-7.47 (m, 1H), 7.45 (s, 1H), 6.70 (s, 1H), 3.77-3.75 (m, 3H), 3, 38 (s, 4H), 2.88 (tl, J = 6.0 Hz, 2H), 2.72 (ls, 4H), 2.48-2.44 (m, 2H), 2.28 (s , 6H), 2.06 (s, 3H), 2.03 (s, 3H), 1.99 (s, 3H), 1.86 (s, 4H). Example 21 Compound 21A:
[495] [495] Except for the replacement of compound 20B by compound 1E, compound 21A was prepared according to the method of preparing compound 1F. Compound 21B:
[496] [496] Except for replacing compound 1F with compound 21A and replacing compound 1D with compound 4C, compound 21B was prepared according to the method to prepare compound 1. 1H NMR (400MHz, CDCl3) δ = 12.46 ( s, 1H), 8.64 (dd, J = 3.5, 9.3 Hz, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 9.3 Hz, 1H), 7.87 (dl, J = 7.8 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.56 (t, J = 7 , 4 Hz, 1H), 7.50-7.44 (m, 1H), 7.41 (s, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 2.77 (ls, 4H), 2.51 (ls, 4H), 2.19 (s, 3H), 2.16 (s, 3H), 2.01 (ls,
[497] [497] Compound 21B (0.1 g, 169 μmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (392 mg, 1.69 mmol) were dissolved in 5 ml DMF, added with DIPEA (87.4 mg, 676 μmol), and heated to 40 ° C with stirring for 2 hours. After the reaction was completed, the reaction solution was concentrated, quenched by the addition of saturated brine and extracted with EtOAc, and the organic phase was dried and concentrated. The crude product was purified by preparative HPLC to generate compound 21. 1H NMR (400 MHz, CD3OD) δ ppm 1.79 (s, 3 H), 1.87-1.97 (m, 4 H), 2, 10 (s, 3 H), 2.13 (s, 2 H), 2.66-2.85 (m, 4 H), 3.20 (q, J = 9.78 Hz, 2 H), 3 , 84 (s, 3 H), 4.65 (ls, 5 H), 4.78-4.85 (m, 2 H), 6.66 (s, 1 H), 7.54-7.67 (m, 3 H), 7.94 (d, J = 8.29 Hz, 1 H), 8.01 (d, J = 8.95 Hz, 1 H), 8.08 (s, 1 H) , 8.22 (dd, J = 9.17, 4.03 Hz, 1 H), 8.27 (d, J = 8.80 Hz, 1 H). LC-MS (ESI): m / z: 673.0 [M + 1]. Example 22
[498] [498] Compound 2,4-dichloro-7-tosyl-7H-pyrrolo [2,3-d] pyrimidine and compound 4B were dissolved in 25 ml of isobutanol, then added with methylsulfonic acid (842.54 mg, 8, 77 mmol, 624.10 μl), and reacted at 110 ° C for 12 hours. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by column chromatography to generate compound 22A. 1H NMR (400MHz, DMSO-d6) δ = 8.83 (dl, J = 5.6 Hz, 1H), 8.20 (dl, J = 9.0 Hz, 1H), 8.08 (dl, J = 8.1 Hz, 1H), 8.03-7.95 (m, 3H), 7.77 (dl, J = 3.7 Hz, 1H), 7.62 (tl, J = 7.5 Hz , 1H), 7.55 - 7.47 (m, 3H), 6.82 (dl, J = 2.9 Hz, 1H), 2.39 (s, 3H), 2.11 (dl, J = 13.2 Hz, 6H). Compound 22B:
[499] [499] Compounds 22A (100 mg, 190.49 μmol) and 2B were dissolved in a mixed solution of 2 ml of toluene and 0.4 ml of tert-butanol, followed by the addition of Pd2 (dba) 3 (17, 4 mg, 19.1 μmol), XPhos (18.2 mg, 38.1 μmol) and K2CO3 (52.6 mg, 380 μmol) consecutively and stirring at 100 ° C for 12 hours. After the reaction was completed, the reaction solution was added with water and extracted three times with DCM. The organic phase was dried over anhydrous Na2SO4, concentrated and purified by thin layer chromatography to generate compound 22B. Compound 22:
[500] [500] Compound 22B was dissolved in a mixed solution of 2 ml i-PrOH and 1 ml of THF, and NaOH (13.0 mg, 327 μmol) was dissolved in 2 ml of water, added to the mixed solution and then , reacted at 100 ° C for 8 hours. After the reaction was completed, the reaction was quenched by adding water and extracted with EtOAc, and the organic phase was concentrated. The crude product was separated by preparative thin layer chromatography to generate compound 22. 1H NMR
[501] [501] Compound 5-bromo-2,4-dichloro-pyrimidine (1.04 g, 4.56 mmol) and compound 4B (0.5 g, 2.28 mmol, 1 eq) were dissolved in ethanol (10 ml), and added with DIEA (1.18 g, 9.12 mmol, 1.59 ml). The reaction was heated to about 90 ° C with stirring for 12 hours. After the reaction solution was concentrated, it was cooled with water and extracted three times with EtOAc, and the organic phase was concentrated to generate compound 23A. 1H NMR (400 MHz, CDCl3) δ ppm 8.48 (dd, J = 9.16, 3.89 Hz, 1 H), 8.38 (s, 1 H), 8.05 (d, J = 9 , 29 Hz, 1 H), 7.91 (d, J = 8.03 Hz, 1 H), 7.73 (d, J = 8.53 Hz, 1 H), 7.54-7.61 ( m, 1 H), 7.47-7.53 (m, 1 H), 2.16 (s, 3 H), 2.19 (s, 3 H). Compound 23:
[502] [502] Except for replacing compound 1D with compound 23A and replacing compound 1F with compound 2B, compound 23 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1 , 83 (sl, 4 H), 1.94 (s, 3 H), 2.03 (d, J = 13.20 Hz, 5 H), 2.00 - 2.06 (m, 1 H), 2.44 (ls, 3 H), 2.70 (ls, 4 H), 3.28 (ls, 4 H), 3.77 (s, 3 H), 6.68 (s, 1 H), 7.42 (s, 1 H), 7.47-7.53 (m, 1 H), 7.54-7.62 (m, 1 H), 7.87 -7.97 (m, 3 H ), 8.06 (d, J = 8.80 Hz, 1 H), 8.18-8.24 (m, 2 H), 8.37 (ls, 1 H). Example 24 Compound 24A:
[503] [503] Compound 23 (0.1 g, 153 μmol) and tributyl (1-ethoxyvinyl) stannane (111 mg, 307 μmol) were dissolved in 3 ml of toluene, and Pd (PPh3) 2Cl2 (10.8 mg, 15.4 μmol), CuBr (6.63 mg, 46.2 μmol, 1.41 μl) and PPh3 (12.1 mg, 46.2 μmol) were added in consecutive portions. The mixture was stirred at 110 ° C under nitrogen gas protection for 12 hours. After the reaction was completed, the reaction solution was quenched by adding KF solution and extracted three times with EtOAc. The organic phase was dried over anhydrous Na2SO4, concentrated and purified by thin layer chromatography to generate compound 24A. Compound 24:
[504] [504] Compound 24A was dissolved in HCl / dioxane (4 M, 65.94 μl) and reacted at room temperature for half an hour. After the reaction was completed, the reaction solution was added with a saturated NaHCO3 solution to adjust the pH to about 9. The mixture was extracted three times with EtOAc, and washes sequentially with water and saturated brine. The organic phase was concentrated. The crude product was purified by preparative HPLC to generate compound 24. 1H NMR (400MHz, DMSO-d6) δ = 11.17 (s, 1H), 9.36-9.28 (m, 1H), 8.85 (s, 1H), 8.28 (dl, J = 13.3 Hz, 2H), 8.06 (dl, J = 9.0 Hz, 1H), 7.96 (ls, 1H), 7.57 (d ld, J = 3.3, 6.3 Hz, 3H), 7.25 (ls, 1H), 6.55 (ls, 1H), 3.74 (s, 3H), 3.31 (ls , 3H), 2.55 (m, 4H), 2.53-2.52 (m, 6H), 2.47 (ls, 4H), 1.81 (ls, 4H), 1.79-1, 75 (m, 6H). Example 25 Compound 25:
[505] [505] Compound 24 (0.1 g, 153 μmol) and cyclopropylboronic acid (52.9 mg, 615 μmol) were dissolved in a mixed solution of 5 ml of toluene and 0.5 ml of water, and added with Pd (OAc) 2 (3.46 mg, 15.4 μmol), K3PO4 (81.7 mg, 384 μmol), and P (Cy) 3 (8.63 mg, 30.8 μmol, 9.98 μl) consecutively . The reaction solution was heated to 110 ° C and stirred for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated, and the crude product was purified by preparative HPLC to generate compound 25. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.55-0.66 (m, 2 H), 0.85-0.96
[506] [506] Compound 24 (0.1 g, 153 μmol) was dissolved in 5 ml of DMF, and zinc powder (5.03 mg, 76.9 μmol), Pd2 (dba) 3 (28.2 mg, 30.7 μmol), DPPF (17.1 mg, 30.8 μmol), and Zn (CN) 2 (36.1 mg, 307 μmol, 19.5 μl) were added consecutively. The reaction solution was heated to 120 ° C and further stirred for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated, and the crude product was purified by preparative HPLC to generate compound 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83 (sl, 4 H),
[507] [507] Compound 24 (0.1 g, 153 μmol) was dissolved in 5 ml of EtOH, and Pd (dppf) Cl2 (11.3 mg, 15.40 μmol) and Et3N (46.7 mg, 461 μmol , 64.2 μl) were added consecutively. The reaction solution was reacted at 80 ° C for 24 hours under an atmosphere of carbon monoxide (344.74 kPa (50 psi)). After the reaction was completed, the reaction solution was filtered and concentrated, and the crude product was purified by preparative TLC to generate compound 27A. Compound 27B:
[508] [508] Compound 27A (60 mg, 93.3 μmol) was dissolved in 2 ml of EtOH, and N2H4 · H2O (95.4 mg, 1.87 mmol, 92.6 μl) was added to it. The reaction solution was heated to 100 ° C and further stirred for 6 hours. After the reaction was completed, the reaction solution was filtered and concentrated, and compound 27B was obtained without further purification. Compound 27:
[509] [509] Compound 27B (30 mg, 47.7 μmol) and HOAc (210 mg, 3.50 mmol) were dissolved in 2 ml of triethyl orthoacetate. The reaction solution was heated to 120 ° C, and further stirred for 1 hour. After the reaction was completed, the reaction solution was filtered and concentrated, and the crude product was purified by preparative HPLC to generate compound 27. 1H NMR (400MHz, CD3OD) δ = 9.17 (dl, J = 6, 5 Hz, 1H), 8.71 (s, 1H), 8.55 (ls, 1H), 8.16 (dl, J = 8.5 Hz, 1H), 8.02 (dl, J = 7, 3 Hz, 1H), 7.69-7.60 (m, 3H), 7.42 (ls, 1H), 6.58 (s, 1H), 4.64 (ls, 4H), 3.83 ( ls, 3H), 2.85 (ls, 3H), 2.66 (ls, 6H), 1.97 (dl, J = 13.1 Hz, 6H), 1.92 (ls, 4H), 1, 30 (bs, 4H). Example 28 Compound 28A:
[510] [510] Except for the substitution of the compound pyrazin-2-ylmethylamine with the compound piperazin-2-one, compound 28A was prepared according to the method for preparing compound 18A. 1H NMR (400 MHz, CDCl3) δ ppm 7.44 (d, J = 2.89 Hz, 1 H), 7.23-7.34 (m, 1 H), 7.16 (dd, J = 9 , 16, 3.01 Hz, 1 H), 4.13 (t, J = 5.21 Hz, 2 H), 3.95 (s, 3 H), 3.37-3.49 (m, 2 H), 3.33 (s, 2 H), 2.92 (t, J = 5.27 Hz, 2 H), 2.84 (tl, J = 5.27 Hz, 2 H).
[511] [511] Except for the replacement of compound 1E by compound 28A, compound 28B was prepared according to the method for preparing compound 1F. 1H NMR (400 MHz, CDCl3) δ ppm 2.85 (dt, J = 15.50, 5.36 Hz, 4 H) 3.31 (s, 2 H) 3.35 - 3.51 (m, 2 H) 3.82 (s, 3 H) 3.89-4.17 (m, 2 H), 6.36 (d, J = 2.89 Hz, 1 H), 6.70 (d, J = 8.66 Hz, 1 H), 7.29 (s, 1 H). Compound 28:
[512] [512] Except for replacing compound 1F with compound 28B and replacing compound 1D with compound 4C, compound 28 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 2.18 (s, 3 H), 2.21 (s, 3 H), 3.45 (ls, 2 H), 3.53-3.73 (m, 4 H),
[513] [513] Except for the substitution of the compound pyrazin-2-ylmethylamine with the compound methane sulfonamide, compound 29A was prepared according to the method for preparing compound 18A. Compound 29B:
[514] [514] Except for the replacement of compound 1E with compound 29A, compound 29B was prepared according to the method for preparing compound 1F. Compound 29:
[515] [515] Except for replacing compound 1F with compound 29B and replacing compound 1D with compound 4C, compound 29 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 2.18 (s, 3 H), 2.21 (s, 3 H), 3.45 (ls, 2 H), 3.53-3.73 (m, 4 H), 3.82 (ls, 2 H) , 3.88 (s, 3 H), 3.97-4.24 (m, 2 H), 6.99 (dl, J = 8.44 Hz, 1 H), 7.11 (d, J = 8.98 Hz, 1 H), 7.31 (ls, 1 H), 7.65-7.78 (m, 2 H), 8.08 (dl, J = 8.19 Hz, 2 H), 8.15 - 8.33 (m, 3 H). Example 30 Compound 30A:
[516] [516] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-
[517] [517] Except for the replacement of compound 1E with compound 30A, compound 30B was prepared according to the method for preparing compound 1F. Compound 30:
[518] [518] Except for replacing compound 1F with compound 30B and replacing compound 1D with compound 4C, compound 30 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 1.78 (s, 3 H), 1.95-2.06 (m, 4 H), 2.09 (s, 3 H), 2.13 (s, 3 H), 2.71 2.83 (m , 4 H), 3.24-3.31 (m, 1 H), 3.71 - 3.81 (m, 1 H), 3.85 (s, 3 H), 3.88-3.96 (m, 4 H), 4.58-4.86 (m, 7 H), 6.67 (s, 1 H), 7.53-7.59 (m, 1 H), 7.61-7 , 68 (m, 2 H), 7.94 (d, J = 8.07 Hz, 1 H), 8.02 (d, J = 9.17 Hz, 1 H), 8.09 (s, 1 H), 8.21 (dd, J = 9.05, 3.91 Hz, 1 H), 8.30 (dl, J = 8.93 Hz, 1 H), 8.55 (s, 1 H) . Example 31 Compound 31A:
[519] [519] Compound 20B (200 mg, 686 μmol) and acetone (199 mg, 3.43 mmol, 252.34 μl) were dissolved in 4 ml of methanol, added with acetic acid (82.4 mg, 1.37 mmol, 78.52 μl), and stirred at 25 ° C for one hour. The reaction solution was cooled, added with NaBH3CN (86.2 mg, 1.37 mmol) and stirred at 0 ° C for one hour. After the reaction was completed, the reaction solution was concentrated, added with a saturated solution of sodium bicarbonate, and extracted three times with DCM. The organic phase was subjected to drying over anhydrous Na2SO4 and concentrated to generate compound 31A. 1H NMR (400 MHz, CDCl3)
[520] [520] Except for the replacement of compound 1E with compound 31A, compound 31B was prepared according to the method for preparing compound 1F. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (d, J = 6.60 Hz, 5 H), 1.82 (dl, J = 7.34 Hz, 4 H), 2.07 (s, 3 H), 2.25 (ls, 1 H), 2.72 (ls, 4 H), 3.28-3.53 (m, 4 H), 3.74 (s, 3 H), 4, 00-4.14 (m, 2 H), 6.42 (s, 1 H), 7.96 (s, 1 H). LC-MS (ESI): m / z: 304.1 [M + 1] Compound 31:
[521] [521] Except for the replacement of compound 1F with compound 32B, compound 31 was prepared according to the method to prepare compound 1. 1H NMR (400 MHz, MeOD) δ ppm 1.23 (d, J = 6.60 Hz, 6 H) 1.66 (s, 2 H) 1.70 (s, 1 H) 1.93 (s, 3 H) 1.96 (s, 7 H) 2.75 (ls, 4 H) 4.58 (s, 8 H) 6.64 (s, 1 H) 7.48 (s, 1 H) 7.87 (d, J = 5.38 Hz, 2 H) 8.07-8.17 (m, 3 H) 8.55 (s, 1 H). LC-MS (ESI): m / z: 639.1 [M + 1]. Example 32 Compound 32A:
[522] [522] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5,5] undecane compounds for 1-bromo-2- fluoro-4-methoxy-5-nitrobenzene and 2-methyl-2,7-diazaspiro [3,5] nonane, compound 32A was prepared according to the method for preparing compound 1E. 1H NMR (400 MHz, CDCl3) δ ppm 2.44 (s, 3 H), 3.15-3.22 (m, 4 H), 3.19 (s, 8 H), 3.98 (s, 3 H), 6.57 (s, 1 H), 8.23 (s, 1 H). Compound 32B:
[523] [523] Except for the substitution of compound 23 with compound 32A and replacement of the tributyl (1-ethoxyvinyl) stanane compound with the tributyl (vinyl) stanane compound, compound 32B was prepared according to the method for preparing compound 24A. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (s, 2 H), 1.80-2.01 (m, 4 H), 2.39 (s, 3 H), 2.91 (s, 2 H), 2.96-3.03 (m, 4 H), 3.51 (s, 1 H), 3.93-4.04 (m, 3 H), 5.27-5.35 ( m, 1 H), 5.71 (d, J = 17.69 Hz, 1 H), 6.51 (s, 1 H), 6.72 (dd, J = 17.63, 10.98 Hz, 1 H), 8.04 (s, 1 H), 8.12 (s, 1 H). Compound 32C:
[524] [524] Except for the replacement of compound 49A with compound 32B, compound 32C was prepared according to the method for preparing compound 49B. Compound 32:
[525] [525] Except for replacing compound 1F with compound 32C and replacing compound 1D with compound 23A, compound 32 was prepared according to the method to prepare compound 1. 1H NMR (400 MHz, CDCl3) δ ppm 0.58 -0.55 (m, 3H) 1.93-2.07 (m, 4H) 2.11-2.05 (s, 9 H) 2.74-2.71 (m, 4 H) 2.76 (s, 3 H), 3.86 (d, J = 2.89 Hz, 8 H), 7.19 (d, J = 3.14 Hz, 1 H), 7.28 (s, 1 H) , 7.37 (s, 1 H), 7.51 (d, J = 9.29 Hz, 1 H), 8.06 (s, 1 H), 8.11 (s, 1 H), 8, 41 (dd, J = 9.16, 3.76 Hz, 1 H), 8.59 (s, 1 H), 11.31 (s, 1 H). Example 33 Compound 33:
[526] [526] Except for replacing compound 1D with compound 23A and replacing compound 1F with compound 31B, compound 33 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 1.22 (d, J = 6.36 Hz, 6 H) 1.70 (s, 3 H) 1.89-2.02 (m, 4 H) 2.10 (d, J = 13.45 Hz, 6 H ) 2.76 (ls, 4 H) 3.85 (s, 3 H) 4.64 (s, 4 H) 6.65 (s, 1 H) 7.55-7.60 (m, 2 H) 7.61-7.69 (m, 1 H) 7.96 (d, J = 8.31 Hz, 1 H) 8.02-8.10 (m, 2 H) 8.19 (s, 1 H ) 8.38 (d, J = 8.80 Hz, 1 H) 8.56 (s, 1 H). LCMS (ESI) m / z: 677.0 [M + 1]. Example 34 Compound 34A:
[527] [527] Except for the replacement of the compound 2,4,5-trichloropyrimidine with the compound 5-bromo-2,4-dichloropyrimidine, compound 34A was prepared according to the method for preparing compound 8E. 1H NMR (400 MHz, CD3OD) δ ppm 2.17 (s, 3 H), 2.21 (s, 3 H), 8.28 (d, J = 9.54 Hz, 1 H), 8.54 (s, 1 H), 8.87 (d, J = 2.01 Hz, 1 H), 8.90 (d, J = 2.01 Hz, 1 H), 9.04 (dd, J = 9 , 41, 4.14 Hz, 1 H). Compound 34B:
[528] [528] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 2-fluoro-4- methoxy-5-nitrotoluene and 3B, compound 34B was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CDCl3-d) δ = 7.74 (s, 1H), 6.47 (s, 1H), 3.86 (s, 3H), 3.27 (dl, J = 12.2 Hz , 2H), 2.71-2.52 (m, 10H), 2.44 (ls, 1H), 2.37-2.29 (m, 1H), 2.68-2.27 (m, 1H ), 2.24 (s, 3H), 2.16 (s, 3H), 1.92 (dl, J = 12.2 Hz, 2H), 1.73-1.59 (m, 2H). Compound 34C:
[529] [529] Except for the replacement of compound 1E with compound 34B, compound 34C was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CDCl3-d)
[530] [530] Except for replacing compound 1F with compound 34C and replacing compound 1D with compound 34A, compound 34 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 1.64 -1.82 (m, 2 H), 2.09 (s, 3 H), 2.14 (s, 3 H), 2.18 (s, 3 H), 2.43 (s, 3 H) , 2.50 (tl, J = 11.43 Hz, 2 H), 2.72 (tl, J = 11.13 Hz, 6 H), 2.82 (ls, 3 H), 3.15-3 , 25 (m, 2 H), 3.37 (s, 1 H), 3.86 (s, 3 H), 6.76 (s, 1 H), 7.61 (s, 1 H), 7 , 99 (d, J = 9.41 Hz, 1 H), 8.23 (s, 1 H), 8.55 (ls, 1 H), 8.83 (dd, J = 17.12, 1, 83 Hz, 2 H), 8.97 (dd, J = 9.48, 4.10 Hz, 1 H). Example 35 Compound 35:
[531] [531] Except for replacing compound 1F with compound 3D and replacing compound 1D with compound 16C, compound 35 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 1.71 (d ld, J = 12.05, 3.26 Hz, 2 H), 1.82 (s, 3H), 1.85 (s, 3 H), 1.98-2.12 (m, 3 H ), 2.17 (quin, J = 7.34 Hz, 2 H), 2.61 (s, 3 H), 2.72 (tl, J = 11.54 Hz, 3 H), 2.94- 2.98 (m, 10 H), 3.15 (tl, J = 7.15 Hz, 3 H), 3.68 (dl, J = 12.55 Hz, 2 H), 3.86 (s, 3 H), 6.34 (dd, J = 8.91, 2.13 Hz, 1 H), 6.65 (d, J = 2.26 Hz, 1 H), 7.43 (d, J = 8.03 Hz, 1 H), 7.62 (d, J = 8.78 Hz, 1 H), 8.00 (s, 1 H), 8.52 (s, 1 H). Example 36 Compound 36:
[532] [532] Except for replacing compound 1F with compound 2B and replacing compound 1D with compound 34A, compound 36 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 2.00 -2.05 (m, 4 H), 2.08 (s, 3 H), 2.14 (s, 3 H), 2.17 (s, 3 H), 2.85 (s, 7 H) , 2.80-2.84 (m, 2 H), 3.85 (d, J = 4.65 Hz, 5 H), 3.80-3.88 (m, 1 H), 3.85- 3.87 (m, 1 H), 6.73 (s, 1 H), 7.62 (s, 1 H), 7.98 (d, J = 9.54 Hz, 1 H), 8.22 (s, 1 H), 8.57 (s, 1 H), 8.83 (dd, J = 18.95, 1.71 Hz, 2 H), 8.95 (dd, J = 9.48, 4.10 Hz, 1 H). Example 37 Compound 37:
[533] [533] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 20C, compound 37 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, MeOD) δ ppm 1.99 -2.03 (m, 4 H), 2.06 (s, 3 H), 2.12 (s, 3 H), 2.16 (s, 3 H), 2.54 (s, 6 H) , 2.77-2.80 (m, 2 H), 2.82 (dl, J = 6.53 Hz, 4 H), 3.17 (t, J = 6.02 Hz, 2 H), 3 , 71 (s, 4 H), 3.84 (s, 4 H), 6.70 (s, 1 H), 7.61 (s, 1 H), 7.95 (dl, J = 9.54 Hz, 1 H), 8.19 (d, J = 1.51 Hz, 1 H), 8.54 (sl, 1 H), 8.79 (d, J = 1.26 Hz, 1 H), 8.84 (s, 1 H), 8.92 (d ld, J = 9.16, 3.39 Hz, 1 H). Example 38 Compound 38A:
[534] [534] Except for the substitution of the compound 2,4,5-trichloropyrimidine for the compound 5-bromo-2,4-dichloropyrimidine and replacement of compound 1C for the compound
[535] [535] Except for replacing compound 1F with compound 3D and replacing compound 1D with compound 38A, compound 38 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, MeOD) δ ppm 1.66 -1.76 (m, 2 H), 1.82 (d, J = 13.30 Hz, 6 H), 2.04 (dl, J = 11.80 Hz, 2 H), 2.17 (quin , J = 7.40 Hz, 2 H), 2.63 (s, 4 H), 2.70 (tl, J = 11.80 Hz, 2 H), 2.97 (tl, J = 7.28 Hz, 12 H), 3.17 (tl, J = 7.28 Hz, 2 H), 3.67 (dl, J = 12.30 Hz, 2 H), 3.85 (s, 3 H), 6.29 (dd, J = 8.78, 2.01 Hz, 1 H), 6.63 (d, J = 2.26 Hz, 1 H), 7.44 (d, J = 8.28 Hz , 1 H), 7.57 (d, J = 8.78 Hz, 1 H), 8.09 (s, 1 H), 8.52 (s, 1 H). Example 39
[536] [536] Except for the replacement of compound 10E by compound 4C, compound 39 was prepared according to the method for preparing compound 20. 1H NMR (400MHz, CD3OD) δ = 9.11 (dd, J = 9.54, 4.27 Hz, 1 H), 8.85 (s, 1 H), 8.80 (s, 1 H), 8.57 (s, 1 H), 8.12 (s, 1 H), 7 , 98 (d, J = 9.54 Hz, 1 H), 7.63 (s, 1 H), 6.73 (s, 1 H), 3.85 (s, 3 H), 3.55 ( s, 4 H), 3.03 (t, J = 6.53 Hz, 2 H), 2.82-2.88 (m, 4 H), 2.65 (t, J = 6.65 Hz, 2 H), 2.46 (s, 6 H), 2.17 (s, 3 H), 2.12-2.15 (m, 1 H), 2.13 (d, J = 3.51 Hz , 5 H), 1.98-2.03 (m, 4 H). Example 40 Compound 40:
[537] [537] Except for replacing compound 1F with compound 32B and replacing compound 1D with compound 34A, compound 40 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 0.86 (tl, J = 7.34 Hz, 3 H), 1.22-1.28 (m, 2 H), 2.03 (s, 4 H), 2.14 (s, 3 H), 2, 18 (s, 3 H), 2.51 (q, J = 7.46 Hz, 2 H), 2.85 (ls, 4 H), 2.89 (s, 3 H), 3.86 (s , 3 H), 3.90 (s, 4 H), 6.79 (s, 1 H), 7.67 (s, 1 H), 8.00 (d, J = 9.54 Hz, 1 H ), 8.26 (s, 1 H), 8.56 (s, 1 H), 8.82 (d, J = 1.83 Hz, 1 H), 8.87 (d, J = 1.83 Hz, 1 H). Example 41 Compound 41A:
[538] [538] Except for the substitution of the compound 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene with the compound 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene and replacement of the compound 3-methyl-3, 9-diazaspiro [5.5] undecane by compound 1-methyl-4- (piperidin-4-yl) piperazine, compound 41 was prepared according to the method for preparing compound 1E. 1H NMR (400 MHz, CDCl3) δ ppm 1.72-1.83 (m, 2 H), 1.98 (dl, J = 12.10 Hz, 4 H), 2.29 (s, 3 H) , 2.64 (dl, J = 4.28 Hz, 5H), 2.70-2.79 (m, 4 H), 3.61 (dl, J = 12.23 Hz, 2 H), 3, 94 (s, 3 H), 6.54 - 6.60 (m, 1 H), 8.18-8.21 (m, 1 H). Compound 41B:
[539] [539] Except for the substitution of compound 23 with compound 41A and replacement of the tributyl (1-ethoxyvinyl) stanane compound with the tributyl (vinyl) stanane compound, compound 41B was prepared according to the method for preparing compound 24A. 1H NMR (400 MHz, CDCl3) δ ppm 1.26-1.42 (m, 1 H), 1.27-1.41 (m, 1 H), 1.66 (s, 3 H), 1, 68-1.78 (m, 2 H), 1.99 (dl, J = 11.86 Hz, 2 H), 2.31 (s, 2 H), 2.39 (ddt, J = 11.20 , 7.57, 3.58, 3.58 Hz, 2 H), 2.50 (ls, 2 H), 2.66 (ls,
[540] [540] Except for the replacement of compound 1E with compound 41B, compound 41C was prepared according to the method for preparing compound 1F. Compound 41:
[541] [541] Except for substitution of compound 1F for compound 41C and substitution of compound 1D for compound
[542] [542] Except for the substitution of compound 1A by the benzo [d] thiazol-5-amine compound, compound 42A was prepared according to the method for preparing compound 1B. 1H NMR (400 MHz, CDCl3) δ ppm 4.37 (sl, 2 H), 6.91 (d, J = 8.56 Hz, 1 H), 7.62-7.75 (m, 1 H) , 9.00 (s, 1 H). Compound 42B:
[543] [543] Except for the replacement of compound 1B with compound 42A, compound 42B was prepared according to the method for preparing compound 1C. Compound 42C:
[544] [544] Except for the replacement of compound 1C with compound 42B, compound 42C was prepared according to the method for preparing compound 1D. 1H NMR (400 MHz, DMSO- d6) δ ppm 2.02 (s, 3 H), 2.05 (s, 3 H), 8.43 (d, J = 9.16 Hz, 1 H), 8 , 47 (s, 1 H), 8.67 (dd, J = 9.16, 3.26 Hz, 1 H), 9.53 - 9.60 (m, 1 H), 12.82 (s, 1 H). Compound 42:
[545] [545] Except for replacing compound 1D with compound 42C and replacing compound 1F with compound 3D, compound 42 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 1.61 -1.73 (m, 2 H), 2.00-2.06 (m, 1 H), 2.04 (dl, J = 14.43 Hz, 1 H), 2.08 (s, 2 H ), 2.07-2.09 (m, 1 H), 2.12 (s, 3 H), 2.30 (s, 3 H), 2.34-2.44 (m, 2 H), 2.54 (ls, 4 H), 2.67-2.77 (m, 4 H), 3.73 (dl, J = 12.47 Hz, 2 H), 3.85 (s, 3 H) , 6.53 (dd, J =
[546] [546] Except for replacing compound 1D with compound 7D and replacing compound 1F with compound 3D, compound 43 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, MeOD) δ ppm 1.67 -1.79 (m, 2 H), 2.06 (dl, J = 12.10 Hz, 2 H), 2.14 (s, 3 H), 2.17 (s, 3 H), 2, 63 (s, 3 H), 2.77 (tl, J = 11.37 Hz, 2 H), 2.95 (ls, 6 H), 3.76 (dl, J = 12.35 Hz, 2 H ), 3.86 (s, 3 H), 4.60 (ls, 2 H), 6.55 (dd, J = 8.68, 2.45 Hz, 1 H), 6.70 (d, J = 2.32 Hz, 1 H), 7.45 (dd, J = 8.13, 4.34 Hz, 1 H), 7.71 (d, J = 8.68 Hz, 1 H), 7, 93 (d, J = 9.29 Hz, 1 H), 8.08 (s, 1 H), 8.25 (dl, J = 8.07 Hz, 1 H), 8.45 (sl, 1 H ), 8.84 (dd, J = 4.28, 1.59 Hz, 1 H), 8.88 (dd, J = 9.11, 3.73 Hz, 1 H). Example 44
[547] [547] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 1-fluoro-5- methoxy-2-methyl-4-nitrobenzene and N, N-dimethylpiperidine-4-amine, compound 44A was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CDCl3) δ = 7.83 (s, 1H), 6.55 (s, 1H), 3.94 (s, 3H), 3.34 (dl, J = 12.5Hz, 2H) , 2.72 (dt, J = 2.0, 11.9 Hz, 2H), 2.35 (s, 6H), 2.32-2.27 (m, 1H), 2.25 (s, 3H ), 1.97 (dl, J = 12.5 Hz, 2H), 1.70 (dq, J = 3.8, 12.0 Hz, 2H). Compound 44B:
[548] [548] Except for the replacement of compound 1E by compound 44A, compound 44B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CDCl3) δ
[549] [549] Except for replacing compound 1F with compound 44B and replacing compound 1D with compound 34A, compound 44 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.93 ( dd, J = 4.3, 9.5 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.79 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.60 (s, 1H), 6.72 (s, 1H), 3.84 (s, 3H), 3 , 16 (dl, J = 11.8 Hz, 2H), 2.69 (tl, J = 11.0 Hz, 2H), 2.53-2.47 (m, 1H), 2.45 (s, 6H ), 2.16 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.04-1.99 (m, 2H), 1.71 (dq, J = 3.8, 11.9 Hz, 2H). Example 45 Compound 45A:
[550] [550] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 1-fluoro-5- methoxy-2-methyl-4-nitrobenzene and 1-methylpiperazine, compound 45A was prepared according to the method for preparing compound 1E. Compound 45B:
[551] [551] Except for the replacement of compound 1E with compound 45A, compound 45B was prepared according to the method for preparing compound 1F. Compound 45:
[552] [552] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 45B, compound 45 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.97 ( dd, J = 4.3, 9.4 Hz, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8, 55 (sl, 1H), 8.24 (s, 1H), 8.01 (d, J = 9.3 Hz, 1H), 7.67 (s, 1H), 6.78 (s, 1H), 3.88 (s, 3H), 3.30-3.12 (m, 2H), 3.09-2.96 (m, 4H), 2.82 (ls, 3H), 2.51 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 2.10 (s, 3H). Example 46 Compound 46A:
[553] [553] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 1-fluoro-5- methoxy-4-nitro-2-vinylbenzene and N, N-dimethylpiperidine-4-amine 23A, compound 46A was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CDCl3) δ = 8.12 (s, 1H), 7.29 (s, 1H), 6.84-6.63 (m, 1H), 6.53 (s, 1H), 5 , 71 (dd, J = 1.0, 17.6 Hz, 1H), 5.30 (dd, J = 1.0, 11.0 Hz, 1H), 4.00-3.96 (m, 3H ), 3.51 (s, 5H), 3.00 (dl, J = 6.6 Hz, 1H), 2.82-2.72 (m, 2H), 2.55 (s, 1H), 2 , 39 (s, 6H), 2.00 (dl, J
[554] [554] Except for the replacement of compound 1E with compound 46A, compound 46B was prepared according to the method for preparing compound 1F. Compound 46:
[555] [555] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 46B, compound 46 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.84 ( s, 2H), 8.80 (ls, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.96 (d, J = 9.5 Hz, 1H), 7, 69 (s, 1H), 6.79 (s, 1H), 3.85 (s, 3H), 3.22-3.08 (m, 3H), 2.87-2.78 (m, 8H) , 2.50 (q, J = 7.3 Hz, 2H), 2.16 (s, 4H), 2.12 (s, 4H), 2.09-1.82 (m, 2H), 0, 85 (tl, J = 7.3 Hz,
[556] [556] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5,5] undecane compounds for 1-fluoro-5- methoxy-2-methyl-4-nitrobenzene and N1, N1, N2-trimethylethane-1,2-diamine, compound 47A was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CDCl3) δ = 7.80 (s, 1H), 6.55 (s, 1H), 3.93 (s, 3H), 3.23-3.16 (m, 2H), 2 , 87 (s, 3H), 2.53-2.47 (m, 2H), 2.24 (s, 9H). Compound 47B:
[557] [557] Except for the replacement of compound 1E with compound 47A, compound 47B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CD3OD-d4) δ = 6.70 (s, 1H), 6.60 (s, 1H), 5.00-4.78 (m, 1H), 4.91 (s, 3H) , 3.81 (s, 3H), 3.02 - 2.95 (m, 2H), 2.60 (s, 3H), 2.46-2.40
[558] [558] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 47B, compound 47 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.98 ( dd, J = 4.2, 9.5 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8, 53 (sl, 1H), 8.25 (s, 1H), 8.04 (d, J = 9.4 Hz, 1H), 7.71 (s, 1H), 6.86 (s, 1H), 3.88 (s, 3H), 3.26 (t, J = 6.6 Hz, 2H), 3.08-2.99 (m, 2H), 2.69 (s, 9H), 2.17 (s, 3H), 2.12 (d, J = 7.6 Hz, 6H). Example 48 Compound 48A:
[559] [559] Compound 34A (100mg, 242 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxathriciclohexane were dissolved in water and 1,4-dioxane, and then added with Pd (dppf) Cl2 (8.87 mg, 12.1 μmol) and K2CO3 (66.9 mg, 484 μmol). The reaction solution was heated to 110 ° C, and stirred for 1 hour under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated, added with ethyl acetate, washed three times with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness and purified by preparative thin layer chromatography to generate compound 48A. Compound 48:
[560] [560] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 34C, compound 48 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 9.03 (sl, 1 H), 8.95 (s, 2 H), 8.18 (d, J = 9.41 Hz, 1 H), 7.90 (s, 1 H), 7.59 (s, 1 H), 7.37 (s, 1 H), 3.98-4.00 (m, 1 H), 3.99 (s, 2 H), 3.97 (s, 1 H), 3, 82 (dl, J = 10.51 Hz, 5 H), 3.70 (dl, J = 10.27 Hz, 3 H), 3.27-3.37 (m, 5 H), 3.09 ( s, 3 H), 2.48-2.65 (m, 4 H), 2.36 (d, J = 12.59 Hz, 6 H), 2.20 (d, J =
[561] [561] Compound 34 (150 mg, 215 μmol, 1 eq) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (72.5 mg, 431 μmol) were added to a mixed solvent of ethylene glycol dimethyl ether and water, then added with Pd (PPh3) 4 (24.9 mg, 21.60 μmol) and Na2CO3 (45.7 mg, 431 μmol), and stirred at 90 ° C for 6 hours under the protection of nitrogen gas. After the reaction was completed, the reaction solution was added with DCM, and washed three times with water. The organic phase was subjected to drying and concentrated to generate a crude product. The crude product was separated by preparative thin layer chromatography to generate compound 49A. Compound 49B:
[562] [562] Compound 49A (90 mg, 113.71 μmol) was dissolved in MeOH (10 ml), and added with wet palladium-carbon (20 mg, 113.71 μmol, 10% purity, 50% water content %). The reaction system was purged with a hydrogen balloon, and stirred at 20-30 ° C for 18 hours under atmospheric pressure. After the reaction was completed, the reaction system was filtered, and the filtrate was concentrated to generate compound 49B. Compound 49:
[563] [563] MnO2 (39.4 mg, 453 μmol, 10 eq) was added to a toluene solution of compound 49B (30 mg, 45.33 μmol, 1 eq), and the mixture was stirred at 30 ° C for 12 hours. After the reaction was completed, the mixture was diluted by adding DCM, and filtered. The filtrate was concentrated to generate a crude product. The crude product was separated by thin layer chromatography to generate compound 49. 1H NMR (400MHz, CD3OD) δ = 9.14 (dd, J = 4.2, 9.5 Hz, 1H), 8.83 (d , J = 2.0 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 7.99 (d, J = 9.8 Hz, 1H ), 7.71 (s, 1H), 6.77 (s, 1H), 3.87 (s, 3H), 3.19 (dl, J = 13.2 Hz, 2H), 2.84-2 , 48 (m, 10H), 2.47-2.38 (m, 1H), 2.35 (s, 3H), 2.17 (s, 3H), 2.14 (s, 3H), 2, 09 (s, 3H), 2.03 (dl, J = 12.0 Hz, 2H), 1.79-1.66 (m, 2H), 1.34 (d, J = 6.8 Hz, 6H ). Example 50 Compound 50:
[564] [564] Compound 34 (0.1 g, 143 umol, 1 eq) and cyclopropylboronic acid (49.4 mg, 575.87 μmol, 4 eq) were added to a mixed solvent of toluene and water, and added with Pd ( OAc) 2 (3.23 mg, 14.4 μmol, 0.1 eq), tricyclohexylphosphine (8.07 mg, 28.7 μmol, 0.2 eq) and K2CO3 (76.4 mg, 359.9 μmol, 2.5 eq). The mixture was stirred at 90 ° C for 6 hours under the protection of nitrogen gas. After the reaction was completed, the reaction system was diluted by adding DCM and washed once with water, and the organic phase was dried and concentrated to generate a crude product. The crude product was separated by preparative acid high performance liquid chromatography to generate compound 50. 1H NMR (400MHz, CD3OD) δ = 9.19 (dd, J = 4.2, 9.5 Hz, 1H), 8, 82 (d, J = 1.7 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.52 (ls, 1H), 7.96 (d, J = 9.5 Hz, 1H), 7.88 (s, 1H), 7.70 (s, 1H), 6.73 (s, 1H), 3.85 (s, 3H), 3.18 (dl, J = 11 , 7 Hz, 2H), 3.02 (ls, 8H), 2.71 (tl, J = 11.7 Hz, 3H), 2.67 (s, 3H), 2.18-2.09 (m , 9H), 2.04 (dl, J = 11.0 Hz, 2H), 1.83-1.71 (m, 3H), 1.08-1.01 (m, 2H), 0.66- 0.60 (m, 2H). Example 51 Compound 51A:
[565] [565] Except for the replacement of the compound 2,4,5-trichloropyrimidine with the compound 5-bromo-2,4-dichloropyrimidine and replacement of compound 1C with compound 42B, compound 51A was prepared according to the method for preparing compound 1D .
[566] [566] Except for replacing compound 1D with compound 51A and replacing compound 1F with compound 34C, compound 51 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 9.31 (s, 1 H), 8.55 (dd, J = 9.17, 3.42 Hz, 1 H), 8.15 (s, 1 H), 8.07 (d, J = 9.17 Hz , 1 H), 7.67 (s, 1 H), 6.72 (s, 1 H), 3.84 (s, 3 H), 3.31 (dt, J = 3.21, 1.64 Hz, 2 H), 2.63-2.98 (m, 10 H), 2.52-2.59 (m, 1 H), 2.48 (s, 3 H), 2.12 (s, 3 H), 2.09 (s, 3 H), 2.04 (s, 3 H), 2.01 (ls, 2 H), 1.64-1.76 (m, 2 H). Example 52 Compound 52A:
[567] [567] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 1-bromo-2- compounds fluoro-4-methoxy-5-nitrobenzene and N, N-dimethylpiperidine-4-amine, compound 52A was prepared according to the method for preparing compound 1E. 52B:
[568] [568] Compound 52A (0.1 g, 279 μmol, 1 eq), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (234 mg, 1.40 mmol, 5 eq) were dissolved in a mixed solvent of DME and H2O, and added with Pd (PPh3) 4 (32.2 mg, 27.9 μmol, 0.1 eq) and Na2CO3 (59.1 mg, 558 μmol, 2 eq ). The reaction system was purged 3 times with nitrogen gas and stirred at 110 ° C for 12 hours under a nitrogen atmosphere. The reaction solution was diluted with DCM, washed three times with water and separated. The organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was evaporated to dryness to generate compound 52B. 52C Compound:
[569] [569] Except for the replacement of compound 49A with compound 52B, compound 52C was prepared according to the method for preparing compound 49B. Compound 52:
[570] [570] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 52C, compound 52 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 0.96 (d, J = 6.85 Hz, 6 H), 1.74 -1.86 (m, 2 H), 2.10 (dl, J = 12.47 Hz, 2 H), 2.14 (s , 3 H) 2.17 (s, 3 H), 2.64 (s, 6 H), 2.85 (tl, J = 11.19 Hz, 3 H), 3.13 (dl, J = 11 , 86 Hz, 3 H), 3.85 (s, 3 H), 6.86 (s, 1 H), 7.58 (s, 1 H), 7.96 (d, J = 9.29 Hz , 1 H), 8.26 (s, 1 H), 8.80 (d, J = 1.83 Hz, 1 H), 8.85 (d, J = 1.83 Hz, 1 H).
[571] [571] Except for the replacement of the compound 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with the compound cyclopropylboronic acid, compound 53A was prepared according to the method for preparing compound 52B. Compound 53B:
[572] [572] Except for the replacement of compound 1E by compound 53A, compound 53B was prepared according to the method for preparing compound 1F. Compound 53:
[573] [573] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 53B, compound 53 was prepared according to the method for preparing compound 1. 1H NMR (400 MHz, CD3OD) δ ppm 0.28 (dl, J = 3.91 Hz, 2 H), 0.59 (dl, J = 7.83 Hz, 2 H), 1.81 to 1.97 (m, 2 H), 2.16 (d , J = 14.43 Hz, 9 H), 2.78 (s, 6 H), 2.80 - 2.88 (m, 2 H), 3.05 (tl, J = 11.86 Hz, 1 H), 3.47 (dl, J = 12.23 Hz, 2 H), 3.86 (s, 3 H), 6.77 (s, 1 H), 7.17 (s, 1 H), 7.95 (d, J = 9.54 Hz, 1 H), 8.24 (s, 1 H), 8.56 (s, 1 H), 8.80 (d, J = 1.83 Hz, 1 H), 8.86 (d, J = 1.83 Hz, 1 H). Example 54 Compound 54A:
[574] [574] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane compounds for 1-chloro-2- fluoro-4-methoxy-5-nitrobenzene and 1-methyl-4- (piperidin-4-yl) piperazine, compound 54A was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CD3OD) δ = 6.79 (s, 1H), 6.68 (s, 1H), 3.84 (s, 3H), 3.24-2.76 (m, 8H), 2 , 72 (bs, 1H), 2.71-2.65 (m, 2H), 2.02 (dl, J = 10.8 Hz, 2H), 1.89-1.71 (m, 2H). Compound 54B:
[575] [575] Except for the replacement of compound 1E by compound 54A, compound 54B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CDCl3) δ = 8.04 (s, 1H), 6.56 (s, 1H), 4.02-3.91 (m, 3H), 3.65 (dl, J = 12, 1 Hz, 2H), 2.81-2.73 (m, 2H), 2.66 (ls, 4H), 2.56-2.37 (m, 5H), 2.31 (s, 3H), 1.98 (dl, J = 12.2 Hz, 2H), 1.84-1.71 (m, 2H). Compound 54:
[576] [576] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 11B, compound 54 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.88 ( dd, J = 4.2, 9.4 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8, 27 (s, 1H), 8.15 (d, J = 9.4 Hz, 1H), 7.97 (s, 1H), 6.78 (s, 1H), 3.90 (s, 3H), 3.39 (dl, J = 11.1 Hz, 2H), 2.95-2.56 (m, 10H), 2.48 (tl, J = 11.6 Hz, 1H), 2.41 (s , 3H), 2.15 (d, J = 14.4 Hz, 6H), 2.01 (dl, J = 11.6 Hz, 2H), 1.82-1.67 (m, 2H). Example 55 Compound 55A:
[577] [577] Except for the replacement of compound 52A with 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, compound 55A was prepared according to the method for preparing compound 52B. 1H NMR (400MHz, CDCl3) δ = 7.95 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 12.3 Hz, 1H), 5.36-5.26 (m , 2H), 3.97 (s, 3H), 2.14 (s, 3H). Compound 55B:
[578] [578] Except for respectively replacing the compounds of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane with compounds 55A and 1-methyl-4 - (piperidin-4-yl) piperazine, compound 55B was prepared according to the method for preparing compound 1E Compound 55C:
[579] [579] Except for the replacement of compound 49A with compound 55B, compound 55C was prepared according to the method for preparing compound 49B.
[580] [580] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 55C, compound 55 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.83 ( d, J = 1.8 Hz, 2H), 8.79 (d, J = 1.8 Hz, 1H), 8.24 (s, 1H), 7.94 (dl, J = 9.8 Hz, 1H), 7.53 (s, 1H), 6.84 (s, 1H), 3.83 (s, 3H), 3.45-3.37 (m, 2H), 3.08 (dl, J = 10.9 Hz, 2H), 2.91-2.47 (m, 1H), 2.79 (tl, J = 11.1 Hz, 8H), 2.41 (ls, 1H), 2.33 (s, 3H), 2.14 (d, J = 14.4 Hz, 6H), 2.03 (dl, J = 11.0 Hz, 2H), 1.77-1.64 (m, 2H) , 1.30 (s, 2H), 0.95 (dl, J = 6.8 Hz, 6H). Example 56 Compound 56A:
[581] [581] Except for the replacement of compound 52A with 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene, compound 56A was prepared according to the method for preparing compound 53A. 1H NMR (400MHz, CDCl3) δ = 7.57 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 11.4 Hz, 1H), 3.94 (s, 3H), 2.08-1.92 (m, 1H), 1.09 -0.94 (m, 2H), 0.81-0.65 (m, 2H). Compound 56B:
[582] [582] Except for respectively substituting 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene and 3-methyl-3,9-diazaspiro [5.5] undecane for compounds 56A and 1-methyl-4 - (piperidin-4-yl) piperazine, compound 56B was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CDCl3) δ = 7.51 (s, 1H), 6.57-6.48 (m, 1H), 3.94 (s, 3H), 3.63 (dl, J = 12, 0 Hz, 2H), 2.83-2.45 (m, 11H), 2.43-2.36 (m, 1H), 2.31 (s, 3H), 2.06-1.93 (m , 4H), 1.79-1.67 (m, 2H), 1.34-1.21 (m, 1H), 1.07-0.94 (m, 2H), 0.78-0.69 (m, 2H). Compound 56C:
[583] [583] Except for the replacement of compound 1E with compound 56B, compound 56C was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CDCl3) δ = 6.62-6.51 (m, 1H), 6.13 (s, 1H), 3.84-3.80 (m, 3H), 3.33-3, 21 (m, 2H), 2.81 - 2.40 (m, 12H), 2.32 (s, 3H), 1.93 (dl, J = 11.5 Hz, 2H), 1.78-1 , 68 (m, 2H), 1.31-1.17 (m, 1H), 0.92-0.84 (m, 2H), 0.67-0.53 (m, 2H). Compound 56:
[584] [584] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 56C, compound 56 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.85- 8.79 (m, 2H), 8.77 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 7.98-7.86 (m, 1H), 7.11 (s, 1H), 6.73 (s, 1H), 3.82 (s, 3H), 3.38 (dl, J = 11.7 Hz, 2H), 2.87-2.49 (m, 10H), 2.42 (tl, J = 11.6 Hz, 1H), 2.33 (s, 3H), 2.13 (d, J = 14.4 Hz, 6H), 2.02 (dl, J = 10.9 Hz, 2H), 1.79-1.64 (m, 2H), 1.42-1.07 (m, 2H), 0.89-0.86 (m, 2H), 0 , 56 (dl, J = 7.8 Hz, 2H), 0.25 (dl, J = 3.8 Hz, 2H). Example 57 Compound 57A:
[585] [585] Except for the substitution of the compound 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene with the compound 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene, compound 57A was prepared according to method for preparing compound 1E 1H NMR (400MHz, CDCl3) δ = 7.75 (s, 1H), 6.48 (s, 1H), 3.87 (s, 3H), 2.93-2.85 ( m, 4H), 2.33 (bs, 4H), 2.23 (s, 3H), 2.16 (s, 3H), 1.61-1.53 (m, 8H). Compound 57B:
[586] [586] Except for the replacement of compound 1E with compound 57A, compound 57B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CDCl3) δ = 6.62 (s, 1H), 6.58 (s, 1H), 3.85 (s, 3H), 3.61-3.50 (m, 2H), 2 , 82-2.75 (m, 4H), 2.41 (ls, 4H), 2.32 (s, 3H), 2.19 (s, 3H), 1.65-1.60 (m, 8H ). 57
[587] [587] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 57B, compound 56 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.89 ( dd, J = 4.2, 9.5 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.91 (d, J = 9.5 Hz, 1H),
[588] [588] Except for the substitution of the compound 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene with the compound 1-fluoro-5-methoxy-4-nitro-2-vinyl benzene, compound 58A was prepared according to the method for preparing compound 1E. 1H NMR (400MHz, CDCl3) δ = 8.03 (s, 1H), 6.64 (dd, J = 11.0, 17.9Hz, 1H), 6.45 (s, 1H), 5.61 ( dd, J = 1.1, 17.7 Hz, 1H), 5.19 (dd, J = 1.1, 10.9 Hz, 1H), 3.89 (s, 3H), 3.02-2 , 93 (m, 4H), 2.36-2.28 (m, 4H), 2.23 (s, 3H), 1.56 (td, J = 5.5, 15.1 Hz, 8H). 58B
[589] [589] Except for the replacement of compound 49A with compound 58A, compound 58B was prepared according to the method for preparing compound 49B. 58
[590] [590] Except for replacing compound 1D with compound 34A and replacing compound 1F with compound 58B, compound 58 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 8.88- 8.82 (m, 2H), 8.80 (d, J = 1.7 Hz, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.96 (d, J = 9.5 Hz, 1H), 7.64 (s, 1H), 6.83 (s, 1H), 3.85 (s, 3H), 3.13 (s, 4H), 2.92-2 , 83 (m, 4H), 2.79 (s, 3H), 2.49 (q, J = 7.6 Hz, 2H), 2.14 (d, J = 14.4 Hz, 6H), 1 , 85 (ls, 4H), 1.74 (ls, 4H), 0.84 (tl, J = 7.5 Hz, 3H).
[591] [591] Except for respectively replacing compounds 1D and 1F with compounds 8E and 3D, compound 59 was prepared according to the method of preparing compound 1. 1H NMR (400MHz, CD3OD) δ = 9.08 (d, J = 4.2, 9.5 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.53 (s , 1H), 8.04 (s, 1H), 7.92 (d, J = 9.5 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 6.63 (d , J = 2.3 Hz, 1H), 6.46 (d, J = 2.3, 8.7 Hz, 1H), 3.82 (s, 3H), 3.74-3.66 (m, 6H), 3.70 (d, J = 12.2 Hz, 2H), 2.69 (t, J = 11.6 Hz, 3H), 2.55 (s, 1H), 2.52 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.00 (d, J = 12.2 Hz, 2H), 1.67 (q, J = 3.7, 12 , 0 Hz, 2H). Example 60 Compound 60
[592] [592] Except for respectively replacing compounds 1D and 1F with compounds 34A and 3D, compound 59 was prepared according to the method of preparing compound 1. 1H
[593] [593] Except for respectively replacing compounds 1D and 1F with compounds 8E and 34C, compound 59 was prepared according to the method of preparing compound 1. 1H
[594] [594] Except for the replacement of compound 1D with compound 8E, compound 10 was prepared according to the method for preparing compound 1. 1H NMR (400MHz, DMSO-d6) δ = 12.92 (s, 1H), 9 , 08-8.94 (m, 1H), 8.87 (dd, J = 2.0, 9.2 Hz, 2H), 8.35 (s, 1H), 8.29- 8.21 (m , 2H), 8.04 (d, J = 9.6 Hz, 1H), 7.72 (s, 1H), 6.90 (s, 1H), 3.84 (s, 3H), 3.00 -2.92 (m, 4H), 2.56 -2.53 (m, 4H), 2.32 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.65-1.54 (m, 8H); LC-MS (ESI): m / z: 655.0 [M + 1]. Comparative Example 1 Comparative Compound 1A:
[595] [595] 4-Nitrobenzene-1,2-diamine (10 g, 65.30 mmol) was dissolved in HCOOH (9.03 g, 187.92 mmol, 7.40 ml), and added with the hydrochloric acid solution (5 M, 100.00 ml). The mixture was stirred at 110 ° C for 15 hours. After the reaction was completed, the reaction solution was adjusted to neutrality with 2M sodium hydroxide solution, and a large amount of solids was precipitated. After filtration, the filter cake was dried to generate a crude product. The crude product was recrystallized from water to generate compound 62A. 1H NMR (400MHz, CD3OD-d6) δ = 8.55 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 8.22-8.19 (m, 1H), 7 , 74 (d, J = 8.8 Hz, 1H). Comparative Compound 1B:
[596] [596] Except for the replacement of compound 1E with compound 62A, compound 62B was prepared according to the method for preparing compound 1F. 1H NMR (400MHz, CD3OD-d6) δ = 7.93 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.93 (s, 1H), 6.78- 6 , 75 (m, 1H). Comparative Compound 1C:
[597] [597] Compound 62B (7.8 g, 58.58 mmol) was dissolved in 100 ml of AcOH, and added with iodine (14.87 g, 58.58 mmol) and sodium acetate (9.61 g, 117.16 mmol), and the reaction was stirred at 25 ° C for 2 hours. After the reaction was completed, acetic acid was removed by concentration under reduced pressure, and the reaction mixture was adjusted to a pH of about 9 with 1M sodium hydroxide solution. The mixture was extracted with dichloromethane and washed consecutively with water and saturated brine, and the organic phase was collected and subjected to drying. After concentration, a crude product was obtained. The crude product was subjected to column chromatography to generate compound 62C. 1H NMR (400MHz, CD3OD-d6) δ = 8.00 (s, 1H), 7.34 (m, J = 8.8Hz, 1H), 6.84 (d, J = 8.8Hz, 1H). Comparative Compound 1D:
[598] [598] Except for replacing compound 1B with compound 62C and replacing compound 1F with compound 31B, compound 62D was prepared according to the method for preparing compound 1C. 1H NMR (400MHz, CD3OD-d6) δ = 7.88 (s, 1H), 7.44 (d, J = 5.2Hz, 1H), 6.61-6.58 (m, 1H), 2, 03 (s, 1H), 1.99 (s, 1H). Comparative Compound 1E:
[599] [599] Except for the replacement of compound 1C with compound 62D, compound 62E was prepared according to the method for preparing compound 1D. 1H NMR (400MHz, DMSO-d6) δ = 12.84 (s, 1H), 12.33 (s, 1H), 8.43-8.36 (m, 3H), 7.82 (d, J = 9.6 Hz, 1H), 2.03 (s, 3H), 1.99 (s, 3H). Comparative Compound 1:
[600] [600] Except for respectively replacing compounds 1D and 1F with compounds 62E and 3D, compound 62 was prepared according to the method to prepare compound 1. 1H NMR (400MHz, CD3OD-d4) d = 8.50 (s , 1H), 8.36-8.08 (m, 2H), 8.00 (s, 1H), 7.82-7.68 (m, 1H), 7.59 (ls, 1H), 6, 63 (d, J = 1.8 Hz, 1H), 6.24 (ls, 1H), 3.84 (s, 3H), 3.66 (dl, J = 11.9 Hz, 2H), 3, 13-2.78 (m, 8H), 2.76-2.56 (m, 6H), 2.01 (dl, J = 14.1 Hz, 8H), 1.80-1.59 (m, 2H). Experimental Example 1: Enzyme Activity Experiment (1) Experimental Procedure
[601] [601] Experimental Results: IC 50 of the compounds of the present application to inhibit the enzymatic activity of EGFR (Δ19del / T790M / C797S) was shown in Table 1.
[602] [602] Conclusion: it can be seen from Table 1 that the preferred compounds of the present application have strong inhibitory effects on the enzymatic activity of EGFR (Δ19del / T790M / C797S). Experimental Example 2: Enzyme Activity Experiment (2)
[603] [603] Data Analysis: Data analysis was performed as formula 205 using the XLfit software, to generate the IC50 of the compounds.
[604] [604] Experimental Results: The IC50 of the compounds of the present application to inhibit the enzymatic activity of EGFR (WT) and EGFR (C797S / T790M / L858R) were shown in Table 1.
[605] [605] Conclusion: It can be seen from Table 1 that the compounds of the present application have better selectivity for the enzymatic activity of EGFR (WT), and better inhibition of the enzymatic activity of EGFR (C797S / T790M / L858R). Table 1
[606] [606] Experimental Method: 1) Cell passage and culture (1) A431 medium: 88% DMEM + 10% fetal bovine serum + 1% L-glutamine + 1% double antibody (2) A431 cells were isolated and subcultured every 3 to 4 days, where the number of cells for the 3-day subculture was 5 and 6 cells per T75 culture flask, and the number of cells for the 4-day subculture was 3 and 6 cells per culture bottle of T75. 2) Day 1: cell plate preparation ⑴ Phosphate Buffer, trypsin, and culture medium was placed in a 37 ° C water bath to preheat.
[607] [607] Experimental Results:
[608] [608] The IC50 of compounds in the present application to inhibit A431 cell activity were shown in Table
[609] [609] Conclusion:
[610] [610] It can be seen from Table 2 that the compounds of the present application have satisfactory selectivity for A431 cells. Experimental Example 4: Cell Anti-Proliferation Experiment (2)
[611] [611] Experimental Method:
[612] [612] For Ba / F3 suspension cells (EGFR
[613] [613] The compounds to be tested were diluted with a three-fold concentration gradient using Echo, and concentrations of 10 doses of 10 μM to 0.508 nM were obtained. The compounds were transferred to a 384-well plate, with 125 nL of compound per well. The cell density was adjusted, and 2000 Ba / F3 cells (EGFR Δ19del / T790M / C797S) were seeded in each well in a 50 μl volume, incubated in a CO2 incubator at 37 ° C for 3 days. After 3 days, 25 μl of the detection reagent was added. The plate was incubated at room temperature for 10 minutes and then dealt with Envision.
[614] [614] Data Analysis:
[615] [615] The reading was converted to the inhibition rate (%) by the following formula: (Max-Sample) / (Max-Min) * 100% ((sample reading with maximum concentration) / (maximum concentration-minimum concentration) * 100%). IC50 data were obtained by adjusting the parametric curve (Model 205 in Activity Base, IDBS).
[616] [616] Experimental Results: The IC 50 values of the compounds of the present application to inhibit the activity of Ba / F3 cells (EGFR Δ19del / T790M / C797S) were shown in Table 2.
[617] [617] Conclusion:
[618] [618] It can be seen from Table 2 that the compounds of the present application have a satisfactory inhibitory effect on Ba / F3 cells with three mutations (EGFR Δ19del / T790M / C797S). Comparative Example 1 has almost no inhibitory effect on Ba / F3 cells with three mutations (EGFR Δ19del / T790M / C797S). Experimental Example 5: Cell Phosphorylation Inhibition Experiment
[619] [619] Experimental Method:
[620] [620] The test compounds and reference compounds were diluted with 100% DMSO to 10 mM or 1 mM, and then a gradient dilution was performed using Echo, 150 nl per well, with a concentration gradient three times and a ten-point dose response curve. The final concentration of the compounds was 100 μM or 10 μM. The suspension cells were centrifuged at 1,000 rpm for 5 minutes, suspended in Hanks' balanced salt solution, and added to a 384-well plate containing the compounds at 10 μl / 120K / well (the cell density of 1, 2 x 107), followed by centrifugation at 1,200 rpm for 30 s and incubation at 37 ° C for 30 minutes. 5 μl of EGF (which was diluted with Hanks' balanced room solution in 0.1% BSA) was added to each well, where the final concentration of EGF was 1 μM. The plate was centrifuged at 1,200 rpm for 30 s and incubated at 37 ° C for 20 minutes. 5 μl of 4X lysis buffer containing the blocking solution was added to each well and then the plate was centrifuged at 1,200 rpm for 30 s, and incubated at 37 ° C for 30 min. 5 μl of 0.25 × Eu and D2 mixture was added to each well, and the plate was centrifuged at 1,200 rpm for 30 s, sealed with light protection film, and incubated at room temperature (22-26 ° C) for 4h to 24h. The fluorescence signals were read at 665nm / 620nm by a microplate reader.
[621] [621] Experimental Results: The IC 50 values of the compounds of the present application to inhibit the phosphorylation activity of pEGFR Ba / F3 cells (EGFR Δ19del / T790M / C797S) were shown in Table 2.
[622] [622] Conclusion:
[623] [623] Since self-phosphorylation of EGFR, namely dimerization, can activate its kinase pathway located within the cell, and many tumors have high or abnormal EGFR expression, it has a very important role in the progress of malignant tumors. Inhibition of the activity of pEGFR Ba / F3 cells (Δ19del / T790M / C797S) can more intuitively show the inhibitory effect of a compound on phosphorylation of the cell model with three Ba / F3 mutants (Δ19del / T790M / C797S), with a purpose of specifically testing compounds in vitro. As can be seen from Table 2, the compounds of the present application have an excellent inhibitory effect on Ba / F3 cell phosphorylation activity (Δ19del / T790M / C797S), while Comparative Example 1 has almost no inhibitory effect on phosphorylation of Ba / F3 cells (Δ19del / T790M / C797S).
[624] [624] Experimental Method:
[625] [625] The in vivo efficacy experiment was carried out on bald BALB / c mice with Ba / F3-derived xenograft (CDX) (Δ19del / T790M / C797S) implanted subcutaneously. The female BALB / c mice, aged 6 to 8 weeks, 18 to 20 g of body weight, were housed in an SPF grade environment, and each cage was ventilated individually (5 mice per cage). All cages, accommodation and water were sterilized before use. All animals have free access to standard certified laboratory and commercial diets. A total of 48 mice acquired from the Beijing Weitonglihua company were used for the study. Each mouse was implanted with cells on the right flank, for tumor growth. The experiment was started when the average tumor volume reached approximately 80 to 120 mm3. The test compounds were administered orally daily, in which the compound Birgatinib (15 mg / kg), compound 34 (5 mg / kg, 15 mg / kg, 45 mg / kg, respectively) and compound 41 (5 mg / kg) kg, 15 mg / kg, 45 mg / kg, respectively) was administered for 13 consecutive days. The data were shown in Table 2. Tumor volume was measured twice a week with a two-dimensional caliper, measured in mm3 and calculated using the following formula: V = 0.5a × b2, where a and b are the long and short diameters of the tumor, respectively. The antitumor efficacy was determined by dividing the average increase in the tumor volume of the treated animals by the compound by the average increase in the tumor volume of the untreated animals. TGI (the tumor inhibition value) was used to assess the tumor growth inhibiting effect of test drugs in vivo, where the TGI of the Birgatinib compound group (15 mg / kg) was 8.6%, the TGI of the compound 34 group (45 mg / kg administered separately) was 101%, and the TGI of the compound 41 group (45 mg / kg administered separately) was 109%.
[626] [626] On Day 14 after administration to the groups for the efficacy experiment, plasma was collected from the mice by collecting submandibular blood before the last administration and 2 hours after the last administration, and plasma samples were collected from the mice in 1h, 4h,
[627] [627] Experimental Results: see Tables 3 and 4. Table 3 Tumor volume (mm3) Dosage compounds Day Day Day Day Day Day Test day 0 2 5 8 10 12 13 Control in N / A 85 143 315 582 765 929 1048 white Birgatinibe 15 mg / kg / day 84 124 292 477 646 880 965 5 mg / kg / day 84 108 212 395 505 748 881 Compound 34 15 mg / kg / day 84 76 107 126 176 292 326 45 mg / kg / day 84 56 32 35 42 73 68 5 mg / kg / day 84 103 203 348 485 707 814 Compound 41 15 mg / kg / day 84 68 69 82 115 146 211 45 mg / kg / day 84 47 24 7 4 0 0 Table 4 Brigatinibe compounds Compound Test compound 34 41 Test items Dosage (mg / kg / day) 15.0 15.0 15.0 T1 / 2 (h) 5.57 10.0 20.5 AUC0-last (nM.h ) 32808 57037 121718 Plasma (nM), 2h 5177 3553 6990 Tumor (nmol / kg), 2h 5807 16667 18567 Lung (nmol / kg), 2h 10217 32533 29567
[628] [628] Conclusion:
[629] [629] The compounds in the present application showed a strong antitumor effect in the bald mouse drug resistance model BALB / c with xenograft (CDX) derived from the subcutaneous implant with Ba / F3 (Δ19del / T790M / C797S). The half-life and amount of exposure in plasma and tissues for the compounds in this application have been significantly improved, indicating that the compounds in this application have satisfactory pharmacokinetic effects in mice. Experimental Example 7: in vivo pharmacodynamics study (2)
[630] [630] Experimental Method:
[631] [631] Experimental indicators and tumor measurement
[632] [632] The tumor diameter was measured twice a week with a neonium. The formula for calculating the tumor volume was: V = 0.5a × b2, where a and b represented the long and short diameters of the tumor, respectively.
[633] [633] The antitumor effect of the compound was assessed by TGI (%).
[634] [634] The relative tumor volume (RTV) was calculated according to the results of the tumor measurement. The calculation formula was RTV = Vt / V0, where V0 was the tumor volume measured during group administration (i.e., D0), and Vt was the tumor volume of the corresponding mice measured at a given time. The same day data were obtained for TRTV and CRTV.
[635] [635] TGI (%) reflected the rate of tumor growth inhibition. TGI (%) = [(1- (average tumor volume at the end of the administration in a treatment group average tumor volume at the start of the treatment group)) / (average tumor volume at the end of treatment in a treatment group) solvent-volume control group of average tumor at the beginning of treatment in the solvent control group)] × 100%.
[636] [636] After the end of the experiments, the tumor weight would be measured and the TGI (%) was calculated.
[637] [637] Experimental results: see Table 5. The TGI of compound 34 on day 23 was 100%. Table 5 Tumor volume (mm3) Compound dosage Day Day Day Day Day Day Day Test day 0 2 6 9 13 16 20 23 Control / 186 257 285 326 482 527 637 921 blank Compound 50 mg / kg 185 198 92 75 40 45 76 111 34 (days 0-
[638] [638] Conclusion:
[639] [639] In a PC-9 subcutaneously transplanted tumor model (Δ19del) in mice, the compounds of the present application have a significant inhibitory effect on tumor growth and tumor shrinkage effect, showing satisfactory antitumor effects.

权利要求:
Claims (29)
[1]
1. COMPOUND OF FORMULA (I) OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, characterized by the ring A to be selected from phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, C5-7 cycloalkenyl and C5-7 cycloalkyl, said phenyl, heteroaryl with 5 to 6 members, heterocycloalkyl with 5 to 7 members, C5-7 cycloalkenyl and C5-7 cycloalkyl are optionally substituted by R6; and the structural unit is not selected from:, R1 is selected from H, halogen, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyloxy and C3-6 cycloalkyloxy, where C1-6 alkyl, C1-6 heteroalkyl , C2-6 alkenyloxy and C3-6 cycloalkyloxy are optionally substituted by groups 1, 2 or 3 R;
R2 is selected from H, halogen, CN, OH, NO2, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, phenyl and heterocyclic groups with 3 to 14 members, with said NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkylyl, phenyl and heterocyclic group with 3 to 14 members are optionally replaced by groups 1, 2 or 3 R; R3 is selected from H, halogen, C1-6 alkoxy, C2-6 alkenyloxy, C3-6 cycloalkyloxy, -OC (= O) NH2, -OC (= O) NHR, - OC (= O) NRR, -NRC ( = O) OR, -NHC (= O) OR, -NHC (= O) OH, -O (CH2) nNRaRb, C1-6 alkyl, C3-6 cycloalkyl and 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms, said C1-6 alkyl, C3-6 cycloalkyl and 5- to 6-membered heterocyclic group containing 1, 2 or 3 N or O atoms are optionally substituted by groups 1, 2 or 3 R; n is selected from 0, 1, 2, 3 or 4; Ra and Rb are each independently selected from H, C1-5 alkyl and C1-5 heteroalkyl, and said C1-5 alkyl and C1-5 heteroalkyl are optionally substituted by groups 1, 2 or 3 R; or alternatively Ra and Rb are joined together to form a 5- to 6-membered heterocyclic ring; R4 and R5 are each independently selected from H, halogen, CN, NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and heterocyclic group with 5 to 6 members, being said NH2, C1-4 alkyl, C1-4 heteroalkyl, C3-6 cycloalkyl, phenyl and 5- to 6-membered heterocyclic group are optionally substituted by groups 1, 2 or 3 R;
or alternatively, R4 and R5 are linked together to form a 5-6 membered ring containing 1, 2 or 3 atoms independently selected from N, S or O, the 5-6 membered ring being optionally substituted by groups 1 , 2 or 3 R; each R6 is independently selected from H, halogen, CN, OH, NH2, C1-6 alkyl, C1-6 heteroalkyl, = O and = S; R7 and R8 are each independently selected from H or C1-6 alkyl; or alternatively R7 and R8 are joined together to form a 5- to 6-membered heterocyclic ring, and the 5- to 6-membered heterocyclic ring is optionally substituted by groups 1, 2 or 3 R; R is selected from halogen, CN, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl and heteroaryl with 5 to 6 members, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C4-6 cycloalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members, phenyl and heteroaryl with 5 to 6 members are optionally substituted by groups 1, 2 or 3 R '; R 'is selected from H, F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CF3, CHF2 and CH2F; "Hetero" represents a hetero atom or a group of hetero atoms, and each "hetero" group in said 5 to 6 membered heterocyclic group, 5 to 6 membered heterocyclic ring, 5 to 7 membered heterocycloalkyl, 3 to 14 membered heterocyclic group , C1-4 heteroalkyl, C1-5 heteroalkyl, C1-6 heteroalkyl, heterocycloalkyl with 3 to 6 members and heteroaryl with 5 to 6 members is independently selected from -C (= O) N (R) -, -N (R) -, -C (= NR) -, - (R) C = N-, -S (= O) 2N (R) -, -S (= O) N (R) -, N, -NH-, - O-, -S-, -C (= O) O-, -C (= O) -, -C (= S) -, - S (= O) -, -S (= O) 2- and - N (R) C (= O) N (R) -; in either case, as described above, the number of the heteroatom or heteroatomic group is each independently selected from 1, 2, or 3.
[2]
2. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 1, characterized in that R is selected from F, Cl, Br, I, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O , (CH3) 2N,,,,, and.
[3]
3. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized in that R1 is selected from H, halogen, C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy and C4-6 cycloalkyloxy, said C1-3 alkyl, C1-3 heteroalkyl, C2-5 alkenyloxy and C4-6 cycloalkyloxy being optionally substituted by groups 1, 2 or 3 R.
[4]
4. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 3, characterized in that R1 is selected from H, F, Cl, Br, I, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O , (CH3) 2CHO, and,
said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH, CH3O, CH3CH2O, CH3CH2CH2O, (CH3) 2CHO, and are optionally substituted by groups 1, 2 or 3 R.
[5]
5. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized in that R2 is selected from H, halogen, CN, OH, NO2, NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members, said NH2, C3-12 cycloalkyl and heterocycloalkyl with 3 to 12 members are optionally substituted by groups 1, 2 or 3 R.
[6]
6. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 5, characterized in that R2 is selected from H, halogen, CN, OH, NH2, NO2, -NHR, - N (R) 2,,,, and .
[7]
7. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 6, characterized in that R2 is selected from H, F, Cl, Br, CN, OH, NH2, NO2,,
,,,,,,,, -NHCH2CH3, -NHCH3, -N (CH3) 2 e.
[8]
8. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized in that R6 is selected from H, F, Cl, Br, CN, OH, NH2, CH3, CH3CH2, CH3CH2CH2, (CH3 ) 2CH, CH3O, = S and = O.
[9]
9. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized by the ring A to be selected from phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl, being whereas said phenyl, thienyl, pyridyl, pyrazinyl, pyrazolyl, cyclopentanonyl, cyclopentenyl, thiazolyl, isothiazolyl and pyrrolyl are optionally substituted by R6.
[10]
10. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 9, characterized by the structural unit being selected from,,,,,,
, and .
[11]
11. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized in that Ra and Rb are each independently selected from H, CH3, CH3CH2 and -S (= O) 2CH3, being whereas said CH3, CH3CH2 and -S (= O) 2CH3 are optionally substituted by groups 1, 2 or 3 R.
[12]
12. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 11, characterized in that Ra and Rb are each independently selected from H,, and -S (= O) 2CH3.
[13]
13. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 12, characterized in that R3 is selected from among, and.
[14]
14. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized in that R3 is selected from H, F, Cl, Br, CH3,
CH3CH2, (CH3) 2CH, e.g.
[15]
15. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized in that R5 is selected from H, F, Cl, Br, I, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH ,,,,,, and, said CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,, and are optionally substituted by groups 1, 2 or 3 R.
[16]
16. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 15, characterized in that R5 is selected from H, Cl, Br, CN, CH3, CH3CH2, CH3CH2CH2, (CH3) 2CH,,,,,,,,, and .
[17]
17. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized in that the structural unit is selected from,,,,,,, and.
[18]
18. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 or 2, characterized in that R7 and R8 are each independently selected from H or CH3.
[19]
19. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to any one of claims 1 to 18, characterized by being selected from,,,,
,,,, wherein R1 is according to any one of claims 1 to 4, R2 is according to any one of claims 1 to 2 or 5 to 7, R3 is according to any one of claims 1 to 2 or 13 to 14, R4 is according to claims 1 to 2 or 17, R5 is according to any one of claims 1 to 2 or 15 to 17, R6 is according to any of claims 1 to 2 or 8, R7 and R8 are according to any one of claims 1 to 2 or 18.
[20]
20. COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, according to claim 19, characterized by being selected from among
,,, wherein R1, R3, R4, R5, R7, R8, R and R 'are according to claim 19.
[21]
21. COMPOUND OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, characterized by being selected from among
.
[22]
22. PHARMACEUTICAL COMPOSITION, characterized in that it comprises a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 21, and a pharmaceutically acceptable carrier.
[23]
23. USE OF THE PHARMACEUTICALLY ACCEPTABLE COMPOUND OR SALT OF THE SAME, as defined in any one of claims 1 to 21, or of the pharmaceutical composition, as defined in claim 22, characterized in that it is in the preparation of a medicament for the treatment of cancer.
[24]
24. USE, according to claim 23, characterized in that the cancer is lung cancer.
[25]
25. USE OF THE PHARMACEUTICALLY ACCEPTABLE COMPOUND OR SALT OF THE SAME, as defined in any of claims 1 to 21, or of the pharmaceutical composition, as defined in claim 22, characterized in that it is in combination with an EGFR monoclonal antibody in the preparation of a medicine for cancer treatment.
[26]
26. CANCER TREATMENT METHOD, characterized in that it comprises administering to a subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 21, or of the pharmaceutical composition, as defined in claim 22 .
[27]
27. CANCER TREATMENT METHOD, characterized in that it comprises administering to a subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 21, or of the pharmaceutical composition, as defined in claim 22 , and an EGFR monoclonal antibody.
[28]
28. METHOD according to claim 27, characterized in that the EGFR monoclonal antibody is cetuximab.
[29]
29. CANCER TREATMENT METHOD, characterized in that it comprises administering to a subject a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 21, or of the pharmaceutical composition, as defined in claim 22 , and a MEK inhibitor.

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法律状态:
2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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