WO2024046512A2 - Nitrogen-containing macrocyclic compound, and preparation method therefor and medical use thereof - Google Patents

Nitrogen-containing macrocyclic compound, and preparation method therefor and medical use thereof Download PDF

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WO2024046512A2
WO2024046512A2 PCT/CN2023/135839 CN2023135839W WO2024046512A2 WO 2024046512 A2 WO2024046512 A2 WO 2024046512A2 CN 2023135839 W CN2023135839 W CN 2023135839W WO 2024046512 A2 WO2024046512 A2 WO 2024046512A2
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alkyl
group
alkoxy
deuterated
cycloalkyl
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PCT/CN2023/135839
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French (fr)
Chinese (zh)
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WO2024046512A3 (en
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沙汉明
齐旬通
张开清
张华洁
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中国医药研究开发中心有限公司
华润深圳湾发展有限公司科学技术研究分公司
深圳清华大学研究院
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Publication of WO2024046512A2 publication Critical patent/WO2024046512A2/en
Publication of WO2024046512A3 publication Critical patent/WO2024046512A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to nitrogen-containing macrocyclic compounds and their preparation methods and medicinal uses. Specifically, the present invention relates to macrocyclic compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing them, and their use as ALK kinase inhibitors for the treatment of diseases related to ALK kinase activity. .
  • Anaplastic lymphoma kinase is a member of the insulin receptor (IR) tyrosine kinase subfamily. It is mainly expressed in adult brain tissue and plays an important role in the development and function of the nervous system (Morris, Oncogene, 1997, 14, 2175-2188). Since the fusion of echinoderm microtubule-associated protein-like 4 to ALK (EML4-ALK) is found in 3-7% of non-small cell lung cancer (NSCLC) patients, ALK inhibitors are rapidly gaining ground as a viable new cancer therapy. Clinically developed and validated (Kinoshita K, Annu. Rep. Med. Chem, 2012, 47, 281-293). In addition, ALK amplification and mutations are also found in patients with neuroblastoma, inflammatory breast cancer, and ovarian cancer (Bergethon K, J. Clin. Oncol, 2012, 30, 863-870).
  • ALK inhibitors that have been marketed include first-generation crizotinib, second-generation ceritinib, alectinib, brigatinib, ensartinib, and third-generation lorlatinib. Clinical treatment has been significantly improved. Greatly extended the patient's survival period. The standard of care for patients with advanced ALK-positive NSCLC has recently shifted from sequential crizotinib, followed by more potent second-generation ALK inhibitors, to first-line second-generation ALK inhibitor therapy (Camidge DR, N.Engl. J. Med, 2012, 379, 2027-2039).
  • the third-generation lorlatinib has also been approved for first-line treatment due to its powerful therapeutic ability and excellent brain penetration, and can overcome the resistance of first- and second-generation ALK inhibitors (Alice T, J.Clin.Oncol, 2019 ). Although most patients derive clinical benefit from third-generation ALK inhibitors, acquired resistance invariably develops and leads to clinical relapse.
  • the inventors After painstaking research, the inventors have designed and synthesized a series of fused-ring macrocyclic compounds, which exhibit ALK kinase inhibitory activity and can be developed as drugs for preventing or treating diseases related to ALK kinase activity.
  • L is selected from -C(R 3 )(R 4 )-, -O- or -N(R 5 )-;
  • Y 1 and Y 2 are each independently selected from C or N;
  • Z 1 and Z 2 are each independently selected from C or N;
  • M 1 , M 2 and M 3 are each independently selected from C or N;
  • Ring A is selected from heterocyclyl, heteroaryl, and aryl, wherein the heterocyclyl, heteroaryl, and aryl are optionally further substituted by one or more R 6 ;
  • Ring B is selected from heteroaryl, aryl, heterocyclyl or cycloalkyl, wherein the heteroaryl, aryl, heterocyclyl or cycloalkyl is optionally further substituted by one or more R 7 ;
  • R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfide Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents of base, heterocyclyl, aryl and
  • R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfide Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents of base, heterocyclyl, aryl and
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group; the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally further selected from deuterium, halogen, amino , oxo group, thio group, nitro group, cyano group, hydroxyl group, mercapto group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, deuterated alkoxy group, haloalkoxy group, hydroxyalkyl group, alkenyl group , substituted by one or more substituents of alkynyl, cycl
  • R 5 is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl and heteroaryl are optionally further selected from deuterium, halogen, Amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl Substituted with one or more substituents of base, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Each R is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, thio, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , - (CH 2 ) q NR b R c , -(CH 2 ) q S(O) p R a , - (CH 2 )
  • any two adjacent R 6 together with the atoms to which they are connected form cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkyl Oxygen, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, thio, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , - (CH 2 ) q NR b R c , -(CH 2 ) q S(O) p R a , - (CH 2
  • two adjacent R 7s together with the atoms to which they are connected form cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further Selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy base, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O
  • R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
  • R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
  • p 0, 1 or 2;
  • q is an integer from 0 to 6.
  • the compound represented by the general formula (I) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein M 1 is a carbon atom.
  • the compound represented by the general formula (I) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof Or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof, or its medicinal salt,
  • Ring A, Ring B, Y 1 , Y 2 , Z 1 , Z 2 , R 1 and R 2 are as defined by the general formula (I).
  • the compound represented by the general formula (I) or the general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer, The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 2 are carbon atoms.
  • each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterium Alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl.
  • the compound represented by general formula (I) or general formula (II) of the present invention The compound or its meso, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt, wherein Ring A is selected from 5 to 10 membered heterogeneous compounds. Ring group, 5 to 10 membered heteroaryl or C 6 -C 10 aryl;, the 5 to 10 membered heterocyclyl, 5 to 10 membered heteroaryl or C 6 -C 10 aryl is optionally further replaced by a or replaced by multiple R 6 ;
  • Each R 6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, 6-10-membered aryl, 5- to 6-membered heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -( CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c ,
  • R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
  • R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
  • p 0, 1 or 2;
  • q is an integer from 0 to 6.
  • each R is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, Cyano group, oxo group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1 -6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl; preferably hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl.
  • any two adjacent R 6 and the atoms to which they are connected together form a C 3-6 cycloalkyl group, a 5- to 6-membered heterocyclyl group, a phenyl group and a 5- to 6-membered heteroaryl group, wherein the C 3-6 Cycloalkyl, 5 to 6 membered heterocyclyl, phenyl and 5 to 6 membered heteroaryl are optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, Mercapto group, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered
  • R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
  • R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
  • p 0, 1 or 2;
  • q is an integer from 0 to 6.
  • the membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl groups are optionally further selected from -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S (
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl Oxygen, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C3-6 cycloalkyl, 5- 6-membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally further selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C Substituted with one or more substituent
  • R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy Base, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally further selected from deuterium, Halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl
  • R b and R c together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclyl group, wherein the 5-8 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
  • p 1 or 2;
  • q is 0 or 1, preferably 0.
  • Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl; preferably R 8 is selected from deuterium, halogen, C 1-6 alkyl, C 1- 6 deuterated alkyl, C 1-6 haloalkyl;
  • each R 8 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl; preferably hydrogen, halogen , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-6 cycloalkyl.
  • Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a Substituted with one or more substituents, the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl are optionally further selected from deuterium, halogen, C
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl;
  • p 1 or 2.
  • Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C (O)R a , -C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c , -(CH 2 )
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, the C 1-6 alkyl Base, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group are optionally further substituted by C 1-6 alkoxy group;
  • R b is selected from hydrogen, C 1-6 alkyl
  • R c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl;
  • R b and R c together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group, wherein the 5-6 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
  • q is 0 or 1
  • p 1 or 2.
  • Ring A is selected from 5 to 10-membered heterocyclyl, 5 to 10-membered heteroaryl or C 6 -C 10 aryl; the 5 to 10-membered heterocyclyl, 5 to 10-membered heteroaryl or C 6 -C 10
  • the aryl group is optionally further substituted by one or more R 6 ;
  • Ring B is selected from C 6 -C 10 aryl or 5- to 10-membered heteroaryl; preferably 5- to 10-membered heteroaryl; further preferably 5-membered heteroaryl; wherein the aryl or heteroaryl is optionally further Replaced by one or more R 7 ;
  • Each R 6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl; preferably hydrogen, halogen, C 1 -6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl group.
  • the compound represented by general formula (I) or general formula (II) of the present invention The compound or its mesomer, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt, wherein,
  • Ring A is selected from Preferred from Ring A is optionally further substituted by one or more R 8 ;
  • Ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, preferably More preferred Ring B is optionally further substituted by one or more R 7 ;
  • Each R 8 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl; preferably hydrogen, halogen, C 1 -6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl group.
  • Ring A is selected from Preferred from Ring A is optionally further substituted by one or more R8 ;
  • Ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, preferably More preferred Ring B is optionally further substituted by one or more R 7 ;
  • Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl , OR a , C(O)R a and -S(O) p R a are substituted by one or more substituents, the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to The 10-membered aryl group and the 5-6 heteroaryl group are optionally further selected from deuterium, halogen, C 1-6 alkyl,
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl;
  • p 1 or 2;
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl group.
  • Ring A is selected from Ring A is optionally further substituted by one or more R8 ;
  • Ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, preferably More preferred Ring B is optionally further substituted by one or more R 7 ;
  • Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C (O)R a , -C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c , -(CH 2 )
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, the C 1-6 alkyl Base, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group are optionally further substituted by C 1-6 alkoxy group;
  • R c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl;
  • R b and R c together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group, wherein the 5-6 membered heterocyclic group
  • the radical is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy Substituted with one or more substituents of base, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • q is 0 or 1
  • p 1 or 2;
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl group.
  • the compound represented by the general formula (I) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III) or its meso, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt,
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently selected from C or N;
  • Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C or N;
  • Ring C is C 5-6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or phenyl;
  • R 9a and R 9b are each independently selected from hydrogen, deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, 6-10-membered aryl and 5- to 6-membered heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a ,
  • R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
  • R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkane alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl and heteroaryl optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy Substituted with one or more substituents of base, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroary
  • R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
  • p 0, 1 or 2;
  • q is an integer from 0 to 6;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2;
  • R 1 , R 2 and R 7 are as defined above.
  • the compound represented by the general formula (III) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein, Selected from
  • Each R 9b is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C (O)R a , -C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c , -(CH 2 )
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, the C 1-6 alkyl Base, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group are optionally further substituted by C 1-6 alkoxy group;
  • R b is selected from hydrogen, C 1-6 alkyl
  • R c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl;
  • R b and R c together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group, wherein the 5-6 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
  • n 0, 1 or 2;
  • q is 0 or 1
  • p 1 or 2.
  • R 7a and R 7b are each independently selected from hydrogen and C 1-6 alkyl.
  • the compound represented by the general formula (I) of the present invention or its meso, racemate, enantiomer, diastereomer, or its Mixture form, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IVA) or formula (IVB) or its meso, racemate, enantiomer, diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Y 3 and Y 4 are each independently selected from CH or N; preferably, Y 3 and Y 4 are both N, or one of Y 3 and Y 4 is N and the other is CH;
  • Ring C is a 5- to 6-membered heterocyclyl group; preferably tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidyl, or piperazinyl;
  • R 9a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen;
  • R 9b is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- Substituted with one or more substituent
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl;
  • R 7a is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl; preferably hydrogen or C 1-6 alkyl;
  • R 7b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl;
  • n 0, 1 or 2; preferably 1 or 2;
  • R 1 and R 2 are as defined by general formula (I).
  • the compound represented by the general formula (I) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or its Mixture form, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (VA) or formula (VB) or its meso, racemate, enantiomer, diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Y 3 and Y 4 are each independently selected from CH or N; preferably, Y 3 and Y 4 are both N, or one of Y 3 and Y 4 is N and the other is CH;
  • X 1 is selected from CR 9c or N;
  • X 2 is selected from CR 9c or N;
  • X 3 is selected from N and X 4 is selected from CR 9c ; or X 3 is selected from CR 9c and X 4 is selected from N;
  • R 9a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen;
  • R 9b is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- Substituted with one or more substituent
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl;
  • R 9c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl;
  • R 7a is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl; preferably hydrogen or C 1-6 alkyl;
  • R 7b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl;
  • n 0, 1 or 2; preferably 1 or 2; more preferably 1;
  • R 1 and R 2 are as defined by general formula (I).
  • the compound represented by the general formula (I) of the present invention or its meso, racemate, enantiomer, diastereomer, or its Mixture form, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (VA) or formula (VB) or its meso, racemate, enantiomer, diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Y 3 and Y 4 are each independently selected from CH or N; preferably, Y 3 and Y 4 are both N, or one of Y 3 and Y 4 is N and the other is CH;
  • X 1 is selected from CR 9c or N;
  • X 2 is selected from CR 9c or N;
  • X 3 is selected from N and X 4 is selected from CR 9c ; or X 3 is selected from CR 9c and X 4 is selected from N;
  • R 9a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen;
  • R 9b is each independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C(O )R a , -C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c , the C 3-6 cycloalkyl, 5
  • R 9c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C(O)R a , - C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c ; preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl;
  • R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, the C 1-6 alkyl, C 1-6 deuterated Alkyl and C 1-6 haloalkyl are optionally further substituted by C 1-6 alkoxy;
  • R b and R c are each independently selected from hydrogen and C 1-6 alkyl
  • R 7a is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl; preferably hydrogen or C 1-6 alkyl;
  • R 7b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl;
  • n 0, 1 or 2; preferably 1 or 2; more preferably 1;
  • q is 0 or 1
  • p 1 or 2;
  • R 1 and R 2 are as defined by general formula (I).
  • R 1 is selected From hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 deuterated alkyl Oxygen group, C 1 -C 6 haloalkoxy group, amino group; preferably hydrogen, deuterium, halogen, more preferably halogen, especially fluorine.
  • the general formula (I), general formula (II), general formula (III), general formula (IVA), general formula (IVB), general formula (VA), The compound represented by the general formula (VB) or its meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein R 2 Selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 deuterated Alkoxy, C 1 -C 6 haloalkoxy, amino; preferably hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl; more preferably C 1 -C 6 alkyl, especially methyl.
  • the general formula (I), general formula (II), general formula (III), general formula (IVA), general formula (IVB), general formula (VA), The compound represented by the general formula (VB) or its meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, C 3-6 cycloalkyl.
  • the general formula (I), general formula (II), general formula (III), general formula (IVA), general formula (IVB), general formula (VA), The compound represented by the general formula (VB) or its meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 haloalkyl Oxygen group, C 1-6 deuterated alkoxy group, C 3-6 cycloalkyl group.
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention further relates to a method for preparing the compound represented by the general formula (II) or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable form.
  • the method of using salt includes the following steps:
  • the compound of formula IIi undergoes an intramolecular coupling reaction to obtain the compound represented by the general formula (II) or its meso, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof;
  • the catalyst is preferably palladium acetate;
  • Ring A, Ring B, Y 1 , Y 2 , Z 1 , Z 2 , R 1 and R 2 are as defined by the general formula (I).
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or Its pharmaceutically acceptable salts, as well as pharmaceutically acceptable carriers or excipients.
  • the present invention further relates to a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same drug combination
  • a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same drug combination
  • the present invention further relates to a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same
  • a pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases associated with ALK kinase activity, preferably malignant neoplastic diseases, such as non-small cell lung cancer.
  • the present invention further relates to a method of inhibiting ALK kinase, which comprises administering to a patient in need thereof an effective amount of a compound according to the present invention or a meso, racemate, enantiomer, diastereomer thereof. enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.
  • the present invention further relates to a method for preventing and/or treating diseases related to ALK kinase activity, which comprises administering to a patient in need an effective amount of a compound according to the present invention or a mesoform or racemate thereof. , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, wherein the disease is preferably a malignant neoplastic disease, such as non- Small Cell Lung Cancer.
  • the present invention further relates to a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same Pharmaceutical compositions for use as ALK kinase inhibitors.
  • the present invention further relates to a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same
  • the compounds of the present invention can form pharmaceutically acceptable acid addition salts with acids.
  • the acid includes inorganic acid and organic acid, particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid , trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the compounds of the present invention can form pharmaceutically acceptable base addition salts with bases.
  • the base includes inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide, etc.
  • compositions containing the active ingredients may be in forms suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives, to provide medicinal preparations that are pleasing to the eye and palatable.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as Such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • water-soluble taste masking substances such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules may also be used in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Oral formulation is available in soft gelatin capsules.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Oral formulation is available in soft gelatin capsules.
  • Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or the condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanoethyleneoxycetylene Heptadecaethyleneoxy cetanol, or the condensation product of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with partial esters derived from fatty acids and hexitols Condensation products of anhydride-derived partial esters, such
  • Aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethylparaben or n-propylparaben
  • colorants such as ethylparaben or n-propylparaben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis, olive, sesame or coconut oil, or a mineral oil, such as liquid paraffin.
  • Oil suspensions may contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as described above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • the pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide. Products such as polyethylene oxide sorbitan monooleate.
  • Emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.
  • compositions of the invention may be in the form of sterile injectable aqueous solutions.
  • Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution.
  • Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerol and treated to form a microemulsion.
  • injectable solutions or microemulsions can be injected into the patient's bloodstream via localized mass injections.
  • solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used.
  • compositions of the present invention may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration.
  • the suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents such as those mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol.
  • sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose any blended fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may be used in the preparation of injectables.
  • the compounds of this invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore dissolve in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerol gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention can contain compounds and their pharmaceutically acceptable salts, hydrates or solvates as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepare it into a clinically acceptable dosage form.
  • the derivatives of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions, etc.
  • the compounds of the present invention can be used as the only active ingredient or can be used in combination with other drugs for treating diseases related to ALK kinase activity. Combination therapy is accomplished by administering the individual treatment components simultaneously, separately, or sequentially.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms Atoms of alkyl groups.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl base, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methyl Pentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment.
  • the substituents are preferably one or more of the following groups, independently selected from alkyl groups: Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl etc. Alkenyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a polycyclic group with 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom). It may contain one or more double bonds, but no ring is fully conjugated. pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is divided into a single spirocycloalkyl group, a double spirocycloalkyl group or a polyspirocycloalkyl group, and is preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocyclic alkyl group.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more rings. multiple double bonds, but No ring has a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl, etc. Cycloalkyl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalky
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • ring atoms excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably it contains 5 to 6 ring atoms, of which 1 to 6 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group with 5 to 20 membered monocyclic rings sharing one atom (called a spiro atom), in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • the spiroheterocyclyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably, it is 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5-membered/6-membered single spiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a polycyclic heterocyclic group with 5 to 20 members, each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds, but no ring has a fully conjugated pi electron system, one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O) m (where m is an integer 0 to 2), and the remaining rings
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but no ring has a completely shared bond.
  • a yoke of pi-electron systems in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • bridged heterocyclyl groups preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocyclyl groups include:
  • heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6 to 10 members, such as benzene base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, carboxyl group or carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and 5 to 14 ring atoms.
  • the heteroaryl group is preferably 5 to 10 yuan, containing 1 to 3 heteroatoms; more preferably, it is 5 yuan or 6 yuan, containing 1 to 2 heteroatoms; preferably, it is imidazolyl, furyl, thienyl, thiazolyl, pyridyl, etc.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, carboxyl group or carboxylate group.
  • bicyclic aryl refers to a carbocyclic aromatic system containing two rings, namely naphthyl; naphthyl may be substituted or unsubstituted.
  • bicyclic heteroaryl refers to an 8 to 10 membered bicyclic heteroaryl system containing 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. including but not limited to
  • fused ring refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other.
  • One or more rings may contain one or more double bonds, but at least one ring is not fully conjugated.
  • the fused ring is preferably a bicyclic fused ring, including but not limited to
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, carboxyl group or carboxylate group.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , hetero
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuteriums, wherein alkyl is as defined above.
  • deuterated alkoxy refers to an alkyl group substituted with one or more deuteriums, where alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • esters refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • sulfonyl refers to compounds containing the group -S(O) 2R , where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • the compounds of the present invention may be in deuterated form.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • Those skilled in the art can refer to relevant literature to synthesize deuterated forms of compounds.
  • Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds, or they may be synthesized using deuterated reagents using conventional techniques.
  • heterocyclyl optionally substituted by an alkyl group means that an alkyl group may but need not be present, and this description includes the case where the heterocyclyl is substituted by an alkyl group and the case where the heterocyclyl is not substituted by an alkyl group.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and have appropriate biological activity.
  • Step 1 Under reducing agent conditions, compound IIa undergoes a reduction reaction to obtain compound IIb.
  • the reducing agent is preferably diisobutylaluminum hydride;
  • Step 2 Under catalyst conditions, compound IIb and IIc undergo an addition reaction to obtain compound IId.
  • the catalyst is preferably isopropyl magnesium chloride;
  • Step 3 Under reducing agent conditions, compound IId undergoes a reduction reaction to obtain compound IIe.
  • the reducing agent is preferably triethylsilane;
  • Step 4 Under catalyst conditions, compound IIe and IIf undergo a coupling reaction to obtain compound IIg.
  • the catalyst is preferably tetrakis triphenylphosphine palladium;
  • Step 5 Under alkaline conditions, compound IIg undergoes a substitution reaction with 5-bromo-3-fluoro-2-nitropyridine to obtain compound IIh.
  • the alkaline conditions are preferably sodium hydride;
  • Step 6 Compound IIh undergoes a reduction reaction under reducing agent conditions to obtain compound IIi.
  • the reducing agent is preferably zinc powder;
  • Step 7 Under catalyst conditions, compound IIi undergoes an intramolecular coupling reaction to obtain compound (II).
  • the catalyst is preferably palladium acetate;
  • X is halogen
  • Ring A, Ring B, Y 1 , Y 2 , Z 1 , Z 2 , R 1 and R 2 are as defined by the general formula (I).
  • Figure 1A shows the efficacy results of the compound of Example 23 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R mice.
  • Figure 1B shows the efficacy results of the compound of Example 36 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R mice.
  • Figure 1C shows the efficacy results of the compound of Example 50 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R mice.
  • Figure 1D shows the efficacy results of the compound of Example 32 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R-L1196M mice.
  • Figure 1E shows the efficacy results of the compound of Example 36 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R-L1196M mice.
  • Figure 1F shows the efficacy results of the compound of Example 50 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R-L1196M mice.
  • Figure 1G shows the efficacy results of the compound of Example 50 of the present invention on subcutaneous transplanted tumors in BaF3 CD74-ROS1 G2032R mice.
  • Figure 2A shows the effect of the compound of Example 23 of the present invention on the body weight of BaF3 EML4-ALK-G1202R mice after subcutaneous tumor transplantation.
  • Figure 2B shows the effect of the compound of Example 36 of the present invention on the body weight of BaF3 EML4-ALK-G1202R mice after subcutaneous tumor transplantation.
  • Figure 2C shows the effect of the compound of Example 50 of the present invention on the body weight of BaF3 EML4-ALK-G1202R mice after subcutaneous tumor transplantation.
  • Figure 2D shows the effect of the compound of Example 32 of the present invention on the body weight of BaF3 EML4-ALK-G1202R-L1196M mice after subcutaneous tumor transplantation.
  • Figure 2E shows the effect of the compound of Example 36 of the present invention on the body weight of BaF3 EML4-ALK-G1202R-L1196M mice after subcutaneous tumor transplantation.
  • Figure 2F shows the effect of the compound of Example 50 of the present invention on the body weight of BaF3 EML4-ALK-G1202R-L1196M mice after subcutaneous tumor transplantation.
  • Figure 2G shows the effect of the compound of Example 50 of the present invention on the body weight of BaF3 CD74-ROS1 G2032R mice after subcutaneous tumor transplantation.
  • the compounds of the present invention are prepared using convenient starting materials and general preparation procedures.
  • the present invention provides typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, other reaction conditions can also be adopted unless otherwise stated. Optimized conditions may vary depending on the specific reactants or solvents used, but in general, reaction optimization steps and conditions can be determined.
  • protecting groups may be used in the present invention to protect certain functional groups to avoid unnecessary reactions.
  • Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, "Protecting Groups in Organic Preparations" by TW Greene and GMWuts (3rd edition, Wiley, New York, 1999 and references cited in the book) describes in detail the protection or deprotection of a large number of protecting groups.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts are given in units of 10 -6 (ppm). NMR was measured using a Brukerdps 300 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was tetramethylmethane. silane (TMS).
  • MS was measured using LC (Agilent 1260 Infinity)/MS (G6125B) mass spectrometer (Manufacturer: Agilent).
  • Preparative high-performance liquid chromatography used lc6000 high-performance liquid chromatography (manufacturer: Chuangxin Tongheng).
  • Thin layer chromatography uses Qingdao Ocean Chemical GF254 silica gel plate.
  • the specifications of the silica gel plate used in the thin layer chromatography for reaction monitoring are 0.20 mm ⁇ 0.25 mm.
  • the specifications of the silica gel plate used in the thin layer chromatography for separation and purification are It's 0.5mm.
  • Silica gel column chromatography uses Qingdao Ocean Silica Gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, Shanghai Bide, Nanjing Yaoshi and other companies.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
  • Reaction solvents organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, diethyl ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • NMP nitrogen-methylpyrrolidone
  • pyridine pyridine
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction time and conditions are, for example, one atmospheric pressure, between -78°C and 200°C, and can be completed in about 1 to 24 hours. If the reaction occurs overnight, the reaction time is generally 16 hours. There are no special instructions in the examples.
  • the reaction temperature is room temperature, which is 20°C to 30°C.
  • the reaction process in the embodiment is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing agent systems used in the reaction are: A: methylene chloride and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, The volume ratio of solvents is adjusted according to the polarity of the compounds.
  • the eluent system of column chromatography and the developing agent system of thin layer chromatography used to purify the compound include: A: methylene chloride and methanol system, B: petroleum ether and ethyl acetate system, the volume ratio of the solvent is based on Depending on the polarity of the compound, you can also add a small amount of alkalinity or acid such as triethylamine and trifluoroacetic acid. sex reagents.
  • Step 2 5-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazole-3-carboxylic acid ethyl ester (1b) preparation
  • Step 5 Preparation of 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylic acid ethyl ester (1e)
  • Step 7 (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)(2,2-dimethyl-2,3-dihydropyrazolo[5,1 -b]evil Preparation of azole-6-yl)methanol (1g)
  • Step 8 6-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyridine
  • Step 9 (R)-1-(2-(5-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl Preparation of )-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethane-1-ol (1i)
  • Step 10 (R)-6-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2 -Methyl-2H-1,2,3-triazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole ( Preparation of 1j)
  • Step 11 (R)-5-bromo-3-(1-(2-(5-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole) Preparation of -6-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (1k)
  • Step 12 (R)-3-fluoro-5,13,13,19-tetramethyl-13,14,17,19-tetrahydro-5H-7,11-(methylene)benzo[l] Oxazolo[3',2':1,5]pyrazolo[4,3-g][1,2,3]triazolo[4,5-j][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (1)
  • Step 3 (R)-1-(2-(4-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl Preparation of )-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)ethane-1-ol (2c)
  • Step 4 (R)-6-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-1 -methyl Preparation of -1H-pyrazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (2d)
  • reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, and concentrated under reduced pressure.
  • Step 5 (R)-5-bromo-3-(1-(2-(4-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole) Preparation of -6-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (2e)
  • Step 6 (R)-3-fluoro-5,13,13,19-tetramethyl-13,14,17,19-tetrahydro-5H-7,11-(methylene)benzo[l] Oxazo[3',2':1,5]pyrazolo[4,3-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene- Preparation of 8-amine(2)
  • Step 4 (S)-1-(2-(1-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl Preparation of )-3-methyl-1H-pyrazol-5-yl)-4-fluorophenyl)ethane-1-ol (3d)
  • Step 5 (S)-6-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-3 Preparation of -methyl-1H-pyrazol-1-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (3e)
  • reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, and concentrated under reduced pressure.
  • Step 6 (S)-5-bromo-3-(1-(2-(1-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole) Preparation of -6-yl)methyl)-3-methyl-1H-pyrazol-5-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (3f)
  • Step 7 (R)-3-fluoro-5,13,13,20-tetramethyl-13,14-dihydro-5H,17H-7,11-(methylene)benzo[l]oxazole And[3',2':1,5]pyrazolo[4,3-g]pyrazolo[1,5-j][1]oxa[4,10]diazacyclotetradecene -Preparation of 8-amine (3)
  • the preparation method was the same as in Example 3, except that 5-iodo-1H-pyrazole was used instead of 5-bromo-3-methyl-1H-pyrazole in step 3 to prepare compound 4.
  • Compound 5 was prepared using the same preparation method as Example 3, except that 5-bromo-1H-1,2,4-triazole was used instead of 5-bromo-3-methyl-1H-pyrazole in step 3.
  • Step 1 Preparation of tert-butyl 2-(5-bromo-2-methyl-2H-1,2,3-triazole-4-carbonyl)pyrrolidine-1-carboxylate (6a)
  • Step 2 Preparation of tert-butyl 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)pyrrolidine-1-carboxylate (6b)
  • Step 4 2-((5-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 Preparation of -methyl-2H-1,2,3-triazol-4-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (6d)
  • Step 6 (R)-1-(5-fluoro-2-(5-((6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-2-methyl-2H- Preparation of 1,2,3-triazol-4-yl)phenyl)ethane-1-ol (6f)
  • Step 7 (11R)-13-fluoro-11,17-dimethyl-2,3,11,17,19,19a-hexahydro-1H-5,9-(methylene)benzo[1] Pyrrolo[1,2-g][1,2,3]triazolo[4,5-j][1]oxa[4,7]diazacyclotetradecen-8-amine(6 ) preparation
  • Step 1 Preparation of 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (7a)
  • Step 2 Preparation of 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (7b)
  • Step 4 Preparation of 2-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (7d)
  • Step 5 Preparation of 2-formyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (7e)
  • Step 6 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(hydroxy)methyl)-6,7-dihydropyrazolo[1, Preparation of 5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (7f)
  • Step 7 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1 , Preparation of 5-a]pyrazine (7g)
  • Step 8 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-methyl-4,5,6,7-tetrahydro Preparation of pyrazole[1,5-a]pyrazine (7h)
  • Step 9 (R)-1-(5-fluoro-2-(2-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a Preparation of ]pyrazin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (7i)
  • Step 10 (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 -Methyl-2H-1,2,3-triazol-4-yl)methyl)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine
  • Step 11 (R)-5-bromo-3-(1-(5-fluoro-2-(2-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazole) And[1,5-a]pyrazin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (7k) preparation
  • Step 12 (R)-3-Fluoro-5,13,20-trimethyl-12,13,14,15,18,20-hexahydro-5H-7,11-(methylene)benzo[ l]pyrazino[1',2:1,5]pyrazolo[4,3-g][1,2,3]triazolo[4,15-j][1]oxa[4]
  • Example 8 (5R)-3-fluoro-5,20-dimethyl-14(trifluoromethyl)-13,14,15,16,18,20-hexahydro-5H-7,11-( Methylene)benzo[l]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,15-j][1 Preparation of ]oxa[4]azacyclotetradecene-8-amine (8)
  • Step 4 (1R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))-5,6,7,8-tetrahydroimidazo[1, Preparation of 2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (8d)
  • Step 5 2-((5-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 -Methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a ]
  • pyridine 8e
  • Step 6 5-bromo-3-((1R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))-5,6,7,8- Tetrahydroimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (8f ) preparation
  • Step 7 (5R)-3-fluoro-5,20-dimethyl-14(trifluoromethyl)-13,14,15,16,18,20-hexahydro-5H-7,11-(methyl Methyl)benzo[l]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,15-j][1] Preparation of oxa[4]azacyclotetradecene-8-amine (8)
  • Step 1 Preparation of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid ethyl ester (9a)
  • Step 4 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-5H-pyrazolo[5, Preparation of 1-b][1,3]oxazine (9d)
  • Step 5 (R)-1-(2-(5-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)methyl Preparation of )-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethane-1-ol (9e)
  • Step 6 (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2 -methyl -2H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (9f) preparation
  • reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, and concentrated under reduced pressure.
  • Step 7 (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine Preparation of -2-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (9g)
  • Step 8 (R)-3-fluoro-5,20-dimethyl-14,15,18,20-tetrahydro-5H,13H-7,11-(methylene)[1,3]oxazine And[3',2':1,5]pyrazolo[4,3-g]benzo[l][1,2,3]triazolo[4,5-j][1]oxa[ 4] Preparation of nitrogen heterocyclic tetradecene-8-amine (9)
  • Step 3 Preparation of: (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid methyl ester (10c)
  • Step 5 Preparation of 4,5-dihydro-7H-pyrazolo[1,5-c][1,3]oxazine-2-carbaldehyde (10e)
  • Step 6 (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(4,5-dihydro-7H-pyrazolo[1,5-c][1 ,3] Preparation of oxazin-2-yl)methanol (10f)
  • Step 7 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-dihydro-7H-pyrazolo[1, Preparation of 5-c][1,3]oxazine (10g)
  • Step 8 (R)-1-(2-(5-((4,5-dihydro-7H-pyrazolo[1,5-c][1,3]oxazin-2-yl)methyl Preparation of )-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethan-1-ol (10h)
  • Step 9 (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 -Methyl-2H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine ( Preparation of 10i)
  • Step 10 (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine Preparation of -2-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (10j)
  • Step 11 (R)-3-fluoro-5,20-dimethyl-12,13,18,20-tetrahydro-5H,15H-7,11-(methylene)[1,3]oxazine And[3',4':1,5]pyrazolo[4,3-g]benzo[1,2,3]triazolo[4,5-j][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (10)
  • Step 6 4-bromo-5-((6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl)-2-methyl-2H-1,2 , Preparation of 3-triazole (11f)
  • Step 7 (R)-1-(2-(5-((6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl)-2-methyl Preparation of -2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethan-1-ol (11g)
  • Step 8 (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl Preparation of (11h)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)-2-nitropyridine (11h)
  • Step 9 (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl) Preparation of (1,2,3-triazol-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (11i)
  • Step 1 (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-(trifluoromethyl)imidazo[1,2-a]pyridine-2- Preparation of methanol (12a)
  • Step 3 (R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl) Preparation of (12c)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (12c)
  • Step 4 (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 Preparation of -methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (12d)
  • Step 5 (R)-5-bromo-3-(1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))imidazo[1,2-a] Preparation of pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (12e)
  • Step 6 (R)-3-fluoro-5,20-dimethyl-14-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo[l ]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]aza Preparation of cyclotetradecen-8-amine (12)
  • Step 1 Preparation of ethyl 8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (13a)
  • the preparation method was the same as in Example 17, except that 4-methylpyridin-2-amine was used instead of 3-methylpyridin-2-amine to obtain compound 18.
  • Step 1 Preparation of 1,1-dichloro-3-((5-fluoropyridin-2-yl)amino)propan-2-one (19a)
  • the preparation method is the same as in Example 15, except that 5-fluoropyridin-2-amine is used instead of 5-methylpyridin-2-amine in step 1, and 3-bromo-4-iodo-1-methyl-1H- Pyrazole replaced 4,5-dibromo-2-methyl-2H-1,2,3-triazole in step 2 to prepare compound 20.
  • 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (5.00g, 18.6mmol), potassium phosphate (7.91g, 37.3mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (1.51g, 0.186mmol) and cyclopropylboronic acid (2.40g, 27.9mmol) were dissolved in 100ml dioxane and stirred at 100°C overnight.
  • the preparation method is the same as that of Example 21, except that 3-bromo-4-iodo-1-methyl-1H-pyrazole is used instead of 4,5-dibromo-2-methyl-2H-1,2,3-triazole. azole to prepare compound 22.
  • Imidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester (2.00g, 10.4mmol) was dissolved in dichloromethane (80mL), and then diisobutyl hydrogenation was slowly added at -78°C.
  • Aluminum (DIBAL-H) (20.8ml, 1M, 20.8mmol), continue stirring for 3 hours.
  • the reaction solution was quenched with water, extracted with EA (50mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 600 mg of the title compound as a yellow oil, yield: 40.0%.
  • Compound 24 was prepared by the same preparation method as Example 16, except that 5-methylpyrimidin-2-amine was used instead of 3-methylpyridin-2-amine in step 1.
  • Step 1 Preparation of pyrazolo[1,5-a]pyridine-2-carboxaldehyde (25a)
  • the preparation method is the same as that of Example 25, except that 3-bromo-4-iodo-1-methyl-1H-pyrazole is used instead of 4,5-dibromo-2-methyl-2H-1,2 in step 2. ,3-triazole to prepare compound 26.
  • Step 2 Preparation of 3-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-fluoro-2-methoxypyridine (27b)
  • Step 4 (5-((5-fluoro-2-hydroxypyridin-3-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (27d) preparation
  • Step 5 (R)-3-((5-(2-(1-((2-Amino-5-bromopyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2- Preparation of methyl-2H-1.2.3-triazol-4-yl)methyl)-5-fluoropyridin-2-ol (27e)
  • Step 6 (R)-3-((5-(2-(1-((2-Amino-5-bromopyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2- Preparation of methyl-2H-1,2,3-triazol-4-yl)methyl)-5-fluoropyridin-2-yl triflate (27f)
  • Step 7 (R)-3,13-difluoro-11,17-dimethyl-17,19-dihydro-11H-5,9-(methylene)benzo[1]pyrido[3, Preparation of 2-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecen-8-amine (27)
  • Step 1 Preparation of ethyl 6-(3,6-dihydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-2-carboxylate (28a)
  • 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.00g, 3.73mmol)
  • (3,6-dihydro-2H-pyran-4-yl)boronic acid 573 mg, 4.47 mmol
  • sodium carbonate 806 mg, 7.46 mmol
  • DPPF palladium dichloride 324 mg, 0.477 mmol
  • Step 2 Preparation of: (6-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (28b)
  • Step 1 Preparation of ethyl 6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate (29a)
  • Step 2 Preparation of ethyl 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-2-carboxylate (31b)
  • Step 1 Preparation of ethyl 6-fluoroimidazo[1,2-a]pyrimidine-2-carboxylate (32a)
  • Compound 35 was prepared by the same preparation method as Example 15, except that 5-(trifluoromethyl)pyrazin-2-amine was used instead of 3-methylpyridin-2-amine in step 1.
  • Step 1 Preparation of ethyl 5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (37a)
  • Step 1 Preparation of 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (38a)
  • Step 1 Preparation of 6-bromoimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (39a)
  • Step 2 Preparation of 6-cyclopropylimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (39b)
  • the preparation method is the same as in Example 12, except that 6-(methylsulfonyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (30d) is used instead of 6-(trifluoromethyl)imidazole in step 1 and [1,2-a]pyridine-2-carboxaldehyde to prepare compound 40.
  • Step 1 Preparation of 6-(cyclopropylsulfonyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (41a)
  • the preparation method is the same as in Example 12, except that 6-(cyclopropylsulfonyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (41b) is used instead of 6-(trifluoromethyl) in step 1 Imidazo[1,2-a]pyridine-2-carboxaldehyde gave compound 42.
  • the preparation method is the same as in Example 12, except that 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-2-carboxaldehyde (31c) is used instead of 6- in step 1 (Trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde gave compound 43.
  • Step 1 Preparation of 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxaldehyde (45a)
  • the preparation method is the same as in Example 12, except that 5-methylimidazo[1,2-a]pyrazine-2-carbaldehyde (44c) is used instead of 6-(trifluoromethyl)imidazo[1 ,2-a]pyridine-2-carboxaldehyde to prepare compound 46.
  • Step 1 Preparation of ethyl 6-vinylimidazo[1,2-b]pyridazine-2-carboxylate (47a)
  • Step 2 Preparation of ethyl 6-ethylimidazo[1,2-b]pyridazine-2-carboxylate (47b)
  • 6-Vinylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (47a) (1.80 g, 8.26 mmol) was dissolved in methanol (80 mL). Palladium on carbon (180 mg, 10% wt) was added. The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere, filtered with suction, and concentrated under reduced pressure to obtain 1.50 g of the title compound as a yellow oil, yield: 82.8%.
  • the preparation method is the same as Example 12, except that 6-ethylimidazo[1,2-b]pyridazine-2-carbaldehyde (47c) is used Substituting 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde in step 1, compound 48 was obtained.
  • the preparation method is the same as in Example 12, except that 6-(trifluoromethyl)imidazo[1,2-a] in step 1 is replaced with 6-methylimidazo[1,2-a]pyrimidine-2-carbaldehyde. ]pyridine-2-carboxaldehyde to prepare compound 49.
  • Step 1 Preparation of imidazo[1,2-a]pyrazine-2-carboxaldehyde (54a)
  • the preparation method is the same as Example 14, except that 6-(methylsulfonyl)imidazo[1,2-a]pyrazine-2-carbaldehyde is used instead of 6-(trifluoromethyl)imidazo[1 ,2-a]pyridine-2-carboxaldehyde to obtain compound 56.
  • Step 1 Preparation of 2-(dichloromethyl)-6,8-dimethyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (57a)
  • Step 1 Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6,8-difluoroimidazo[1,2-a]pyridine (59a)
  • Step 1 Preparation of 2-(dichloromethyl)-6,8-difluoro-2,3-dihydroimidazo[1,2-a]pyridin-2-ol (60a)

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Abstract

The present invention relates to a nitrogen-containing macrocyclic compound, and a preparation method therefor and the medical use thereof. Specifically, the present invention relates to a nitrogen-containing macrocyclic compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and the use thereof as an ALK kinase inhibitor for treating diseases related to ALK kinase activity. The definition of each substituent in general formula (I) is the same as that in the description.

Description

含氮大环类化合物及其制备方法和医药用途Nitrogen-containing macrocyclic compounds and their preparation methods and medicinal uses 技术领域Technical field
本发明涉及含氮大环类化合物及其制备方法和医药用途。具体地，本发明涉及通式(I)所示的大环类化合物，其制备方法，含有其的药物组合物，以及其作为ALK激酶抑制剂，用于治疗与ALK激酶活性相关的疾病的用途。The present invention relates to nitrogen-containing macrocyclic compounds and their preparation methods and medicinal uses. Specifically, the present invention relates to macrocyclic compounds represented by general formula (I), their preparation methods, pharmaceutical compositions containing them, and their use as ALK kinase inhibitors for the treatment of diseases related to ALK kinase activity. .
背景技术Background technique
间变性淋巴瘤激酶(ALK)是胰岛素受体(IR)酪氨酸激酶亚家族的成员。它主要在成年脑组织中表达，在神经系统的发育和功能中起着重要作用(Morris,Oncogene，1997，14，2175-2188)。由于在3-7％的非小细胞肺癌(NSCLC)患者中发现了棘皮动物微管相关蛋白样4与ALK(EML4-ALK)的融合，使得ALK抑制剂作为一种可行的新癌症疗法快速在临床上开发和验证(Kinoshita K，Annu.Rep.Med.Chem，2012，47，281-293)。另外，在神经母细胞瘤、炎症性乳腺癌和卵巢癌患者中也有ALK的扩增和突变(Bergethon K，J.Clin.Oncol，2012,30，863-870)。Anaplastic lymphoma kinase (ALK) is a member of the insulin receptor (IR) tyrosine kinase subfamily. It is mainly expressed in adult brain tissue and plays an important role in the development and function of the nervous system (Morris, Oncogene, 1997, 14, 2175-2188). Since the fusion of echinoderm microtubule-associated protein-like 4 to ALK (EML4-ALK) is found in 3-7% of non-small cell lung cancer (NSCLC) patients, ALK inhibitors are rapidly gaining ground as a viable new cancer therapy. Clinically developed and validated (Kinoshita K, Annu. Rep. Med. Chem, 2012, 47, 281-293). In addition, ALK amplification and mutations are also found in patients with neuroblastoma, inflammatory breast cancer, and ovarian cancer (Bergethon K, J. Clin. Oncol, 2012, 30, 863-870).
目前对于ALK融合突变NSCLC的治疗方式主要是ALK抑制剂的靶向治疗。已上市的ALK抑制剂包括一代的克唑替尼，二代的色瑞替尼、阿来替尼、布加替尼、恩沙替尼，以及三代的劳拉替尼，临床治疗明显改善，较大地延长了患者的生存期。对晚期ALK阳性NSCLC患者的标准治疗最近已经从序贯的克唑替尼，然后是更有效的第二代ALK抑制剂，转变为一线的二代ALK抑制剂治疗(Camidge DR，N.Engl.J.Med，2012，379，2027-2039)。而三代的劳拉替尼也凭借其强大的治疗能力以及优异的脑穿透性获批一线治疗，并且能克服一代和二代ALK抑制剂的耐药(Alice T，J.Clin.Oncol，2019)。虽然大多数患者从第三代ALK抑制剂中获得临床益处，但获得性耐药总是会发展并导致临床复发。The current treatment for NSCLC with ALK fusion mutations is mainly targeted therapy with ALK inhibitors. ALK inhibitors that have been marketed include first-generation crizotinib, second-generation ceritinib, alectinib, brigatinib, ensartinib, and third-generation lorlatinib. Clinical treatment has been significantly improved. Greatly extended the patient's survival period. The standard of care for patients with advanced ALK-positive NSCLC has recently shifted from sequential crizotinib, followed by more potent second-generation ALK inhibitors, to first-line second-generation ALK inhibitor therapy (Camidge DR, N.Engl. J. Med, 2012, 379, 2027-2039). The third-generation lorlatinib has also been approved for first-line treatment due to its powerful therapeutic ability and excellent brain penetration, and can overcome the resistance of first- and second-generation ALK inhibitors (Alice T, J.Clin.Oncol, 2019 ). Although most patients derive clinical benefit from third-generation ALK inhibitors, acquired resistance invariably develops and leads to clinical relapse.
一些研究报道了导致劳拉替尼耐药的复合突变(Recondo G，Clin.Cancer.Res，2020，26，242-255)。包括G1202R+L1196M在内的其他复合突变对所有的ALK抑制剂都有很高的抗药性(Hayato Mizuta，Nature communications，2021)。因此，临床上迫切需要开发能够克服这些耐药性复合突变的药物来解决临床上的未满足需求。Some studies have reported compound mutations leading to lorlatinib resistance (Recondo G, Clin. Cancer. Res, 2020, 26, 242-255). Other compound mutations, including G1202R+L1196M, are highly resistant to all ALK inhibitors (Hayato Mizuta, Nature communications, 2021). Therefore, there is an urgent clinical need to develop drugs that can overcome these drug-resistant compound mutations to address unmet clinical needs.
发明内容Contents of the invention
本发明人经过潜心研究，设计合成了一系列稠环大环类化合物，其显示出ALK激酶的抑制活性，可以被开发为预防或治疗与ALK激酶活性相关的疾病的药物。After painstaking research, the inventors have designed and synthesized a series of fused-ring macrocyclic compounds, which exhibit ALK kinase inhibitory activity and can be developed as drugs for preventing or treating diseases related to ALK kinase activity.
因此，一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、 非对映异构体、或其混合物形式、或其可药用盐，
Therefore, a compound represented by general formula (I) or its meso, racemate, enantiomer, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
其中，in,
L选自-C(R3)(R4)-、-O-或-N(R5)-；L is selected from -C(R 3 )(R 4 )-, -O- or -N(R 5 )-;
Y1和Y2各自独立地选自C或N；Y 1 and Y 2 are each independently selected from C or N;
Z1和Z2各自独立地选自C或N；Z 1 and Z 2 are each independently selected from C or N;
M1、M2和M3各自独立地选自C或N；M 1 , M 2 and M 3 are each independently selected from C or N;
环A选自杂环基、杂芳基、芳基，其中所述的杂环基、杂芳基、芳基任选进一步被一个或多个R6所取代；Ring A is selected from heterocyclyl, heteroaryl, and aryl, wherein the heterocyclyl, heteroaryl, and aryl are optionally further substituted by one or more R 6 ;
环B选自杂芳基、芳基、杂环基或环烷基，其中所述杂芳基、芳基、杂环基或环烷基任选进一步被一个或多个R7所取代；Ring B is selected from heteroaryl, aryl, heterocyclyl or cycloalkyl, wherein the heteroaryl, aryl, heterocyclyl or cycloalkyl is optionally further substituted by one or more R 7 ;
R1选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfide Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents of base, heterocyclyl, aryl and heteroaryl;
R2选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfide Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents of base, heterocyclyl, aryl and heteroaryl;
R3和R4各自独立地选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group; the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are optionally further selected from deuterium, halogen, amino , oxo group, thio group, nitro group, cyano group, hydroxyl group, mercapto group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, deuterated alkoxy group, haloalkoxy group, hydroxyalkyl group, alkenyl group , substituted by one or more substituents of alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5选自氢、氘、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、 氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；R 5 is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl and heteroaryl are optionally further selected from deuterium, halogen, Amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl Substituted with one or more substituents of base, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
每个R6各自独立地选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、硫代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；Each R is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, thio, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , - (CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O) R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R a ; the alkyl group, alkoxy group, alkenyl group, alkynyl group, ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl , one or more substituents of haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replace;
或者，任意相邻的两个R6与其相连的原子一起形成环烷基、杂环基、芳基和杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa中的一个或多个取代基所取代；Alternatively, any two adjacent R 6 together with the atoms to which they are connected form cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally Further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkyl Oxygen, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R a Substituted by one or more substituents;
每个R7各自独立地选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、硫代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, thio, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , - (CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O) R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R a ; the alkyl group, alkoxy group, alkenyl group, alkynyl group, ring Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl , one or more substituents of haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replace;
或者，相邻的两个R7与其相连的原子一起形成环烷基、杂环基、芳基和杂芳基，其中所述环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa中 的一个或多个取代基所取代；Alternatively, two adjacent R 7s together with the atoms to which they are connected form cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further Selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy base, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , - (CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R a Substituted by one or more substituents;
Ra选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者，Rb和Rc与它们相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
p为0、1或2；p is 0, 1 or 2;
q为0至6的整数。q is an integer from 0 to 6.
在一个优选的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中M1为碳原子。In a preferred embodiment, the compound represented by the general formula (I) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein M 1 is a carbon atom.
在另一个优选的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中M2和M3为碳原子。In another preferred embodiment, the compound represented by the general formula (I) of the present invention or its meso, racemate, enantiomer, diastereomer, or its mixtures, or pharmaceutically acceptable salts thereof, wherein M 2 and M 3 are carbon atoms.
在另一个优选的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中M2和M3为氮原子。In another preferred embodiment, the compound represented by the general formula (I) of the present invention or its meso, racemate, enantiomer, diastereomer, or its mixture form, or a pharmaceutically acceptable salt thereof, wherein M 2 and M 3 are nitrogen atoms.
在另一个优选的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中M2和M3之一为碳原子，另一个为氮原子。In another preferred embodiment, the compound represented by the general formula (I) of the present invention or its meso, racemate, enantiomer, diastereomer, or its in the form of a mixture, or a pharmaceutically acceptable salt thereof, in which one of M2 and M3 is a carbon atom and the other is a nitrogen atom.
在一个实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
In one embodiment, the compound represented by the general formula (I) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, Or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof, or its medicinal salt,
其中，环A、环B、Y1、Y2、Z1、Z2、R1和R2如通式(I)所定义。Among them, Ring A, Ring B, Y 1 , Y 2 , Z 1 , Z 2 , R 1 and R 2 are as defined by the general formula (I).
在一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中Z1和Z2为碳原子。In a preferred embodiment, the compound represented by the general formula (I) or the general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer, The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 2 are carbon atoms.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中Z1和Z2之一为碳原子，另一个为氮原子。In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, in which one of Z1 and Z2 is a carbon atom and the other is a nitrogen atom.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中Y1和Y2为碳原子。In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Y 1 and Y 2 are carbon atoms.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中Y1和Y2之一为碳原子，另一个为氮原子。In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein one of Y 1 and Y 2 is a carbon atom and the other is a nitrogen atom.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环B选自C6-C10芳基或5至10元杂芳基；优选5至10元杂芳基；进一步优选5元杂芳基；其中所述芳基或杂芳基任选进一步被一个或多个R7所取代；R7如通式(I)所定义。In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is selected from C 6 -C 10 aryl or 5 to 10-membered heteroaryl; preferably 5 to 10-membered heteroaryl; further preferably 5 Metaheteroaryl; wherein the aryl or heteroaryl is optionally further substituted by one or more R 7 ; R 7 is as defined by general formula (I).
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环B选自吡咯基、吡唑基、咪唑基、三唑基、四唑基，优选更优选环B任选进一步被一个或多个R7所取代；R7如通式(I)所定义。In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, preferably More preferred Ring B is optionally further substituted by one or more R 7 ; R 7 is as defined in general formula (I).
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中每个R7各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基；优选氢或C1-6烷基；更优选C1-6烷基。In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterium Alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化 合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自5至10元杂环基、5至10元杂芳基或C6-C10芳基；，所述5至10元杂环基、5至10元杂芳基或C6-C10芳基任选进一步被一个或多个R6所取代；In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention The compound or its meso, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt, wherein Ring A is selected from 5 to 10 membered heterogeneous compounds. Ring group, 5 to 10 membered heteroaryl or C 6 -C 10 aryl;, the 5 to 10 membered heterocyclyl, 5 to 10 membered heteroaryl or C 6 -C 10 aryl is optionally further replaced by a or replaced by multiple R 6 ;
每个R6各自独立地选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基、5至6元杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa；所述C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基、5至6元杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基和5至6元杂芳基的一个或多个取代基所取代；Each R 6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, 6-10-membered aryl, 5- to 6-membered heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -( CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R a ; the C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group , 5- to 6-membered heterocyclic group, 6-10-membered aryl group, 5- to 6-membered heteroaryl group optionally further selected from deuterium, halogen, amino, oxo group, thio group, nitro, cyano group, hydroxyl group , mercapto group, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy base, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl and 5 to 6 Substituted with one or more substituents of the heteroaryl group;
Ra选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者，Rb和Rc与它们相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
p为0、1或2；p is 0, 1 or 2;
q为0至6的整数。q is an integer from 0 to 6.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，每个R6各自独立地选自氢、氘、卤素、氨基、羟基、巯基、 氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-6环烷基、5至6元杂环基；优选氢、卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基。In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein each R is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, Cyano group, oxo group, C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1 -6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl; preferably hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自5至6元杂环基、5至6元杂芳基或苯基，所述5至6元杂环基、5至6元杂芳基或苯基进一步被一个或多个R6所取代；In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Ring A is selected from 5 to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or phenyl, and the 5- to 6-membered heterocyclyl , 5- to 6-membered heteroaryl or phenyl group further substituted by one or more R 6 ;
其中，任意相邻的两个R6与其相连的原子一起形成C3-6环烷基、5至6元杂环基、苯基和5至6元杂芳基，其中所述C3-6环烷基、5至6元杂环基、苯基和5至6元杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基、5至6元杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa和-(CH2)qNRbS(O)pRa中的一个或多个取代基所取代；Among them, any two adjacent R 6 and the atoms to which they are connected together form a C 3-6 cycloalkyl group, a 5- to 6-membered heterocyclyl group, a phenyl group and a 5- to 6-membered heteroaryl group, wherein the C 3-6 Cycloalkyl, 5 to 6 membered heterocyclyl, phenyl and 5 to 6 membered heteroaryl are optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, Mercapto group, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 membered Heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -( CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a and -(CH 2 ) q NR b S(O) p R a are substituted by one or more substituents;
Ra选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者，Rb和Rc与它们相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
p为0、1或2；p is 0, 1 or 2;
q为0至6的整数。q is an integer from 0 to 6.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、 或其可药用盐，其中，任意相邻的两个R6与其相连的原子一起形成5至6元杂环基、苯基和5至6元杂芳基，其中所述5至6元杂环基、苯基和5至6元杂芳基任选进一步被选自氘、卤素、氨基、羟基、巯基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-6环烷基、5至6元杂环基的一个或多个取代基所取代；优选被选自氢、卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基的一个或多个基团所取代。In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, Or a pharmaceutically acceptable salt thereof, wherein any two adjacent R 6 together with the atoms to which they are connected form a 5- to 6-membered heterocyclyl group, a phenyl group and a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group Cyclic groups, phenyl groups and 5 to 6 membered heteroaryl groups are optionally further selected from deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl base, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 3-6 cycloalkyl group, 5 to 6 membered heterocyclyl group Substituted with one or more substituents; preferably substituted with one or more groups selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl.
在另一个优选的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中任意相邻的两个R6与其相连的原子一起形成5至6元杂环基、苯基和5至6元杂芳基，其中所述5至6元杂环基、苯基和5至6元杂芳基任选进一步被选自-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa和-(CH2)qNRbS(O)pRa中的一个或多个取代基所取代；In another preferred embodiment, the compound represented by the general formula (I) of the present invention or its meso, racemate, enantiomer, diastereomer, or its Mixture form, or a pharmaceutically acceptable salt thereof, in which any two adjacent R 6 together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, phenyl and a 5- to 6-membered heteroaryl, wherein the 5 to 6 The membered heterocyclyl, phenyl and 5- to 6-membered heteroaryl groups are optionally further selected from -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S (O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a and -(CH 2 ) q NR b S(O) p R a represented by one or more substituents replace;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-6环烷基、5-6元杂环基、苯基和5-6元杂芳基，其中所述C3-6环烷基、5-6元杂环基、苯基和5-6元杂芳基任选进一步被选自氘、卤素、氨基、氰基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5-6杂环基、苯基和5-6元杂芳基中的一个或多个取代基所取代；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl Oxygen, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C3-6 cycloalkyl, 5- 6-membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally further selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C Substituted with one or more substituents in 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclyl, phenyl and 5-6 membered heteroaryl;
Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5-6元杂环基、苯基和5-6元杂芳基，其中所述C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5-6元杂环基、苯基和5-6元杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy Base, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally further selected from deuterium, Halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl , substituted by one or more substituents in alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者，Rb和Rc与它们相连的氮原子一起形成5-8元杂环基，其中所述5-8元杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclyl group, wherein the 5-8 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
p为1或2；p is 1 or 2;
q为0或1，优选0。q is 0 or 1, preferably 0.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、 或其可药用盐，其中，环A选自 优选自环A任选进一步被一个或多个R8所取代；In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from Preferred from Ring A is optionally further substituted by one or more R8 ;
每个R8各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基；优选地R8选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基；Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl; preferably R 8 is selected from deuterium, halogen, C 1-6 alkyl, C 1- 6 deuterated alkyl, C 1-6 haloalkyl;
优选地，每个R8各自独立地选自氢、氘、卤素、氨基、羟基、巯基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-6环烷基、5至6元杂环基；优选氢、卤素、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、C3-6环烷基。Preferably, each R 8 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl; preferably hydrogen, halogen , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 3-6 cycloalkyl.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自 优选自环A任选进一步被一个或多个R8所取代；In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from Preferred from Ring A is optionally further substituted by one or more R8 ;
每个R8各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、ORa、C(O)Ra和-S(O)pRa中的一个或多个取代基所取代，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a Substituted with one or more substituents, the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl are optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy Substituted by one or more substituents;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl;
p为1或2。p is 1 or 2.
在另一个优选的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自 环A任选进一步被一个或多个R8所取代；In another preferred embodiment, the compound represented by general formula (I) or general formula (II) of the present invention or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from Ring A is optionally further substituted by one or more R8 ;
每个R8各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、-(CH2)qRa、-(CH2)qORa、-C(O)Ra、-C(O)NRbRc、-S(O)pRa和-(CH2)qNRbRc、-(CH2)qNRbS(O)pRa，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C (O)R a , -C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c , -(CH 2 ) q NR b S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl are optionally further selected from deuterium, halogen, C 1-6 alkyl, One or more substituents of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy replace;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-6环烷基、5-6元杂环基，所述C1-6烷基、C1-6氘代烷基、C1-6卤代烷基任选进一步被C1-6烷氧基取代；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, the C 1-6 alkyl Base, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group are optionally further substituted by C 1-6 alkoxy group;
Rb选自氢、C1-6烷基；R b is selected from hydrogen, C 1-6 alkyl;
Rc选自氢、C1-6烷基、C3-6环烷基、5-6元杂环基；R c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl;
或者，Rb和Rc与它们相连的氮原子一起形成5-6元杂环基，其中所述5-6元杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group, wherein the 5-6 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
q为0或1；q is 0 or 1;
p为1或2。p is 1 or 2.
在一个具体的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In a specific embodiment, the compound represented by the general formula (I) or the general formula (II) or its meso, racemate, enantiomer, diastereomer, form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,
环A选自5至10元杂环基、5至10元杂芳基或C6-C10芳基；所述5至10元杂环基、5至10元杂芳基或C6-C10芳基任选进一步被一个或多个R6所取代；Ring A is selected from 5 to 10-membered heterocyclyl, 5 to 10-membered heteroaryl or C 6 -C 10 aryl; the 5 to 10-membered heterocyclyl, 5 to 10-membered heteroaryl or C 6 -C 10 The aryl group is optionally further substituted by one or more R 6 ;
环B选自C6-C10芳基或5至10元杂芳基；优选5至10元杂芳基；进一步优选5元杂芳基；其中所述芳基或杂芳基任选进一步被一个或多个R7所取代；Ring B is selected from C 6 -C 10 aryl or 5- to 10-membered heteroaryl; preferably 5- to 10-membered heteroaryl; further preferably 5-membered heteroaryl; wherein the aryl or heteroaryl is optionally further Replaced by one or more R 7 ;
每个R6各自独立地选自氢、氘、卤素、氨基、羟基、巯基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-6环烷基、5至6元杂环基；优选氢、卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基；Each R 6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl; preferably hydrogen, halogen, C 1 -6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;
每个R7各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基；优选氢或C1-6烷基；更优选C1-6烷基。Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl group.
在另一个具体的实施方案中，本发明所述的通式(I)或通式(II)所示的化 合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another specific embodiment, the compound represented by general formula (I) or general formula (II) of the present invention The compound or its mesomer, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt, wherein,
环A选自 优选自 环A任选进一步被一个或多个R8所取代；Ring A is selected from Preferred from Ring A is optionally further substituted by one or more R 8 ;
环B选自吡咯基、吡唑基、咪唑基、三唑基、四唑基，优选 更优选环B任选进一步被一个或多个R7所取代；Ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, preferably More preferred Ring B is optionally further substituted by one or more R 7 ;
每个R8各自独立地选自氢、氘、卤素、氨基、羟基、巯基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-6环烷基、5至6元杂环基；优选氢、卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基；Each R 8 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl; preferably hydrogen, halogen, C 1 -6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl;
每个R7各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基；优选氢或C1-6烷基；更优选C1-6烷基。Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl group.
在另一个具体的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another specific embodiment, the compound represented by general formula (I) or general formula (II) or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein,
环A选自 优选自 环A任选进一步被一个或多个R8所取代；Ring A is selected from Preferred from Ring A is optionally further substituted by one or more R8 ;
环B选自吡咯基、吡唑基、咪唑基、三唑基、四唑基，优选 更优选环B任选进一步被一个或多个R7所取代；Ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, preferably More preferred Ring B is optionally further substituted by one or more R 7 ;
每个R8各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、 C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、ORa、C(O)Ra和-S(O)pRa中的一个或多个取代基所取代，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl , OR a , C(O)R a and -S(O) p R a are substituted by one or more substituents, the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to The 10-membered aryl group and the 5-6 heteroaryl group are optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Substituted with one or more substituents of C 1-6 deuterated alkoxy group or C 1-6 haloalkoxy group;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl;
p为1或2；p is 1 or 2;
每个R7各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基；优选氢或C1-6烷基；更优选C1-6烷基。Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl group.
在另一个具体的实施方案中，本发明所述的通式(I)或通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another specific embodiment, the compound represented by general formula (I) or general formula (II) or its meso, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein,
环A选自 环A任选进一步被一个或多个R8所取代；Ring A is selected from Ring A is optionally further substituted by one or more R8 ;
环B选自吡咯基、吡唑基、咪唑基、三唑基、四唑基，优选 更优选环B任选进一步被一个或多个R7所取代；Ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, preferably More preferred Ring B is optionally further substituted by one or more R 7 ;
每个R8各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、-(CH2)qRa、-(CH2)qORa、-C(O)Ra、-C(O)NRbRc、-S(O)pRa和-(CH2)qNRbRc、-(CH2)qNRbS(O)pRa，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C (O)R a , -C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c , -(CH 2 ) q NR b S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl are optionally further selected from deuterium, halogen, C 1-6 alkyl, One or more substituents of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy replace;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-6环烷基、5-6元杂环基，所述C1-6烷基、C1-6氘代烷基、C1-6卤代烷基任选进一步被C1-6烷氧基取代；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, the C 1-6 alkyl Base, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group are optionally further substituted by C 1-6 alkoxy group;
Rc选自氢、C1-6烷基、C3-6环烷基、5-6元杂环基；R c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl;
或者，Rb和Rc与它们相连的氮原子一起形成5-6元杂环基，其中所述5-6元杂环 基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group, wherein the 5-6 membered heterocyclic group The radical is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy Substituted with one or more substituents of base, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
q为0或1；q is 0 or 1;
p为1或2；p is 1 or 2;
每个R7各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基；优选氢或C1-6烷基；更优选C1-6烷基。Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group; preferably hydrogen or C 1-6 alkyl group; more preferably C 1-6 alkyl group.
在一个具体的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
In a specific embodiment, the compound represented by the general formula (I) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III) or its meso, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt,
其中，in,
Y1、Y2、Y3、Y4、Y5各自独立地选自C或N；Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently selected from C or N;
Z1、Z2、Z3、Z4、Z5各自独立地选自C或N；Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C or N;
环C为C5-6环烷基、5至6元杂环基、5至6元杂芳基或苯基；Ring C is C 5-6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or phenyl;
R9a和R9b各自独立地选自氢、氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基和5至6元杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa中的一个或多个取代基所取代；R 9a and R 9b are each independently selected from hydrogen, deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, 6-10-membered aryl and 5- to 6-membered heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R is substituted by one or more substituents in a ;
Ra选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷 基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkane alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl and heteroaryl optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy Substituted with one or more substituents of base, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
或者，Rb和Rc与它们相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
p为0、1或2；p is 0, 1 or 2;
q为0至6的整数；q is an integer from 0 to 6;
m为0、1、2或3；m is 0, 1, 2 or 3;
n为0、1或2；n is 0, 1 or 2;
R1、R2、R7如前所定义。R 1 , R 2 and R 7 are as defined above.
在一个优选的实施方案中，本发明所述的通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，选自 In a preferred embodiment, the compound represented by the general formula (III) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein, Selected from
每个R9b各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、-(CH2)qRa、-(CH2)qORa、-C(O)Ra、-C(O)NRbRc、-S(O)pRa和-(CH2)qNRbRc、-(CH2)qNRbS(O)pRa，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；Each R 9b is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C (O)R a , -C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c , -(CH 2 ) q NR b S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl are optionally further selected from deuterium, halogen, C 1-6 alkyl, One or more substituents of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy replace;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-6环烷基、5-6元杂环基，所述C1-6烷基、C1-6氘代烷基、C1-6卤代烷基任选进一步被C1-6烷氧基取代；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, the C 1-6 alkyl Base, C 1-6 deuterated alkyl group, C 1-6 haloalkyl group are optionally further substituted by C 1-6 alkoxy group;
Rb选自氢、C1-6烷基； R b is selected from hydrogen, C 1-6 alkyl;
Rc选自氢、C1-6烷基、C3-6环烷基、5-6元杂环基；R c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl;
或者，Rb和Rc与它们相连的氮原子一起形成5-6元杂环基，其中所述5-6元杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group, wherein the 5-6 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
m为0、1或2；m is 0, 1 or 2;
q为0或1；q is 0 or 1;
p为1或2。p is 1 or 2.
在另一个优选的实施方案中，本发明所述的通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another preferred embodiment, the compound represented by the general formula (III) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or its Mixtures, or pharmaceutically acceptable salts thereof, wherein:
选自 Selected from
R7a和R7b各自独立地选自氢和C1-6烷基。R 7a and R 7b are each independently selected from hydrogen and C 1-6 alkyl.
在另一个具体的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IVA)或式(IVB)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
In another specific embodiment, the compound represented by the general formula (I) of the present invention or its meso, racemate, enantiomer, diastereomer, or its Mixture form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IVA) or formula (IVB) or its meso, racemate, enantiomer, diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中，in,
Y3、Y4各自独立地选自CH或N；优选地，Y3和Y4均为N，或者Y3和Y4之一为N，另一个为CH； Y 3 and Y 4 are each independently selected from CH or N; preferably, Y 3 and Y 4 are both N, or one of Y 3 and Y 4 is N and the other is CH;
环C为5至6元杂环基；优选四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基；Ring C is a 5- to 6-membered heterocyclyl group; preferably tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidyl, or piperazinyl;
R9a选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基；优选氢或C1-6烷基；更优选氢；R 9a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen;
R9b各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、ORa、C(O)Ra和-S(O)pRa，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；优选氢、C1-6烷基、C1-6卤代烷基；更优选C1-6烷基、C1-6卤代烷基；R 9b is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- Substituted with one or more substituents of 6 deuterated alkoxy, C 1-6 haloalkoxy; preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl; more preferably C 1-6 alkyl , C 1-6 haloalkyl;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl;
R7a选自氢、氘、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基；优选氢或C1-6烷基；R 7a is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl; preferably hydrogen or C 1-6 alkyl;
R7b选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基；R 7b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl;
m为0、1或2；优选1或2；m is 0, 1 or 2; preferably 1 or 2;
R1、R2如通式(I)所定义。R 1 and R 2 are as defined by general formula (I).
在另一个具体的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(VA)或式(VB)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，

In another specific embodiment, the compound represented by the general formula (I) of the present invention or its mesobody, racemate, enantiomer, diastereomer, or its Mixture form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VA) or formula (VB) or its meso, racemate, enantiomer, diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中，in,
Y3、Y4各自独立地选自CH或N；优选地，Y3和Y4均为N，或者Y3和Y4之一为N，另一个为CH；Y 3 and Y 4 are each independently selected from CH or N; preferably, Y 3 and Y 4 are both N, or one of Y 3 and Y 4 is N and the other is CH;
X1选自CR9c或N；X 1 is selected from CR 9c or N;
X2选自CR9c或N；X 2 is selected from CR 9c or N;
X3选自N且X4选自CR9c；或者X3选自CR9c且X4选自N；X 3 is selected from N and X 4 is selected from CR 9c ; or X 3 is selected from CR 9c and X 4 is selected from N;
R9a选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基；优选氢或C1-6烷基；更优选氢；R 9a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen;
R9b各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、ORa、C(O)Ra和-S(O)pRa，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；R 9b is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- Substituted with one or more substituents of 6 deuterated alkoxy and C 1-6 haloalkoxy;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl;
R9c选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基；优选氢、C1-6烷基、C1-6卤代烷基；R 9c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl;
R7a选自氢、氘、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基；优选氢或C1-6烷基；R 7a is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl; preferably hydrogen or C 1-6 alkyl;
R7b选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基；R 7b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl;
n为0、1或2；优选1或2；更优选1；n is 0, 1 or 2; preferably 1 or 2; more preferably 1;
R1、R2如通式(I)所定义。R 1 and R 2 are as defined by general formula (I).
在另一个具体的实施方案中，本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(VA)或式(VB)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
In another specific embodiment, the compound represented by the general formula (I) of the present invention or its meso, racemate, enantiomer, diastereomer, or its Mixture form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VA) or formula (VB) or its meso, racemate, enantiomer, diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中，in,
Y3、Y4各自独立地选自CH或N；优选地，Y3和Y4均为N，或者Y3和Y4之一为N，另一个为CH；Y 3 and Y 4 are each independently selected from CH or N; preferably, Y 3 and Y 4 are both N, or one of Y 3 and Y 4 is N and the other is CH;
X1选自CR9c或N；X 1 is selected from CR 9c or N;
X2选自CR9c或N；X 2 is selected from CR 9c or N;
X3选自N且X4选自CR9c；或者X3选自CR9c且X4选自N；X 3 is selected from N and X 4 is selected from CR 9c ; or X 3 is selected from CR 9c and X 4 is selected from N;
R9a选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基；优选氢或C1-6烷基；更优选氢；R 9a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen;
R9b各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、-(CH2)qRa、-(CH2)qORa、-C(O)Ra、-C(O)NRbRc、-S(O)pRa和-(CH2)qNRbRc，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代； R 9b is each independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C(O )R a , -C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c , the C 3-6 cycloalkyl, 5 to 6-membered heterocycle base, 6 to 10 membered aryl group, 5 to 6 heteroaryl group optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1 Substituted with one or more substituents of -6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy;
R9c选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、-(CH2)qRa、-(CH2)qORa、-C(O)Ra、-C(O)NRbRc、-S(O)pRa和-(CH2)qNRbRc；优选氢、C1-6烷基、C1-6卤代烷基；R 9c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C(O)R a , - C(O)NR b R c , -S(O) p R a and -(CH 2 ) q NR b R c ; preferably hydrogen, C 1-6 alkyl, C 1-6 haloalkyl;
Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-6环烷基，所述C1-6烷基、C1-6氘代烷基、C1-6卤代烷基任选进一步被C1-6烷氧基取代；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, the C 1-6 alkyl, C 1-6 deuterated Alkyl and C 1-6 haloalkyl are optionally further substituted by C 1-6 alkoxy;
Rb和Rc各自独立地选自氢和C1-6烷基；R b and R c are each independently selected from hydrogen and C 1-6 alkyl;
R7a选自氢、氘、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基；优选氢或C1-6烷基；R 7a is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl; preferably hydrogen or C 1-6 alkyl;
R7b选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基；R 7b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl;
n为0、1或2；优选1或2；更优选1；n is 0, 1 or 2; preferably 1 or 2; more preferably 1;
q为0或1；q is 0 or 1;
p为1或2；p is 1 or 2;
R1、R2如通式(I)所定义。R 1 and R 2 are as defined by general formula (I).
在一个优选的实施方案中，本发明所述的通式(I)、通式(II)、通式(III)、通式(IVA)、通式(IVB)、通式(VA)、通式(VB)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R1选自氢、氘、卤素、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6氘代烷氧基、C1-C6卤代烷氧基、氨基；优选氢、氘、卤素，更优选卤素，特别是氟。In a preferred embodiment, the general formula (I), general formula (II), general formula (III), general formula (IVA), general formula (IVB), general formula (VA), general formula (VA), general formula The compound represented by formula (VB) or its mesobody, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected From hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 deuterated alkyl Oxygen group, C 1 -C 6 haloalkoxy group, amino group; preferably hydrogen, deuterium, halogen, more preferably halogen, especially fluorine.
在另一个优选的实施方案中，本发明所述的通式(I)、通式(II)、通式(III)、通式(IVA)、通式(IVB)、通式(VA)、通式(VB)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R2选自氢、氘、卤素、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6氘代烷氧基、C1-C6卤代烷氧基、氨基；优选氢、氘、卤素、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基；更优选C1-C6烷基，特别是甲基。In another preferred embodiment, the general formula (I), general formula (II), general formula (III), general formula (IVA), general formula (IVB), general formula (VA), The compound represented by the general formula (VB) or its meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein R 2 Selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 deuterated Alkoxy, C 1 -C 6 haloalkoxy, amino; preferably hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl; more preferably C 1 -C 6 alkyl, especially methyl.
在另一个优选的实施方案中，本发明所述的通式(I)、通式(II)、通式(III)、通式(IVA)、通式(IVB)、通式(VA)、通式(VB)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R3和R4各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6氘代烷氧基、C3-6环烷基。In another preferred embodiment, the general formula (I), general formula (II), general formula (III), general formula (IVA), general formula (IVB), general formula (VA), The compound represented by the general formula (VB) or its meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 deuterated alkoxy, C 3-6 cycloalkyl.
在另一个优选的实施方案中，本发明所述的通式(I)、通式(II)、通式(III)、通式(IVA)、通式(IVB)、通式(VA)、通式(VB)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R5选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6卤代烷基、C1-6氘代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6氘代烷氧基、C3-6环烷基。 In another preferred embodiment, the general formula (I), general formula (II), general formula (III), general formula (IVA), general formula (IVB), general formula (VA), The compound represented by the general formula (VB) or its meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein R 5 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 haloalkyl Oxygen group, C 1-6 deuterated alkoxy group, C 3-6 cycloalkyl group.
本发明的典型化合物，包括但不限于：























Typical compounds of the present invention include, but are not limited to:























或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其可药用盐。Or its meso, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt.
本发明进一步涉及一种制备通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
The present invention further relates to a method for preparing the compound represented by the general formula (II) or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable form. The method of using salt includes the following steps:
在催化剂存在下，式IIi的化合物发生分子内偶联反应得到通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐；所述催化剂优选醋酸钯；In the presence of a catalyst, the compound of formula IIi undergoes an intramolecular coupling reaction to obtain the compound represented by the general formula (II) or its meso, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof; the catalyst is preferably palladium acetate;
其中，环A、环B、Y1、Y2、Z1、Z2、R1和R2如通式(I)所定义。Among them, Ring A, Ring B, Y 1 , Y 2 , Z 1 , Z 2 , R 1 and R 2 are as defined by the general formula (I).
本发明进一步提供一种药物组合物，其包含根据本发明所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体或赋形剂。The present invention further provides a pharmaceutical composition comprising a compound according to the present invention or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or Its pharmaceutically acceptable salts, as well as pharmaceutically acceptable carriers or excipients.
本发明进一步涉及根据本发明所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合 物在制备ALK激酶抑制剂中的用途。The present invention further relates to a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same drug combination The use of substances in the preparation of ALK kinase inhibitors.
本发明进一步涉及根据本发明所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物在制备预防和/或治疗与ALK激酶活性相关的疾病的药物中的用途，所述疾病优选恶性肿瘤疾病，所述恶性肿瘤疾病例如非小细胞肺癌。The present invention further relates to a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same The use of a pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases associated with ALK kinase activity, preferably malignant neoplastic diseases, such as non-small cell lung cancer.
本发明进一步涉及一种抑制ALK激酶的方法，其包括向有需要的患者施用有效量的根据本发明所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，或包含其的药物组合物。The present invention further relates to a method of inhibiting ALK kinase, which comprises administering to a patient in need thereof an effective amount of a compound according to the present invention or a meso, racemate, enantiomer, diastereomer thereof. enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same.
本发明进一步涉及一种预防和/或治疗与ALK激酶活性相关的疾病的方法，其包括向有需要的患者施用有效量的根据本发明所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，或包含其的药物组合物，其中所述疾病优选恶性肿瘤疾病，所述恶性肿瘤疾病例如非小细胞肺癌。The present invention further relates to a method for preventing and/or treating diseases related to ALK kinase activity, which comprises administering to a patient in need an effective amount of a compound according to the present invention or a mesoform or racemate thereof. , enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, wherein the disease is preferably a malignant neoplastic disease, such as non- Small Cell Lung Cancer.
本发明进一步涉及根据本发明所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物，其用作ALK激酶抑制剂。The present invention further relates to a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same Pharmaceutical compositions for use as ALK kinase inhibitors.
本发明进一步涉及根据本发明所述的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者包含其的药物组合物，其用于预防和/或治疗与ALK激酶活性相关的疾病，其中所述疾病优选恶性肿瘤疾病，所述恶性肿瘤疾病例如非小细胞肺癌。The present invention further relates to a compound according to the present invention or its meso, racemate, enantiomer, diastereoisomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof or comprising the same A pharmaceutical composition for preventing and/or treating diseases related to ALK kinase activity, wherein the disease is preferably a malignant tumor disease, such as non-small cell lung cancer.
按照本发明所属领域的常规方法，本发明化合物可以与酸生成药学上可接受的酸式加成盐。所述酸包括无机酸和有机酸，特别优选盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。According to conventional methods in the field of this invention, the compounds of the present invention can form pharmaceutically acceptable acid addition salts with acids. The acid includes inorganic acid and organic acid, particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid , trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
按照本发明所属领域的常规方法，本发明化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。According to conventional methods in the field to which the present invention belongs, the compounds of the present invention can form pharmaceutically acceptable base addition salts with bases. The base includes inorganic bases and organic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide, etc.
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊、或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例 如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。Pharmaceutical compositions containing the active ingredients may be in forms suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives, to provide medicinal preparations that are pleasing to the eye and palatable. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as Such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time. For example, water-soluble taste masking substances such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or time extending substances such as ethyl cellulose, cellulose acetate butyrate may be used.
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。Hard gelatin capsules may also be used in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Oral formulation is available in soft gelatin capsules.
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents, which may be natural The resulting phospholipids, such as lecithin, or the condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanoethyleneoxycetylene Heptadecaethyleneoxy cetanol, or the condensation product of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with partial esters derived from fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents and one or more sweeteners. Flavoring agents such as sucrose, saccharin or aspartame.
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis, olive, sesame or coconut oil, or a mineral oil, such as liquid paraffin. Oil suspensions may contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as described above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide. Products such as polyethylene oxide sorbitan monooleate. Emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such preparations may also contain demulcents, preservatives, coloring agents and antioxidants.
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。The pharmaceutical compositions of the invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. Sterile injectable preparations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol and treated to form a microemulsion. Injectable solutions or microemulsions can be injected into the patient's bloodstream via localized mass injections. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the compounds of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used.
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。 无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。Pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents such as those mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose any blended fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerol gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycols.
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc. In addition, the optimal treatment method such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
本发明可以含有化合物及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗与ALK激酶活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。The present invention can contain compounds and their pharmaceutically acceptable salts, hydrates or solvates as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepare it into a clinically acceptable dosage form. The derivatives of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions, etc. The compounds of the present invention can be used as the only active ingredient or can be used in combination with other drugs for treating diseases related to ALK kinase activity. Combination therapy is accomplished by administering the individual treatment components simultaneously, separately, or sequentially.
术语说明Terminology
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异 丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms Atoms of alkyl groups. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl base, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methyl Pentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available point of attachment. The substituents are preferably one or more of the following groups, independently selected from alkyl groups: Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl etc. Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom). It may contain one or more double bonds, but no ring is fully conjugated. pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the rings, the spirocycloalkyl group is divided into a single spirocycloalkyl group, a double spirocycloalkyl group or a polyspirocycloalkyl group, and is preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocyclic alkyl group. Non-limiting examples of spirocycloalkyl groups include:
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但 没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more rings. multiple double bonds, but No ring has a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a complete Conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
所述环烷基环可以稠合于芳基、杂芳基或杂环基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl, etc. Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably it contains 5 to 6 ring atoms, of which 1 to 6 are heteroatoms. 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为6至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或 5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 membered monocyclic rings sharing one atom (called a spiro atom), in which one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of shared spiro atoms between the rings, the spiroheterocyclyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably, it is 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5-membered/6-membered single spiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为6至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
The term "fused heterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members, each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds, but no ring has a fully conjugated pi electron system, one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, or S(O) m (where m is an integer 0 to 2), and the remaining rings The atom is carbon. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为6至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, but no ring has a completely shared bond. A yoke of pi-electron systems in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
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杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、 杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。Heterocyclyl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio group, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6 to 10 members, such as benzene base and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, carboxyl group or carboxylate group.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and 5 to 14 ring atoms. The heteroaryl group is preferably 5 to 10 yuan, containing 1 to 3 heteroatoms; more preferably, it is 5 yuan or 6 yuan, containing 1 to 2 heteroatoms; preferably, it is imidazolyl, furyl, thienyl, thiazolyl, pyridyl, etc. Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably Pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, carboxyl group or carboxylate group.
术语“双环芳基”指含有两个环的碳环芳香系统，即萘基；萘基可以是取代或未取代的。The term "bicyclic aryl" refers to a carbocyclic aromatic system containing two rings, namely naphthyl; naphthyl may be substituted or unsubstituted.
术语“双环杂芳基”指8至10元双环杂芳基系统，其中包含1至4个选自氮、氧和/或硫中的原子。包括但不限于 The term "bicyclic heteroaryl" refers to an 8 to 10 membered bicyclic heteroaryl system containing 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. including but not limited to
可以是取代或未取代的。Can be substituted or unsubstituted.
术语“稠合环”指两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但至少一个环不具有完全共轭的π电子的芳香系统，同时也至少一个环具有完全共轭的π电子的芳香系统，其中环原子中选自0个、1个或多个选自氮、氧或S(O)n(其中n选自0、1或2)的杂原子，其余环原子为碳。稠合环优选双环稠合环，包括但不限于 The term "fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other. One or more rings may contain one or more double bonds, but at least one ring is not fully conjugated. An aromatic system with π electrons, and also an aromatic system with at least one ring having fully conjugated π electrons, in which 0, 1 or more ring atoms are selected from nitrogen, oxygen or S(O) n (where n is a heteroatom selected from 0, 1 or 2), and the remaining ring atoms are carbon. The fused ring is preferably a bicyclic fused ring, including but not limited to
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基和环烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkyl, Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio group, carboxyl group or carboxylate group.
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
术语“氘代烷基”指被一个或多个氘取代的烷基，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuteriums, wherein alkyl is as defined above.
术语“氘代烷氧基”指被一个或多个氘取代的烷基，其中烷氧基如上所定义。The term "deuterated alkoxy" refers to an alkyl group substituted with one or more deuteriums, where alkoxy is as defined above.
术语“羟烷基”指被一个或多个羟基取代的烷基，其中烷基如上所定义。 The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
术语“羟基”指-OH基团。The term "hydroxy" refers to the -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“氨基”指-NH2。The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO2。The term "nitro" refers to -NO2 .
术语“氧代基”指＝O。The term "oxo" refers to =O.
术语“硫代基”指＝S。The term "thio" refers to =S.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“巯基”指-SH。The term "mercapto" refers to -SH.
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。The term "ester" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), where alkyl and cycloalkyl are as defined above.
术语“酰基”指含有-C(O)R基团的化合物，其中R为如上所定义的烷基、环烷基、杂环基、芳基、杂芳基。The term "acyl" refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
术语“磺酰基”指含有-S(O)2R基团的化合物，其中R为如上所定义的烷基、环烷基、杂环基、芳基、杂芳基。The term "sulfonyl" refers to compounds containing the group -S(O) 2R , where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
本发明化合物可以为氘化形式。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成。The compounds of the present invention may be in deuterated form. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated forms of compounds. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds, or they may be synthesized using deuterated reagents using conventional techniques.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基”意味着烷基可以但不必须存在，该说明包括杂环基被烷基取代的情形和杂环基不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "heterocyclyl optionally substituted by an alkyl group" means that an alkyl group may but need not be present, and this description includes the case where the heterocyclyl is substituted by an alkyl group and the case where the heterocyclyl is not substituted by an alkyl group.
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and have appropriate biological activity.
本发明化合物的合成方法Synthetic methods of compounds of the present invention
本发明通式(II)所示的化合物可以通过以下方案1进行制备
The compound represented by the general formula (II) of the present invention can be prepared by the following Scheme 1
方案1plan 1
步骤1：在还原剂条件下，化合物IIa发生还原反应得到化合物IIb，所述还原剂优选二异丁基氢化铝；Step 1: Under reducing agent conditions, compound IIa undergoes a reduction reaction to obtain compound IIb. The reducing agent is preferably diisobutylaluminum hydride;
步骤2：在催化剂条件下，化合物IIb与IIc发生加成反应得到化合物IId，所述催化剂优选异丙基氯化镁；Step 2: Under catalyst conditions, compound IIb and IIc undergo an addition reaction to obtain compound IId. The catalyst is preferably isopropyl magnesium chloride;
步骤3：在还原剂条件下，化合物IId发生还原反应得到化合物IIe，所述还原剂优选三乙基硅烷；Step 3: Under reducing agent conditions, compound IId undergoes a reduction reaction to obtain compound IIe. The reducing agent is preferably triethylsilane;
步骤4：在催化剂条件下，化合物IIe与IIf发生偶联反应得到化合物IIg，所述催化剂优选四三苯基膦钯；Step 4: Under catalyst conditions, compound IIe and IIf undergo a coupling reaction to obtain compound IIg. The catalyst is preferably tetrakis triphenylphosphine palladium;
步骤5：在碱性条件下，化合物IIg与5-溴-3-氟-2-硝基吡啶发生取代反应得到化合物IIh，所述碱性条件优选氢化钠；Step 5: Under alkaline conditions, compound IIg undergoes a substitution reaction with 5-bromo-3-fluoro-2-nitropyridine to obtain compound IIh. The alkaline conditions are preferably sodium hydride;
步骤6：在还原剂条件下，化合物IIh发生还原反应得到化合物IIi，所述还原剂优选锌粉；Step 6: Compound IIh undergoes a reduction reaction under reducing agent conditions to obtain compound IIi. The reducing agent is preferably zinc powder;
步骤7：在催化剂条件下，化合物IIi发生分子内偶联反应得到化合物(II)，所述催化剂优选醋酸钯；Step 7: Under catalyst conditions, compound IIi undergoes an intramolecular coupling reaction to obtain compound (II). The catalyst is preferably palladium acetate;
其中：in:
X为卤素；X is halogen;
环A、环B、Y1、Y2、Z1、Z2、R1和R2如通式(I)所定义。Ring A, Ring B, Y 1 , Y 2 , Z 1 , Z 2 , R 1 and R 2 are as defined by the general formula (I).
附图说明Description of drawings
图1A为本发明实施例23化合物对BaF3 EML4-ALK-G1202R小鼠皮下移植瘤的药效结果。Figure 1A shows the efficacy results of the compound of Example 23 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R mice.
图1B为本发明实施例36化合物对BaF3 EML4-ALK-G1202R小鼠皮下移植瘤的药效结果。Figure 1B shows the efficacy results of the compound of Example 36 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R mice.
图1C为本发明实施例50化合物对BaF3 EML4-ALK-G1202R小鼠皮下移植瘤的药效结果。Figure 1C shows the efficacy results of the compound of Example 50 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R mice.
图1D为本发明实施例32化合物对BaF3 EML4-ALK-G1202R-L1196M小鼠皮下移植瘤的药效结果。 Figure 1D shows the efficacy results of the compound of Example 32 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R-L1196M mice.
图1E为本发明实施例36化合物对BaF3 EML4-ALK-G1202R-L1196M小鼠皮下移植瘤的药效结果。Figure 1E shows the efficacy results of the compound of Example 36 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R-L1196M mice.
图1F为本发明实施例50化合物对BaF3 EML4-ALK-G1202R-L1196M小鼠皮下移植瘤的药效结果。Figure 1F shows the efficacy results of the compound of Example 50 of the present invention on subcutaneous transplanted tumors in BaF3 EML4-ALK-G1202R-L1196M mice.
图1G为本发明实施例50化合物对BaF3 CD74-ROS1 G2032R小鼠皮下移植瘤的药效结果。Figure 1G shows the efficacy results of the compound of Example 50 of the present invention on subcutaneous transplanted tumors in BaF3 CD74-ROS1 G2032R mice.
图2A为本发明实施例23化合物对BaF3 EML4-ALK-G1202R小鼠皮下肿瘤移植后体重的影响。Figure 2A shows the effect of the compound of Example 23 of the present invention on the body weight of BaF3 EML4-ALK-G1202R mice after subcutaneous tumor transplantation.
图2B为本发明实施例36化合物对BaF3 EML4-ALK-G1202R小鼠皮下肿瘤移植后体重的影响。Figure 2B shows the effect of the compound of Example 36 of the present invention on the body weight of BaF3 EML4-ALK-G1202R mice after subcutaneous tumor transplantation.
图2C为本发明实施例50化合物对BaF3 EML4-ALK-G1202R小鼠皮下肿瘤移植后体重的影响。Figure 2C shows the effect of the compound of Example 50 of the present invention on the body weight of BaF3 EML4-ALK-G1202R mice after subcutaneous tumor transplantation.
图2D为本发明实施例32化合物对BaF3 EML4-ALK-G1202R-L1196M小鼠皮下肿瘤移植后体重的影响。Figure 2D shows the effect of the compound of Example 32 of the present invention on the body weight of BaF3 EML4-ALK-G1202R-L1196M mice after subcutaneous tumor transplantation.
图2E为本发明实施例36化合物对BaF3 EML4-ALK-G1202R-L1196M小鼠皮下肿瘤移植后体重的影响。Figure 2E shows the effect of the compound of Example 36 of the present invention on the body weight of BaF3 EML4-ALK-G1202R-L1196M mice after subcutaneous tumor transplantation.
图2F为本发明实施例50化合物对BaF3 EML4-ALK-G1202R-L1196M小鼠皮下肿瘤移植后体重的影响。Figure 2F shows the effect of the compound of Example 50 of the present invention on the body weight of BaF3 EML4-ALK-G1202R-L1196M mice after subcutaneous tumor transplantation.
图2G本发明实施例50化合物对BaF3 CD74-ROS1 G2032R小鼠皮下肿瘤移植后体重的影响。Figure 2G shows the effect of the compound of Example 50 of the present invention on the body weight of BaF3 CD74-ROS1 G2032R mice after subcutaneous tumor transplantation.
具体实施方式Detailed ways
进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例不限制本发明的范围。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。The compounds of the invention and their preparation are further understood by means of the examples, which illustrate some methods of making or using the compounds. However, it is to be understood that these examples do not limit the scope of the invention. Variations of the invention now known or further developed are deemed to be within the scope of the invention described and claimed herein.
本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件，诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明，其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变，但在通常情况下，反应优化步骤和条件都能得到确定。The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. The present invention provides typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, other reaction conditions can also be adopted unless otherwise stated. Optimized conditions may vary depending on the specific reactants or solvents used, but in general, reaction optimization steps and conditions can be determined.
另外，本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。 In addition, some protecting groups may be used in the present invention to protect certain functional groups to avoid unnecessary reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, "Protecting Groups in Organic Preparations" by TW Greene and GMWuts (3rd edition, Wiley, New York, 1999 and references cited in the book) describes in detail the protection or deprotection of a large number of protecting groups.
化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤，例如过滤、萃取、蒸馏、结晶、柱层析色谱法、薄层色谱法、高效液相色谱法或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然，其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。The isolation and purification of compounds and intermediates adopt appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, thin layer chromatography, high performance liquid chromatography or a mixture of the above methods. . For its specific usage, please refer to the examples described in the present invention. Of course, other similar separation and purification means can also be used. They can be characterized using conventional methods including physical constants and spectral data.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10-6(ppm)的单位给出。NMR的测定是用Brukerdps 300型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts are given in units of 10 -6 (ppm). NMR was measured using a Brukerdps 300 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was tetramethylmethane. silane (TMS).
MS的测定用LC(Agilent 1260 Infinity)/MS(G6125B)质谱仪(生产商：安捷伦)。MS was measured using LC (Agilent 1260 Infinity)/MS (G6125B) mass spectrometer (Manufacturer: Agilent).
制备高效液相色谱法使用lc6000高效液相色谱仪(生产商：创新通恒)。Preparative high-performance liquid chromatography used lc6000 high-performance liquid chromatography (manufacturer: Chuangxin Tongheng).
薄层色谱法(TLC)使用青岛海洋化工GF254硅胶板，反应监测用薄层色谱法使用的硅胶板采用的规格是0.20mm～0.25mm，分离纯化用薄层色谱法使用的硅胶板采用的规格是0.5mm。Thin layer chromatography (TLC) uses Qingdao Ocean Chemical GF254 silica gel plate. The specifications of the silica gel plate used in the thin layer chromatography for reaction monitoring are 0.20 mm ~ 0.25 mm. The specifications of the silica gel plate used in the thin layer chromatography for separation and purification are It's 0.5mm.
硅胶柱层析色谱法使用青岛海洋硅胶100～200目、200～300目和300～400目硅胶为载体。Silica gel column chromatography uses Qingdao Ocean Silica Gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得、南京药石等公司。The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, Shanghai Bide, Nanjing Yaoshi and other companies.
实施例中无特殊说明，反应能够均在氮气氛下进行。There are no special instructions in the examples, and the reactions can all be carried out under a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.
反应溶剂、有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应，包括，如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、乙醚、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。实施例中无特殊说明，溶液是指水溶液。Reaction solvents, organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, diethyl ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. There is no special explanation in the examples, and the solution refers to an aqueous solution.
本发明中所描述的化学反应一般在常压下进行。反应时间和条件为，例如，一个大气压下，-78℃至200℃之间，大约1至24小时内完成。如果反应过夜，则反应时间一般为16小时。实施例中无特殊说明，反应的温度为室温，为20℃～30℃。The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction time and conditions are, for example, one atmospheric pressure, between -78°C and 200°C, and can be completed in about 1 to 24 hours. If the reaction occurs overnight, the reaction time is generally 16 hours. There are no special instructions in the examples. The reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，C：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。The reaction process in the embodiment is monitored by thin layer chromatography (TLC). The developing agent systems used in the reaction are: A: methylene chloride and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, The volume ratio of solvents is adjusted according to the polarity of the compounds.
纯化化合物采用的柱层析色谱法的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和三氟乙酸等碱性或酸 性试剂进行调节。The eluent system of column chromatography and the developing agent system of thin layer chromatography used to purify the compound include: A: methylene chloride and methanol system, B: petroleum ether and ethyl acetate system, the volume ratio of the solvent is based on Depending on the polarity of the compound, you can also add a small amount of alkalinity or acid such as triethylamine and trifluoroacetic acid. sex reagents.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to one skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the method of the present invention.
实施例Example
实施例1：(R)-3-氟-5,13,13,19-四甲基-13,14,17,19-四氢-5H-7,11-(亚甲基)苯并[l]噁唑并[3',2':1,5]吡唑并[4,3-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(1)的制备
Example 1: (R)-3-fluoro-5,13,13,19-tetramethyl-13,14,17,19-tetrahydro-5H-7,11-(methylene)benzo[l ]oxazolo[3',2':1,5]pyrazolo[4,3-g][1,2,3]triazolo[4,5-j][1]oxa[4] Preparation of nitrogen heterocyclic tetradecene-8-amine (1)
步骤1：5-羟基-1H-吡唑-3-甲酸乙酯(1a)的制备Step 1: Preparation of 5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (1a)
于室温将草酰乙酸二乙酯钠盐(30.0g，143mmol)溶于甲苯(200mL)中，搅拌20分钟，加入醋酸(200mL)，搅拌30分钟，再加入肼盐酸盐(19.5g，28.5mmol)，升温至100℃搅拌24h。将反应液加水淬灭，用乙酸乙酯萃取(100mL x3)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物10.0g。收率44.8％。Dissolve diethyl oxaloacetate sodium salt (30.0g, 143mmol) in toluene (200mL) at room temperature, stir for 20 minutes, add acetic acid (200mL), stir for 30 minutes, then add hydrazine hydrochloride (19.5g, 28.5 mmol), heated to 100°C and stirred for 24h. Quench the reaction solution with water and extract with ethyl acetate (100mL x3). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 10.0 g of the title compound as a white solid. The yield is 44.8%.
LC-MS：m/z 157[M+H]+。LC-MS: m/z 157[M+H] + .
步骤2：5-((1-(叔丁氧基)-2-甲基-1-氧代丙烷-2-基)氧基)-1H-吡唑-3-羧酸乙酯(1b)的制备Step 2: 5-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazole-3-carboxylic acid ethyl ester (1b) preparation
于室温，向5-羟基-1H-吡唑-3-甲酸乙酯(1a)(9.00g，57.6mmol)的N,N- 二甲基甲酰胺(DMF)(100mL)溶液中加入2-溴-2-甲基丙酸叔丁酯(15.4g，69.2mmol)、碳酸铯(37.5g，115mmol)和四丁基碘化铵(2.12g，5.76mmol)，于室温搅拌2h。加入水淬灭，将反应液用乙酸乙酯萃取(100mL x 3)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物11.3g。收率65.8％。To the N,N- To a solution of dimethylformamide (DMF) (100 mL), tert-butyl 2-bromo-2-methylpropionate (15.4g, 69.2mmol), cesium carbonate (37.5g, 115mmol) and tetrabutylammonium iodide were added. (2.12g, 5.76mmol), stirred at room temperature for 2h. Water was added to quench, and the reaction solution was extracted with ethyl acetate (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 11.3 g of the title compound as a white solid. The yield is 65.8%.
LC-MS：m/z 299[M+H]+。LC-MS: m/z 299[M+H] + .
步骤3：2-((3-(乙氧基羰基)-1H-吡唑-5-基)氧基)-2-甲基丙酸(1c)的制备Step 3: Preparation of 2-((3-(ethoxycarbonyl)-1H-pyrazol-5-yl)oxy)-2-methylpropionic acid (1c)
于0℃向5-((1-(叔丁氧基)-2-甲基-1-氧代丙烷-2-基)氧基)-1H-吡唑-3-羧酸乙酯(1b)(11.3g，37.9mmol)的二氯甲烷(10.0mL)溶液中加入三氟乙酸(50.0mL)，于室温搅拌3h。将反应液直接浓缩用于下一步反应。5-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)-1H-pyrazole-3-carboxylic acid ethyl ester (1b) at 0°C Trifluoroacetic acid (50.0 mL) was added to a solution of (11.3 g, 37.9 mmol) in dichloromethane (10.0 mL), and stirred at room temperature for 3 h. The reaction solution was directly concentrated and used for the next reaction.
LC-MS：m/z 243[M+H]+。LC-MS: m/z 243[M+H] + .
步骤4：5-((1-羟基-2-甲基丙-2-基)氧基)-1H-吡唑-3-甲酸乙酯(1d)的制备Step 4: Preparation of ethyl 5-((1-hydroxy-2-methylprop-2-yl)oxy)-1H-pyrazole-3-carboxylate (1d)
于0℃，向2-((3-(乙氧基羰基)-1H-吡唑-5-基)氧基)-2-甲基丙酸(1c)(9.00g，37.1mmol)的四氢呋喃(10.0mL)溶液中加入硼烷溶液(74.3mL，74.3mmol，1M)，于室温搅拌3h。将反应液缓慢加入甲醇淬灭，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物7.80g。两步收率92.2％。To 2-((3-(ethoxycarbonyl)-1H-pyrazol-5-yl)oxy)-2-methylpropanoic acid (1c) (9.00 g, 37.1 mmol) in tetrahydrofuran ( Add borane solution (74.3 mL, 74.3 mmol, 1 M) to the solution (10.0 mL) and stir at room temperature for 3 h. The reaction solution was quenched by slowly adding methanol and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 7.80 g of the title compound as a white solid. The two-step yield was 92.2%.
LC-MS：m/z 229[M+H]+。LC-MS: m/z 229[M+H] + .
步骤5：2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-甲酸乙酯(1e)的制备Step 5: Preparation of 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylic acid ethyl ester (1e)
于室温，向5-((1-羟基-2-甲基丙-2-基)氧基)-1H-吡唑-3-甲酸乙酯(1d)(5.33g，23.3mmol)的二氯甲烷(50.0mL)溶液中加入四溴化碳(7.73g，23.3mmol)和三苯基膦(6.12g，23.3mmol)。于0℃加入N,N-二异丙基乙胺(DIEA)(9.04g，70.1mmol)，升至室温搅拌过夜。将反应液直接浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物2.75g。收率56.2％。To 5-((1-hydroxy-2-methylprop-2-yl)oxy)-1H-pyrazole-3-carboxylic acid ethyl ester (1d) (5.33 g, 23.3 mmol) in dichloromethane at room temperature (50.0 mL) solution were added carbon tetrabromide (7.73g, 23.3mmol) and triphenylphosphine (6.12g, 23.3mmol). Add N,N-diisopropylethylamine (DIEA) (9.04g, 70.1mmol) at 0°C, raise to room temperature and stir overnight. The reaction solution was directly concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 2.75 g of the title compound as a white solid. The yield is 56.2%.
LC-MS：m/z 211[M+H]+。LC-MS: m/z 211[M+H] + .
步骤6：2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-甲醛(1f)的制备Step 6: Preparation of 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carbaldehyde (1f)
氮气氛下，于-78℃向2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-甲酸乙酯(1e)(2.75g，14.0mmol)的二氯甲烷(30.0mL)溶液中加入二异丁基氢化铝(DIBAL-H)(42.0mL，42.0mmol)，继续搅拌1.5小时。将反应液缓慢加入甲醇淬灭，加入1M盐酸调节PH～7，用二氯甲烷萃取(50mL x 3)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物1.70g，收率73.1％。Under nitrogen atmosphere, add 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylic acid ethyl ester (1e) (2.75g, 14.0mmol) at -78°C. ) in dichloromethane (30.0 mL), add diisobutylaluminum hydride (DIBAL-H) (42.0 mL, 42.0 mmol), and continue stirring for 1.5 hours. Slowly add methanol to the reaction solution to quench it, add 1M hydrochloric acid to adjust the pH to 7, and extract with dichloromethane (50mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 1.70 g of the title compound as a white solid, with a yield of 73.1%.
LC-MS：m/z 167[M+H]+。LC-MS: m/z 167[M+H] + .
步骤7：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁 唑-6-基)甲醇(1g)的制备Step 7: (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)(2,2-dimethyl-2,3-dihydropyrazolo[5,1 -b]evil Preparation of azole-6-yl)methanol (1g)
氮气氛下，于-78℃向4,5-二溴-2-甲基-2H-1,2,3-三唑(3.14g，13.1mmol)的四氢呋喃(30.0mL)溶液中加入正丁基锂(5.26mL，13.1mmol)。继续搅拌1小时，加入2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-甲醛(1f)(1.0g，6.57mmol)，再搅拌1小时，加入饱和氯化铵溶液淬灭，EA萃取，合并有机相，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝10:1)，得到白色固体状的标题化合物900mg。收率41.8％。Under a nitrogen atmosphere, n-butyl was added to a solution of 4,5-dibromo-2-methyl-2H-1,2,3-triazole (3.14g, 13.1mmol) in tetrahydrofuran (30.0mL) at -78°C. Lithium (5.26 mL, 13.1 mmol). Continue stirring for 1 hour, add 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carbaldehyde (1f) (1.0g, 6.57mmol), and stir for another 1 hour hour, add saturated ammonium chloride solution to quench, extract with EA, combine the organic phases, and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=10:1) to obtain 900 mg of the title compound as a white solid. Yield 41.8%.
LC-MS：m/z 328[M+H]+。LC-MS: m/z 328[M+H] + .
步骤8：6-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(1h)的制备Step 8: 6-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyridine Preparation of zolo[5,1-b]oxazole (1h)
于室温，向(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲醇(1g)(1.70g，5.43mmol)的三氟乙酸(20.0mL)溶液中加入三乙基硅烷(2.50g，21.7mmol)，于60℃搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)，得到淡黄色油状的标题化合物1.1g。收率65.1％。To (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(2,2-dimethyl-2,3-dihydropyrazolo[5, Add triethylsilane (2.50g, 21.7mmol) to a solution of 1-b]oxazol-6-yl)methanol (1g) (1.70g, 5.43mmol) in trifluoroacetic acid (20.0mL), and stir at 60°C overnight . The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 1.1 g of the title compound as a light yellow oil. Yield 65.1%.
LC-MS：m/z 312[M+H]+。LC-MS: m/z 312[M+H] + .
步骤9：(R)-1-(2-(5-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙烷-1-醇(1i)的制备Step 9: (R)-1-(2-(5-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl Preparation of )-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethane-1-ol (1i)
氮气氛下，于室温向6-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(1h)(550mg，1.76mmol)的甲苯(10.0mL)、乙醇(2mL)和水(2mL)混合溶液中加入四三苯基膦钯(204mg，0.176mmol)、碳酸钠(749mg，7.07mmol)和(R)-5-氟-3-甲基苯并[c][1,2]噁硼烷-1(3H)-醇(322mg，1.94mmol)。氮气氛下，升至70℃搅拌过夜。将反应液用水稀释。用乙酸乙酯萃取(50mL x 3)。合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到黄色固体状的标题化合物300mg，收率45.9％。Under nitrogen atmosphere, add 6-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-2,2-dimethyl-2,3 at room temperature. -To a mixed solution of dihydropyrazolo[5,1-b]oxazole (1h) (550mg, 1.76mmol) in toluene (10.0mL), ethanol (2mL) and water (2mL), tetrakistriphenylphosphine palladium was added (204mg, 0.176mmol), sodium carbonate (749mg, 7.07mmol) and (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborane-1(3H)-ol (322mg ,1.94mmol). Under nitrogen atmosphere, raise to 70°C and stir overnight. Dilute the reaction solution with water. Extract with ethyl acetate (50mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 300 mg of the title compound as a yellow solid, with a yield of 45.9%.
LC-MS：m/z 372[M+H]+。LC-MS: m/z 372[M+H] + .
步骤10：(R)-6-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-5-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(1j)的制备Step 10: (R)-6-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2 -Methyl-2H-1,2,3-triazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole ( Preparation of 1j)
于0℃，向(R)-1-(2-(5-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙烷-1-醇(1i)(280mg，0.784mmol)的四氢呋喃(7.0mL)溶液中加入氢化钠(47.0mg，1.17mmol)。升至室温搅拌1小时，加入5-溴-3-氟-2-硝基吡啶(207mg，0.941mmol)。于室温搅拌过夜。加水淬灭，乙酸乙酯萃取，合并有机相，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)，得到黄色固体状的标题化合物260mg，收率58.0％。To (R)-1-(2-(5-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl) Methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethane-1-ol (1i) (280 mg, 0.784 mmol) in tetrahydrofuran (7.0 mL) solution was added sodium hydride (47.0 mg, 1.17 mmol). The mixture was raised to room temperature and stirred for 1 hour, and 5-bromo-3-fluoro-2-nitropyridine (207 mg, 0.941 mmol) was added. Stir at room temperature overnight. Add water to quench, extract with ethyl acetate, combine the organic phases, and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 260 mg of the title compound as a yellow solid, with a yield of 58.0%.
LC-MS：m/z 572[M+H]+。 LC-MS: m/z 572[M+H] + .
步骤11：(R)-5-溴-3-(1-(2-(5-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙氧基)吡啶-2-胺(1k)的制备Step 11: (R)-5-bromo-3-(1-(2-(5-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole) Preparation of -6-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (1k)
将(R)-6-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-5-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(1j)(260mg，0.450mmol)溶于乙醇(5.00mL)和水(1.00mL)的混合溶液，加入铁粉(127mg，2.27mmol)和氯化铵(196mg，3.64mmol)。于70℃搅拌2小时。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)。得到淡黄色固体的标题化合物190mg，收率77.1％。(R)-6-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2-methyl Base-2H-1,2,3-triazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (1j) (260 mg, 0.450 mmol) was dissolved in a mixed solution of ethanol (5.00 mL) and water (1.00 mL), and iron powder (127 mg, 2.27 mmol) and ammonium chloride (196 mg, 3.64 mmol) were added. Stir at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1). 190 mg of the title compound was obtained as a pale yellow solid, with a yield of 77.1%.
LC-MS：m/z 542[M+H]+。LC-MS: m/z 542[M+H] + .
步骤12：(R)-3-氟-5,13,13,19-四甲基-13,14,17,19-四氢-5H-7,11-(亚甲基)苯并[l]噁唑并[3',2':1,5]吡唑并[4,3-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(1)的制备Step 12: (R)-3-fluoro-5,13,13,19-tetramethyl-13,14,17,19-tetrahydro-5H-7,11-(methylene)benzo[l] Oxazolo[3',2':1,5]pyrazolo[4,3-g][1,2,3]triazolo[4,5-j][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (1)
于室温，向(R)-5-溴-3-(1-(2-(5-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙氧基)吡啶-2-胺(1k)(190mg，0.350mmol)的叔戊醇(3.0mL)溶液中加入醋酸钯(39.3mg，0.170mmol)、正丁基二(1-金刚烷基)膦(251mg，0.702mmol，2.00equiv)和醋酸钾(172mg，1.75mmol，5.00)。氮气氛下，于120℃搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)，得到粗品。粗品通过高效液相色谱法纯化(色谱柱型号：XBridge Prep OBD C18 Column，30*150mm，5μm；流动相A：水(10mmol/L碳酸氢铵+0.1％氨水)，流动相B：乙腈；流速：60mL/min；梯度：47％B至74％B，在8min内，74％B)，得到白色固体状的标题化合物1.1mg。收率9.26％。To (R)-5-bromo-3-(1-(2-(5-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxan) Azol-6-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (1k)( To a solution of 190 mg, 0.350 mmol) in tert-amyl alcohol (3.0 mL) were added palladium acetate (39.3 mg, 0.170 mmol), n-butylbis(1-adamantyl)phosphine (251 mg, 0.702 mmol, 2.00 equiv) and potassium acetate (172mg, 1.75mmol, 5.00). Under nitrogen atmosphere, stir at 120°C overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1) to obtain a crude product. The crude product was purified by high performance liquid chromatography (column model: : 60 mL/min; gradient: 47% B to 74% B, within 8 min, 74% B) to obtain 1.1 mg of the title compound as a white solid. The yield is 9.26%.
LC-MS：m/z 462[M+H]+。LC-MS: m/z 462[M+H] + .
实施例2：(R)-3-氟-5,13,13,19-四甲基-13,14,17,19-四氢-5H-7,11-(亚甲基)苯并[l]噁唑并[3',2':1,5]吡唑并[4,3-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(2)的制备

Example 2: (R)-3-fluoro-5,13,13,19-tetramethyl-13,14,17,19-tetrahydro-5H-7,11-(methylene)benzo[l ]oxazolo[3',2':1,5]pyrazolo[4,3-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene -Preparation of 8-amine (2)

步骤1：(3-溴-1-甲基-1H-吡唑-4-基)(2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲醇(2a)的制备Step 1: (3-Bromo-1-methyl-1H-pyrazol-4-yl)(2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole- Preparation of 6-yl)methanol (2a)
氮气氛下，于-78℃向4,5-二溴-2-甲基-2H-1,2,3-三唑(469mg，1.50mmol)的四氢呋喃(8.00mL)溶液中加入正丁基锂(0.780mL，1.95mmol)。继续搅拌1小时，加入2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-甲醛(1f)(250mg，1.50mmol)再搅拌1小时，加入饱和氯化铵溶液淬灭，EA萃取。无水硫酸钠干燥，过滤，滤液减压浓缩得残余物400mg，未纯化直接用于下一步反应。Under nitrogen atmosphere, n-butyllithium was added to a solution of 4,5-dibromo-2-methyl-2H-1,2,3-triazole (469 mg, 1.50 mmol) in tetrahydrofuran (8.00 mL) at -78°C. (0.780mL, 1.95mmol). Continue stirring for 1 hour, add 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carbaldehyde (1f) (250mg, 1.50mmol) and stir for another 1 hour. Add saturated ammonium chloride solution to quench, and extract with EA. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 400 mg of residue, which was directly used in the next reaction without purification.
LC-MS：m/z 327[M+H]+。LC-MS: m/z 327[M+H] + .
步骤2：6-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(2b)的制备Step 2: 6-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1 -b] Preparation of oxazole (2b)
于室温，向(3-溴-1-甲基-1H-吡唑-4-基)(2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲醇(2a)(300mg，0.920mmol)的三氟乙酸(4.00mL)溶液中加入三乙基硅烷(426mg，3.68mmol)，于60℃搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)，得到淡黄色油状的标题化合物250mg，收率87.6％。To (3-bromo-1-methyl-1H-pyrazol-4-yl)(2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole at room temperature Triethylsilane (426 mg, 3.68 mmol) was added to a solution of -6-yl)methanol (2a) (300 mg, 0.920 mmol) in trifluoroacetic acid (4.00 mL), and the mixture was stirred at 60° C. overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 250 mg of the title compound as a light yellow oil, with a yield of 87.6%.
LC-MS：m/z 310[M+H]+。LC-MS: m/z 310[M+H] + .
步骤3：(R)-1-(2-(4-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-1-甲基-1H-吡唑-3-基)-4-氟苯基)乙烷-1-醇(2c)的制备Step 3: (R)-1-(2-(4-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl Preparation of )-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)ethane-1-ol (2c)
氮气氛下，于室温，向6-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(60mg，1.93mmol)的甲苯(5.00mL)、乙醇(2.50mL)和水(1.00mL)混合溶液中加入四三苯基膦钯(223mg，0.192mmol)、碳酸钠(820mg，7.74mmol)和(R)-5-氟-3-甲基苯并[c][1,2]噁硼烷-1(3H)-醇(468mg，2.12mmol，1.10equiv)。氮气氛下，70℃搅拌过夜。将反应液用水稀释，用乙酸乙酯萃取(50mL x 2)。合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到黄色固体状的标题化合物160mg，收率22.4％。Under nitrogen atmosphere, at room temperature, to 6-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazole To a mixed solution of para[5,1-b]oxazole (60 mg, 1.93 mmol) in toluene (5.00 mL), ethanol (2.50 mL) and water (1.00 mL) was added tetrakis triphenylphosphine palladium (223 mg, 0.192 mmol) , sodium carbonate (820mg, 7.74mmol) and (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborane-1(3H)-ol (468mg, 2.12mmol, 1.10equiv ). Stir overnight at 70°C under nitrogen atmosphere. The reaction solution was diluted with water and extracted with ethyl acetate (50mL x 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 160 mg of the title compound as a yellow solid, with a yield of 22.4%.
LC-MS：m/z 371[M+H]+。LC-MS: m/z 371[M+H] + .
步骤4：(R)-6-((3-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-5-氟苯基)-1-甲基 -1H-吡唑-4-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(2d)的制备Step 4: (R)-6-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-1 -methyl Preparation of -1H-pyrazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (2d)
于0℃，向(R)-1-(2-(4-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-1-甲基-1H-吡唑-3-基)-4-氟苯基)乙烷-1-醇(2c)(160mg，0.432mmol)的四氢呋喃(3.0mL)溶液中加入氢化钠(60％在油中，25.9mg，0.648mmol)，于室温搅拌1小时，加入5-溴-3-氟-2-硝基吡啶(114mg，0.518mmol)。于室温搅拌过夜。将反应液加水淬灭，乙酸乙酯萃取，合并有机相，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)，得到黄色固体状的标题化合物190mg，收率77.1％。To (R)-1-(2-(4-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl) To a solution of methyl)-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)ethane-1-ol (2c) (160 mg, 0.432 mmol) in tetrahydrofuran (3.0 mL) was added hydrogenated Sodium (60% in oil, 25.9 mg, 0.648 mmol), stir at room temperature for 1 hour, add 5-bromo-3-fluoro-2-nitropyridine (114 mg, 0.518 mmol). Stir at room temperature overnight. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 190 mg of the title compound as a yellow solid, with a yield of 77.1%.
LC-MS：m/z 571[M+H]+。LC-MS: m/z 571[M+H] + .
步骤5：(R)-5-溴-3-(1-(2-(4-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-1-甲基-1H-吡唑-3-基)-4-氟苯基)乙氧基)吡啶-2-胺(2e)的制备Step 5: (R)-5-bromo-3-(1-(2-(4-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole) Preparation of -6-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (2e)
将(R)-6-((3-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-5-氟苯基)-1-甲基-1H-吡唑-4-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(2d)(190mg，0.330mmol)溶于乙醇(5.00mL)和水(1.00mL)的混合溶液中，加入铁粉(93.0mg，1.66mmol)和氯化铵(143mg，2.66mmol)。于70℃搅拌2小时。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)。得到淡黄色固体的标题化合物140mg，收率77.8％。(R)-6-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-1-methyl (1H-pyrazol-4-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (2d) (190 mg, 0.330 mmol) Dissolve in a mixed solution of ethanol (5.00 mL) and water (1.00 mL), add iron powder (93.0 mg, 1.66 mmol) and ammonium chloride (143 mg, 2.66 mmol). Stir at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1). 140 mg of the title compound was obtained as a pale yellow solid, with a yield of 77.8%.
LC-MS：m/z 541[M+H]+。LC-MS: m/z 541[M+H] + .
步骤6：(R)-3-氟-5,13,13,19-四甲基-13,14,17,19-四氢-5H-7,11-(亚甲基)苯并[l]噁唑并[3',2':1,5]吡唑并[4,3-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(2)的制备Step 6: (R)-3-fluoro-5,13,13,19-tetramethyl-13,14,17,19-tetrahydro-5H-7,11-(methylene)benzo[l] Oxazo[3',2':1,5]pyrazolo[4,3-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene- Preparation of 8-amine(2)
于室温，向(R)-5-溴-3-(1-(2-(4-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-1-甲基-1H-吡唑-3-基)-4-氟苯基)乙氧基)吡啶-2-胺(2e)(140mg，0.259mmol)的叔戊醇(5.00mL)溶液中加入醋酸钯(58.0mg，0.259mmol)、正丁基二(1-金刚烷基)膦(186mg，0.518mmol)和醋酸钾(127mg，1.29mmol)。氮气氛下，于120℃搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)，得到粗品。粗品通过高效液相色谱法纯化(色谱柱型号：XBridge Prep OBD C18 Column，30*150mm，5μm；流动相A：水(10mmol/L碳酸氢铵+0.1％氨水)，流动相B：乙腈；流速：60mL/min；梯度：47％B至74％B，在8min内，74％B)，得到白色固体状的标题化合物1.5mg，收率1.25％。To (R)-5-bromo-3-(1-(2-(4-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxan) Azol-6-yl)methyl)-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (2e) (140 mg, 0.259 mmol) Palladium acetate (58.0 mg, 0.259 mmol), n-butylbis(1-adamantyl)phosphine (186 mg, 0.518 mmol) and potassium acetate (127 mg, 1.29 mmol) were added to the solution of tert-amyl alcohol (5.00 mL). Under nitrogen atmosphere, stir at 120°C overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1) to obtain a crude product. The crude product was purified by high performance liquid chromatography (column model: : 60 mL/min; gradient: 47% B to 74% B, within 8 min, 74% B) to obtain 1.5 mg of the title compound as a white solid, with a yield of 1.25%.
LC-MS：m/z 461[M+H]+。LC-MS: m/z 461[M+H] + .
实施例3：(R)-3-氟-5,13,13,20-四甲基-13,14-二氢-5H,17H-7,11-(亚甲基)苯并[l]噁唑并[3',2':1,5]吡唑并[4,3-g]吡唑并[1,5-j][1]氧杂[4,10]二氮杂环十四碳烯-8-胺(3)的制备
Example 3: (R)-3-Fluoro-5,13,13,20-tetramethyl-13,14-dihydro-5H,17H-7,11-(methylene)benzo[l]oxane Azolo[3',2':1,5]pyrazolo[4,3-g]pyrazolo[1,5-j][1]oxa[4,10]diazacyclotetradecane Preparation of en-8-amine (3)
步骤1：(2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲醇(3a)的制备Step 1 Preparation of: (2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanol (3a)
于室温，将2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-甲酸乙酯(1e)(4.0g，19.0mmol)溶于四氢呋喃(40.0mL)中。于0℃，加入1.0M四氢铝锂溶液(28.5mL，28.5mmol)，于室温搅拌1h。缓慢加入1.00mL水淬灭，再加入甲醇(30毫升)，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物2.80g，收率87.5％。At room temperature, 2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylic acid ethyl ester (1e) (4.0g, 19.0mmol) was dissolved in tetrahydrofuran ( 40.0mL). At 0°C, add 1.0M lithium aluminum tetrahydrogen solution (28.5 mL, 28.5 mmol), and stir at room temperature for 1 h. Slowly add 1.00 mL of water to quench, then add methanol (30 mL), and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 2.80 g of the title compound as a white solid, with a yield of 87.5%.
LC-MS：m/z 169[M+H]+。LC-MS: m/z 169[M+H] + .
步骤2：(2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基磺酸盐(3b)的制备Step 2 Preparation of: (2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanesulfonate (3b)
于0℃，向(2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲醇(3a)(1.70g，10.1mmol)的二氯甲烷(20.0mL)溶液中加入三乙胺(2.04g，20.2mmol)、甲基磺酰氯(1.73g，15.1mmol)，于室温搅拌过夜。加入饱和氯化铵溶液淬灭，将反应液用二氯甲烷萃取(20mL x 3)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩，得到淡黄色油状的标题化合物1.20g，直接用于下一步反应。To (2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanol (3a) (1.70 g, 10.1 mmol) was added to the solution at 0°C. Triethylamine (2.04g, 20.2mmol) and methylsulfonyl chloride (1.73g, 15.1mmol) were added to the methyl chloride (20.0mL) solution, and the mixture was stirred at room temperature overnight. Add saturated ammonium chloride solution to quench, and extract the reaction solution with dichloromethane (20mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, and the filtrate is concentrated under reduced pressure to obtain 1.20 g of the title compound as a light yellow oil, which is directly used in the next reaction.
LC-MS：m/z 247[M+H]+。LC-MS: m/z 247[M+H] + .
步骤3：6-((5-溴-3-甲基-1H-吡唑-1-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(3c)的制备Step 3: 6-((5-bromo-3-methyl-1H-pyrazol-1-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1 -b] Preparation of oxazole (3c)
于室温，向(2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基磺酸盐(3b)(536mg，2.58mmol)和5-溴-3-甲基-1H-吡唑(400mg，2.15mmol)的DMF(5.00mL)溶液中加入碳酸铯(1.39g，4.30mmol)，于室温搅拌过夜。将反应液加入水淬灭，用乙酸乙酯萃取(20mL x 3)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物480mg，两步收率72.0％。To (2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanesulfonate (3b) (536 mg, 2.58 mmol) at room temperature To a solution of 5-bromo-3-methyl-1H-pyrazole (400 mg, 2.15 mmol) in DMF (5.00 mL), cesium carbonate (1.39 g, 4.30 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was quenched by adding water and extracted with ethyl acetate (20mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 480 mg of the title compound as a white solid. The two-step yield is 72.0%. .
LC-MS：m/z 311[M+H]+。 LC-MS: m/z 311[M+H] + .
步骤4：(S)-1-(2-(1-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-3-甲基-1H-吡唑-5-基)-4-氟苯基)乙烷-1-醇(3d)的制备Step 4: (S)-1-(2-(1-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methyl Preparation of )-3-methyl-1H-pyrazol-5-yl)-4-fluorophenyl)ethane-1-ol (3d)
氮气氛下，于室温向6-((5-溴-3-甲基-1H-吡唑-1-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(3c)(450mg，1.25mmol)的甲苯(10.0mL)、乙醇(2.00mL)和水(2.00mL)混合溶液中加入四三苯基膦钯(145mg，0.125mmol)、碳酸钠(532mg，5.02mmol)和(R)-5-氟-3-甲基苯并[c][1,2]噁硼烷-1(3H)-醇(250mg，1.50mmol)。氮气氛下，于80℃搅拌过夜。将反应液用水稀释。用乙酸乙酯萃取(3X50毫升)。合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到黄色固体状的标题化合物430mg，收率92.9％。Under nitrogen atmosphere, add 6-((5-bromo-3-methyl-1H-pyrazol-1-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo at room temperature. To a mixed solution of [5,1-b]oxazole (3c) (450 mg, 1.25 mmol) in toluene (10.0 mL), ethanol (2.00 mL) and water (2.00 mL) was added tetrakis triphenylphosphine palladium (145 mg, 0.125 mmol), sodium carbonate (532 mg, 5.02 mmol) and (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborane-1(3H)-ol (250 mg, 1.50 mmol) . Under nitrogen atmosphere, stir at 80°C overnight. Dilute the reaction solution with water. Extract with ethyl acetate (3X50 ml). The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 430 mg of the title compound as a yellow solid, with a yield of 92.9%.
LC-MS：m/z 371[M+H]+。LC-MS: m/z 371[M+H] + .
步骤5：(S)-6-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-5-氟苯基)-3-甲基-1H-吡唑-1-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(3e)的制备Step 5: (S)-6-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-3 Preparation of -methyl-1H-pyrazol-1-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (3e)
于0℃，向(S)-1-(2-(1-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-3-甲基-1H-吡唑-5-基)-4-氟苯基)乙烷-1-醇(3d)(400mg，1.08mmol)的四氢呋喃(5.00mL)溶液中加入NaH(86mg，2.60mmol)，于室温搅拌1小时，加入5-溴-3-氟-2-硝基吡啶(285mg，1.29mmol)。继续搅拌过夜。将反应液加水淬灭，乙酸乙酯萃取，合并有机相，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)，得到黄色固体状的标题化合物350mg，收率56.8％。To (S)-1-(2-(1-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl) To a solution of methyl)-3-methyl-1H-pyrazol-5-yl)-4-fluorophenyl)ethane-1-ol (3d) (400 mg, 1.08 mmol) in tetrahydrofuran (5.00 mL) was added NaH (86 mg, 2.60 mmol), stirred at room temperature for 1 hour, and added 5-bromo-3-fluoro-2-nitropyridine (285 mg, 1.29 mmol). Continue stirring overnight. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 350 mg of the title compound as a yellow solid, with a yield of 56.8%.
LC-MS：m/z 571[M+H]+。LC-MS: m/z 571[M+H] + .
步骤6：(S)-5-溴-3-(1-(2-(1-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-3-甲基-1H-吡唑-5-基)-4-氟苯基)乙氧基)吡啶-2-胺(3f)的制备Step 6: (S)-5-bromo-3-(1-(2-(1-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole) Preparation of -6-yl)methyl)-3-methyl-1H-pyrazol-5-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (3f)
将(S)-6-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-5-氟苯基)-3-甲基-1H-吡唑-1-基)甲基)-2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑(3e)(350mg，0.614mmol)溶于乙醇(5.00mL)和水(1.00mL)的混合溶液中加入铁粉(171mg，3.07mmol)和氯化铵(265mg，4.91mmol)。于70℃搅拌2小时。所得残余物减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)。得到淡黄色固体的标题化合物280mg，收率84.4％。(S)-6-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-3-methyl (1H-pyrazol-1-yl)methyl)-2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazole (3e) (350 mg, 0.614 mmol) Iron powder (171 mg, 3.07 mmol) and ammonium chloride (265 mg, 4.91 mmol) were added to a mixed solution dissolved in ethanol (5.00 mL) and water (1.00 mL). Stir at 70°C for 2 hours. The obtained residue was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1). 280 mg of the title compound was obtained as a light yellow solid, with a yield of 84.4%.
LC-MS：m/z 541[M+H]+。LC-MS: m/z 541[M+H] + .
步骤7：(R)-3-氟-5,13,13,20-四甲基-13,14-二氢-5H,17H-7,11-(亚甲基)苯并[l]噁唑并[3',2':1,5]吡唑并[4,3-g]吡唑并[1,5-j][1]氧杂[4,10]二氮杂环十四碳烯-8-胺(3)的制备Step 7: (R)-3-fluoro-5,13,13,20-tetramethyl-13,14-dihydro-5H,17H-7,11-(methylene)benzo[l]oxazole And[3',2':1,5]pyrazolo[4,3-g]pyrazolo[1,5-j][1]oxa[4,10]diazacyclotetradecene -Preparation of 8-amine (3)
于室温，向(S)-5-溴-3-(1-(2-(1-((2,2-二甲基-2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲基)-3-甲基-1H-吡唑-5-基)-4-氟苯基)乙氧基)吡啶-2-胺(3f)(300mg，0.55mmol)的叔戊醇(5.00mL)溶液中加入醋酸钯(124mg，0.55mmol)、正丁基二(1-金刚烷基)膦(398.3mg，1.11mmol)和醋酸钾(272mg，2.77mmol)。氮气氛下，于 120℃搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)，得到粗品。粗品通过高效液相色谱法纯化(色谱柱型号：XBridge Prep OBD C18 Column，30*150mm，5μm；流动相A：水(10mmol/L碳酸氢铵+0.1％氨水)，流动相B：乙腈；流速：60mL/min；梯度：47％B至74％B，在8min内，74％B)，得到白色固体状的标题化合物4.0mg，收率1.56％。To (S)-5-bromo-3-(1-(2-(1-((2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxan) Azol-6-yl)methyl)-3-methyl-1H-pyrazol-5-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (3f) (300 mg, 0.55 mmol) To a solution of tert-amyl alcohol (5.00 mL) were added palladium acetate (124 mg, 0.55 mmol), n-butyldi(1-adamantyl)phosphine (398.3 mg, 1.11 mmol) and potassium acetate (272 mg, 2.77 mmol). Under nitrogen atmosphere, at Stir overnight at 120°C. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1) to obtain a crude product. The crude product was purified by high performance liquid chromatography (column model: XBridge Prep OBD C18 Column, 30*150mm, 5μm; mobile phase A: water (10mmol/L ammonium bicarbonate + 0.1% ammonia), mobile phase B: acetonitrile; flow rate : 60 mL/min; gradient: 47% B to 74% B, within 8 min, 74% B) to obtain 4.0 mg of the title compound as a white solid, with a yield of 1.56%.
LC-MS：m/z 461[M+H]+。LC-MS: m/z 461[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.66(dd,J＝10.5,2.7Hz,1H),7.26(dd,J＝8.5,6.1Hz,1H),7.23–7.09(m,2H),6.23(dt,J＝7.2,3.6Hz,1H),6.15(d,J＝0.9Hz,1H),5.80(d,J＝1.9Hz,1H),5.44–5.32(m,3H),5.18(d,J＝15.8Hz,1H),4.12(q,J＝9.6Hz,2H),2.16(s,3H),1.66(d,J＝6.5Hz,3H),1.59(s,3H),1.52(s,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.66 (dd, J＝10.5, 2.7Hz, 1H), 7.26 (dd, J＝8.5, 6.1Hz, 1H), 7.23–7.09 (m, 2H), 6.23(dt,J＝7.2,3.6Hz,1H),6.15(d,J＝0.9Hz,1H),5.80(d,J＝1.9Hz,1H),5.44–5.32(m,3H),5.18(d ,J＝15.8Hz,1H),4.12(q,J＝9.6Hz,2H),2.16(s,3H),1.66(d,J＝6.5Hz,3H),1.59(s,3H),1.52(s ,3H).
实施例4：(R)-3-氟-5,13,13-三甲基-13,14-二氢-5H,17H-7,11-(亚甲基)苯并[l]噁唑并[3',2':1,5]吡唑并[4,3-g]吡唑并[1,5-j][1]氧杂[4,10]二氮杂环十四碳烯-8-胺(4)的制备
Example 4: (R)-3-fluoro-5,13,13-trimethyl-13,14-dihydro-5H,17H-7,11-(methylene)benzo[l]oxazolo [3',2':1,5]pyrazolo[4,3-g]pyrazolo[1,5-j][1]oxa[4,10]diazacyclotetradecene- Preparation of 8-amine (4)
与实施例3的制备方法相同，除了用5-碘-1H-吡唑代替步骤3中的5-溴-3-甲基-1H-吡唑，制得化合物4。The preparation method was the same as in Example 3, except that 5-iodo-1H-pyrazole was used instead of 5-bromo-3-methyl-1H-pyrazole in step 3 to prepare compound 4.
LC-MS：m/z 447[M+H]+。LC-MS: m/z 447[M+H] + .
实施例5：(R)-3-氟-5,13,13-四甲基-13,14-二氢-5H,17H-7,11-(亚甲基)苯并[l]噁唑并[3',2':1,5]吡唑并[4,3-g][1,2,4]三唑并[1,5-j][1]氧杂[4,10]二氮杂环十四碳烯-8-胺(5)的制备
Example 5: (R)-3-fluoro-5,13,13-tetramethyl-13,14-dihydro-5H,17H-7,11-(methylene)benzo[l]oxazolo [3',2':1,5]pyrazolo[4,3-g][1,2,4]triazolo[1,5-j][1]oxa[4,10]diaza Preparation of heterocyclic tetradecene-8-amine (5)
与实施例3的制备方法相同，除了用5-溴-1H-1,2,4-三唑代替步骤3中的5-溴-3-甲基-1H-吡唑，制得化合物5。Compound 5 was prepared using the same preparation method as Example 3, except that 5-bromo-1H-1,2,4-triazole was used instead of 5-bromo-3-methyl-1H-pyrazole in step 3.
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.74(dd,J＝10.6,2.7Hz,1H),7.46(dd,J＝8.6,6.0Hz,1H),7.28–7.18(m,2H),6.49–6.39(m,1H),6.09(d,J＝1.9Hz,1H),5.61(d,J＝16.0Hz,1H),5.36(s,1H),5.31(d,J＝3.5Hz,2H),4.12(q,J＝9.6Hz,2H),1.72(d,J＝6.4Hz,3H),1.56(d,J＝27.2Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.52(s,1H),7.74(dd,J＝10.6,2.7Hz,1H),7.46(dd,J＝8.6,6.0Hz,1H),7.28– 7.18(m,2H),6.49–6.39(m,1H),6.09(d,J＝1.9Hz,1H),5.61(d,J＝16.0Hz,1H),5.36(s,1H),5.31(d ,J＝3.5Hz,2H),4.12(q,J＝9.6Hz,2H),1.72(d,J＝6.4Hz,3H),1.56(d,J＝27.2Hz,6H).
实施例6：(11R)-13-氟-11,17-二甲基-2,3,11,17,19,19a-六氢-1H-5,9-(亚甲基)苯并[1]吡咯并[1,2-g][1,2,3]三唑并[4,5-j][1]氧杂[4,7]二氮杂环十四碳烯-8-胺(6)的制备

Example 6: (11R)-13-fluoro-11,17-dimethyl-2,3,11,17,19,19a-hexahydro-1H-5,9-(methylene)benzo[1 ]pyrrolo[1,2-g][1,2,3]triazolo[4,5-j][1]oxa[4,7]diazacyclotetradecen-8-amine ( 6) Preparation

步骤1：2-(5-溴-2-甲基-2H-1,2,3-三唑-4-羰基)吡咯烷-1-羧酸叔丁酯(6a)的制备Step 1: Preparation of tert-butyl 2-(5-bromo-2-methyl-2H-1,2,3-triazole-4-carbonyl)pyrrolidine-1-carboxylate (6a)
将4,5-二溴-2-甲基-2H-1,2,3-三唑(698mg，2.91mmol)溶于50ml四氢呋喃中，于-78℃缓慢滴加正丁基锂(1.58ml,1.60M，2.52mmol)。于-78℃搅拌0.5h，加入2-(甲氧基(甲基)氨基甲酰基)吡咯烷-1-羧酸叔丁酯(500mg，1.94mmol)，继续搅拌2h。加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色泡沫状标题化合物600mg，收率：86.6％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (698mg, 2.91mmol) in 50ml tetrahydrofuran, and slowly add n-butyllithium (1.58ml, 1.60M, 2.52mmol). Stir at -78°C for 0.5h, add 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (500mg, 1.94mmol), and continue stirring for 2h. Add water to quench, extract with EA (50mL 1), 600 mg of the title compound was obtained as yellow foam, yield: 86.6%.
LC-MS：m/z＝359[M+H]+。LC-MS: m/z=359[M+H] + .
步骤2：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)吡咯烷-1-羧酸叔丁酯(6b)的制备Step 2: Preparation of tert-butyl 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)pyrrolidine-1-carboxylate (6b)
将化合物6a(600mg，1.67mmol)溶于3ml EtOH和3mL水合肼中，于80℃搅拌4h，降至室温，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得无色油状标题化合物210mg，收率：36.4％。Compound 6a (600 mg, 1.67 mmol) was dissolved in 3 ml EtOH and 3 mL hydrazine hydrate, stirred at 80°C for 4 h, cooled to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/ EA=1:1-1:2), 210 mg of the title compound was obtained as colorless oil, yield: 36.4%.
LC-MS：m/z＝345[M+H]+。LC-MS: m/z=345[M+H] + .
步骤3：2-((5-(4-氟-2-((R)-1-羟乙基)苯基)-2H-1,2,3-三唑-4-基)甲基)吡咯烷-1-羧酸叔丁酯(6c)的制备Step 3: 2-((5-(4-fluoro-2-((R)-1-hydroxyethyl)phenyl)-2H-1,2,3-triazol-4-yl)methyl)pyrrole Preparation of alkane-1-carboxylic acid tert-butyl ester (6c)
将化合物6b(210mg，0.610mmol)、(R)-5-氟-3-甲基苯并[c][1,2]氧杂硼酸-1(3H)-醇(121mg，0.730mmol)、四三苯基膦钯(35.8mg，0.031mmol)、碳酸钠(131mg，1.22mmol)溶于10ml甲苯/EtOH/H2O(2:1:0.4)中，于95℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得油状标题化合物230mg，收率：95.0％。Compound 6b (210 mg, 0.610 mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborate-1(3H)-ol (121 mg, 0.730 mmol), tetrakis Triphenylphosphine palladium (35.8 mg, 0.031 mmol) and sodium carbonate (131 mg, 1.22 mmol) were dissolved in 10 ml of toluene/EtOH/H 2 O (2:1:0.4), and stirred at 95°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 230 mg of the title compound as oil, yield: 95.0%.
LC-MS：m/z＝391[M+H]+。LC-MS: m/z=391[M+H] + .
步骤4：2-((5-(2-((R)-1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-4-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)吡咯烷-1-羧酸叔丁酯(6d)的制备Step 4: 2-((5-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 Preparation of -methyl-2H-1,2,3-triazol-4-yl)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (6d)
将化合物6c(230mg，0.588mmol)溶于10ml四氢呋喃中，于0℃加入钠氢(NaH)(70.6mg，1.76mmol)，于0℃搅拌0.5h，加入5-溴-3-氟-2-硝基吡啶(169mg，0.706mmol)，冰水淬灭，EA萃取，减压浓缩，残余物用硅胶柱层析 色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物280mg，收率：78.8％。Dissolve compound 6c (230mg, 0.588mmol) in 10ml tetrahydrofuran, add sodium hydrogen (NaH) (70.6mg, 1.76mmol) at 0°C, stir at 0°C for 0.5h, add 5-bromo-3-fluoro-2- Nitropyridine (169 mg, 0.706 mmol), quenched with ice water, extracted with EA, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Separate and purify by chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 280 mg of the title compound as a yellow solid, yield: 78.8%.
LC-MS：m/z＝605[M+H]+。LC-MS: m/z=605[M+H] + .
步骤5：5-溴-3-(1-(5-氟-2-(2-甲基-5-(吡咯烷-2-基甲基)-2H-1,2,3-三唑-4-基)苯基)乙氧基)-2-硝基吡啶(6e)的制备Step 5: 5-bromo-3-(1-(5-fluoro-2-(2-methyl-5-(pyrrolidin-2-ylmethyl))-2H-1,2,3-triazole-4 Preparation of -(yl)phenyl)ethoxy)-2-nitropyridine (6e)
将化合物6d(280mg，4.36mmol)溶于10ml二氯甲烷中，加入三氟乙酸(TFA)(3ml)，于室温搅拌过夜，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得油状标题化合物180mg，收率：77.3％。Compound 6d (280 mg, 4.36 mmol) was dissolved in 10 ml of dichloromethane, trifluoroacetic acid (TFA) (3 ml) was added, stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. After purification (mobile phase: PE/EA=1:1-2:1), 180 mg of the title compound was obtained as oil, yield: 77.3%.
LC-MS：m/z＝505[M+H]+。LC-MS: m/z=505[M+H] + .
步骤6：(R)-1-(5-氟-2-(5-((6-氟咪唑并[1,2-a]吡啶-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)苯基)乙烷-1-醇(6f)的制备Step 6: (R)-1-(5-fluoro-2-(5-((6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)-2-methyl-2H- Preparation of 1,2,3-triazol-4-yl)phenyl)ethane-1-ol (6f)
将化合物6e(180mg，0.356mmol)、TBAI(131mg，0.356mmol)和碳酸钾(K2CO3)(98mg，0.712mmol)溶于10ml二甲基亚砜中，于95℃搅拌过夜，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得油状标题化合物77.0mg，收率：51.0％。Compound 6e (180 mg, 0.356 mmol), TBAI (131 mg, 0.356 mmol) and potassium carbonate (K 2 CO 3 ) (98 mg, 0.712 mmol) were dissolved in 10 ml dimethyl sulfoxide, stirred at 95°C overnight, and the reaction was The liquid was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 77.0 mg of the title compound as an oil, yield: 51.0%.
LC-MS：m/z＝425[M+H]+。LC-MS: m/z=425[M+H] + .
步骤7：(11R)-13-氟-11,17-二甲基-2,3,11,17,19,19a-六氢-1H-5,9-(亚甲基)苯并[1]吡咯并[1,2-g][1,2,3]三唑并[4,5-j][1]氧杂[4,7]二氮杂环十四碳烯-8-胺(6)的制备Step 7: (11R)-13-fluoro-11,17-dimethyl-2,3,11,17,19,19a-hexahydro-1H-5,9-(methylene)benzo[1] Pyrrolo[1,2-g][1,2,3]triazolo[4,5-j][1]oxa[4,7]diazacyclotetradecen-8-amine(6 ) preparation
将化合物6f(77.0mg，0.181mmol)溶于5ml乙醇和1ml水中，依次加入铁粉(50.7mg，0.905mmol)和氯化铵(78.2mg，1.45mmol)，于70℃搅拌2h，将反应液减压浓缩，残余物通过高效制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物1.00mg，收率：1.90％。Compound 6f (77.0 mg, 0.181 mmol) was dissolved in 5 ml of ethanol and 1 ml of water, iron powder (50.7 mg, 0.905 mmol) and ammonium chloride (78.2 mg, 1.45 mmol) were added in sequence, stirred at 70°C for 2 h, and the reaction solution was Concentrate under reduced pressure, and the residue is separated by high-performance preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), 1.00 mg of the title compound was obtained as a white solid, yield: 1.90%.
LC-MS：m/z＝395[M+H]+。LC-MS: m/z=395[M+H] + .
实施例7：(R)-3-氟-5,13,20-三甲基-12,13,14,15,18,20-六氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[1',2:1,5]吡唑并[4,3-g][1,2,3]三唑并[4,15-j][1]氧杂[4]氮杂环十四碳烯-8-胺(7)的制备

Example 7: (R)-3-fluoro-5,13,20-trimethyl-12,13,14,15,18,20-hexahydro-5H-7,11-(methylene)benzo [l]Pyrazino[1',2:1,5]pyrazolo[4,3-g][1,2,3]triazolo[4,15-j][1]oxa[4 ] Preparation of azacyclotetradecene-8-amine (7)

步骤1：1-(2-((叔丁氧基羰基)氨基)乙基)-1H-吡唑-3,5-二羧酸二乙酯(7a)的制备Step 1: Preparation of 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (7a)
于室温，将3,5-吡唑羧酸二乙酯(15g，0.0707mol)、N-Boc-溴乙胺(18.9g，0.0848mol)溶于150ml DMF中。于0℃，加入碳酸铯(27.6g,0.0848mmol)，缓慢升至室温搅拌过夜。加水淬灭，EA萃取(150mL x 3)，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得白色固体标题化合物18.0g，收率：72.0％。Dissolve 3,5-pyrazole carboxylic acid diethyl ester (15g, 0.0707mol) and N-Boc-bromoethylamine (18.9g, 0.0848mol) in 150ml DMF at room temperature. At 0°C, add cesium carbonate (27.6g, 0.0848mmol), slowly raise to room temperature and stir overnight. Quench with water, extract with EA (150mL x 3), wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 18.0g of the title compound as a white solid, yield: 72.0%.
LC-MS：m/z＝356[M+H]+。LC-MS: m/z=356[M+H] + .
步骤2：4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸乙酯(7b)的制备Step 2: Preparation of 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (7b)
于0℃，将1-(2-((叔丁氧基羰基)氨基)乙基)-1H-吡唑-3,5-二羧酸二乙酯(7a)(18.0g，0.0507mol)溶于4N HCl的二氧六环溶液(150mL)，于室温搅拌4h。加入饱和碳酸氢钠溶液(150ml)，继续搅拌1h，DCM萃取(200mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物8.00g，收率：75.4％。Dissolve 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (7a) (18.0g, 0.0507mol) at 0°C. In 4N HCl in dioxane solution (150 mL), stir at room temperature for 4 h. Add saturated sodium bicarbonate solution (150ml), continue stirring for 1 hour, extract with DCM (200mL x 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 8.00g of the title compound as a yellow oil, yield: 75.4%.
LC-MS：m/z＝210[M+H]+。LC-MS: m/z=210[M+H] + .
步骤3：(4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)甲醇(7c)的制备Step 3 Preparation of: (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (7c)
于室温，将4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸乙酯(7b)(8.00g，0.0382mol)溶于150ml THF中。于0℃，加入四氢铝锂(5.79g，0.152mol)，升至70℃搅拌过夜。降至室温，依次加入5.79ml水、5.79ml 15％氢氧化钠水溶液和17ml水，于室温搅拌半小时，过滤，滤液减压浓缩，得黄色油状标题化合物3.20g，收率：54.4％。Dissolve 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (7b) (8.00g, 0.0382mol) in 150ml at room temperature THF. At 0°C, add lithium aluminum tetrahydride (5.79g, 0.152mol), raise the temperature to 70°C and stir overnight. Lower to room temperature, add 5.79ml of water, 5.79ml of 15% sodium hydroxide aqueous solution and 17ml of water in sequence, stir at room temperature for half an hour, filter, and concentrate the filtrate under reduced pressure to obtain 3.20g of the title compound as yellow oil, yield: 54.4%.
LC-MS：m/z＝154[M+H]+。LC-MS: m/z=154[M+H] + .
步骤4：2-(羟甲基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯(7d)的制备Step 4: Preparation of 2-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (7d)
于室温，将(4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)甲醇(7c)(3.20g，0.0209mol)溶于DCM(50ml)中。于0℃加入二碳酸二叔丁酯(5.47g，0.0251mmol)，缓慢升至室温搅拌1h，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:10-1:5)，得黄色固体标题化合物3.50g，收率：66.0％。 Dissolve (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (7c) (3.20g, 0.0209mol) in DCM (50ml) at room temperature . Add di-tert-butyl dicarbonate (5.47g, 0.0251mmol) at 0°C, slowly raise to room temperature and stir for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA =1:10-1:5), 3.50g of the title compound was obtained as a yellow solid, yield: 66.0%.
LC-MS：m/z＝254[M+H]+。LC-MS: m/z=254[M+H] + .
步骤5：2-甲酰基-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯(7e)的制备Step 5: Preparation of 2-formyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (7e)
于室温，将2-(羟甲基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯(7d)(3.50g，13.7mmol)溶于DCE(50ml)中，加入二氧化锰(4.78g，55.1mmol)，于60℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:10-1:5)，得白色油状标题化合物2.30g，收率：66.7％。At room temperature, 2-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (7d) (3.50g, 13.7mmol ) was dissolved in DCE (50 ml), added manganese dioxide (4.78 g, 55.1 mmol), and stirred at 60°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:10-1:5) to obtain 2.30g of the title compound as white oil, yield: 66.7%.
LC-MS：m/z＝252[M+H]+。LC-MS: m/z=252[M+H] + .
步骤6：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)(羟基)甲基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯(7f)的制备Step 6: 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(hydroxy)methyl)-6,7-dihydropyrazolo[1, Preparation of 5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (7f)
于室温，将4,5-二溴-2-甲基-2H-1,2,3-三唑(1.42g，5.97mmol)溶于20ml THF中。于-78℃，滴加正丁基锂溶液(2.15ml，2.5M，5.97mmol)，继续搅拌0.5h，加入2-甲酰基-6,7-二氢吡唑并[1,5-a]吡嗪-5-(4H)-羧酸叔丁酯(7e)(1.00g，3.98mmol)，继续搅拌2h，加水淬灭。EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得白色固体标题化合物1.50g，收率：54.9％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (1.42g, 5.97mmol) in 20ml THF at room temperature. At -78°C, add n-butyllithium solution (2.15ml, 2.5M, 5.97mmol) dropwise, continue stirring for 0.5h, and add 2-formyl-6,7-dihydropyrazolo[1,5-a] Pyrazine-5-(4H)-carboxylic acid tert-butyl ester (7e) (1.00g, 3.98mmol), continue stirring for 2 hours, and add water to quench. Extract EA (50mL 1.50 g of the title compound as a white solid, yield: 54.9%.
LC-MS：m/z＝413[M+H]+。LC-MS: m/z=413[M+H] + .
步骤7：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪(7g)的制备Step 7: 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[1 , Preparation of 5-a]pyrazine (7g)
于室温，将2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)((羟基)甲基)-6,7-二氢吡唑并[1,5-a]吡嗪-5(4H)-羧酸叔丁酯(7f)(1.50g，3.63mmol)溶于三氟乙酸(5ml)中，加入三乙基硅烷(2ml)，缓慢升温至60℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:100-1:10)，得黄色固体标题化合物720mg，收率：67.2％。At room temperature, 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)((hydroxy)methyl)-6,7-dihydropyrazolo[ 1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (7f) (1.50g, 3.63mmol) was dissolved in trifluoroacetic acid (5ml), added triethylsilane (2ml), and slowly heated up Stir overnight at 60°C. The reaction solution is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:100-1:10) to obtain 720 mg of the title compound as a yellow solid, yield :67.2%.
LC-MS：m/z＝297[M+H]+。LC-MS: m/z=297[M+H] + .
步骤8：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-5-甲基-4,5,6,7-四氢吡唑[1,5-a]吡嗪(7h)的制备Step 8: 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-methyl-4,5,6,7-tetrahydro Preparation of pyrazole[1,5-a]pyrazine (7h)
于室温，将2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪(7g)(720mg，2.43mmol)、甲醛(37％在H2O中)(0.35ml，9.72mmol)、TEA(490mg，4.86mmol)溶于MeOH(10ml)中，加入氰基硼氢化钠(610mg，9.72mmol)，于室温搅拌6h。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:100-1:10)，得黄色固体标题化合物320mg，收率：42.4％。At room temperature, 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrazine (7g) (720mg, 2.43mmol), formaldehyde (37% in H 2 O) (0.35ml, 9.72mmol), TEA (490mg, 4.86mmol) were dissolved in MeOH (10ml) , add sodium cyanoborohydride (610 mg, 9.72 mmol), and stir at room temperature for 6 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:100-1:10) to obtain 320 mg of the title compound as a yellow solid, yield: 42.4%.
LC-MS：m/z＝311[M+H]+。LC-MS: m/z=311[M+H] + .
步骤9：(R)-1-(5-氟-2-(2-甲基-5-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙-1-醇(7i)的制备Step 9: (R)-1-(5-fluoro-2-(2-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a Preparation of ]pyrazin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (7i)
于室温，将2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-5-甲基-4,5,6,7-四氢吡唑 [1,5-a]吡嗪(7h)(200mg，0.643mmol)、(R)-5-氟-3-甲基苯[c][1,2]氧杂硼酸-1(3H)-醇(117mg，0.707mmol)、四三苯基膦钯(74.2mg，0.0643mmol)、碳酸钠(136mg，1.28mmol)溶于5ml DMF/H2O(4:1)中。于95℃搅拌过夜，将反应液加水淬灭，EA萃取，合并有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物110mg，收率：46.2％。At room temperature, 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-methyl-4,5,6,7-tetrazol Hydropyrazole [1,5-a]pyrazine (7h) (200mg, 0.643mmol), (R)-5-fluoro-3-methylbenzene[c][1,2]oxaboric acid-1(3H)-ol (117 mg, 0.707 mmol), tetrakis triphenylphosphine palladium (74.2 mg, 0.0643 mmol), and sodium carbonate (136 mg, 1.28 mmol) were dissolved in 5 ml DMF/H 2 O (4:1). Stir overnight at 95°C, quench the reaction solution with water, extract with EA, combine the organic phases and concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) , 110 mg of the title compound was obtained as a yellow solid, yield: 46.2%.
LC-MS：m/z＝371.19[M+H]+。LC-MS: m/z=371.19[M+H] + .
步骤10：(R)-2-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-4-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪(7j)的制备Step 10: (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 -Methyl-2H-1,2,3-triazol-4-yl)methyl)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine Preparation of (7j)
于室温，将(R)-1-(5-氟-2-(2-甲基-5-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙-1-醇(7i)(110mg，0.297mmol)溶于10ml THF中。于0℃加入NaH(35.6mg，0.891mmol)，继续搅拌0.5h，加入5-溴-3-氟-2-硝基吡啶(78mg，0.356mmol)，升温至60℃搅拌过夜。将反应液用冰水淬灭，EA萃取，合并有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物82mg，收率：48.5％。At room temperature, (R)-1-(5-fluoro-2-(2-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (7i) (110mg, 0.297mmol) dissolved in 10ml THF . Add NaH (35.6 mg, 0.891 mmol) at 0°C, continue stirring for 0.5 h, add 5-bromo-3-fluoro-2-nitropyridine (78 mg, 0.356 mmol), raise the temperature to 60°C and stir overnight. The reaction solution was quenched with ice water, extracted with EA, the combined organic phases were concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain a yellow solid Title compound 82 mg, yield: 48.5%.
LC-MS：m/z＝571[M+H]+。LC-MS: m/z=571[M+H] + .
步骤11：(R)-5-溴-3-(1-(5-氟-2-(2-甲基-5-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙氧基)吡啶-2-胺(7k)的制备Step 11: (R)-5-bromo-3-(1-(5-fluoro-2-(2-methyl-5-((5-methyl-4,5,6,7-tetrahydropyrazole) And[1,5-a]pyrazin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (7k) preparation
于室温，将(R)-2-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-4-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪(7j)(82mg，0.143mmol)溶于EtOH(5ml)和1ml H2O(5ml)中，依次加入Fe粉(40mg，0.719mmol)和氯化铵(61mg，1.14mmol)，升温至70℃搅拌2h。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物50mg，收率：64.9％。At room temperature, (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)- 2-Methyl-2H-1,2,3-triazol-4-yl)methyl)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra Azine (7j) (82mg, 0.143mmol) was dissolved in EtOH (5ml) and 1ml H 2 O (5ml), Fe powder (40mg, 0.719mmol) and ammonium chloride (61mg, 1.14mmol) were added in sequence, and the temperature was raised to 70 ℃ and stir for 2h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 50 mg of the title compound as a yellow solid, yield: 64.9%.
LC-MS：m/z＝541[M+H]+。LC-MS: m/z=541[M+H] + .
步骤12：(R)-3-氟-5,13,20-三甲基-12,13,14,15,18,20-六氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[1',2:1,5]吡唑并[4,3-g][1,2,3]三唑并[4,15-j][1]氧杂[4]氮杂环十四碳烯-8-胺(7)的制备Step 12: (R)-3-Fluoro-5,13,20-trimethyl-12,13,14,15,18,20-hexahydro-5H-7,11-(methylene)benzo[ l]pyrazino[1',2:1,5]pyrazolo[4,3-g][1,2,3]triazolo[4,15-j][1]oxa[4] Preparation of nitrogen heterocyclic tetradecene-8-amine (7)
于室温，将(R)-5-溴-3-(1-(5-氟-2-(2-甲基-5-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙氧基)吡啶-2-胺(7k)(50mg，0.092mmol)溶于叔戊醇(2ml)中，加入乙酸钾(36mg，0.369mmol)、醋酸钯(20mg，0.092mmol)、正丁基二(1-金刚烷基)膦(92mg，0.184mmol)，氮气氛下，缓慢升温至120℃搅拌16小时。加10mL水淬灭，EA萃取(10mL x 3)，饱和食盐水洗涤(10mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高效制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物1.6mg，收率：3.8％。 At room temperature, (R)-5-bromo-3-(1-(5-fluoro-2-(2-methyl-5-((5-methyl-4,5,6,7-tetrahydropyridine) Azolo[1,5-a]pyrazin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (7k) (50mg, 0.092mmol) was dissolved in tert-amyl alcohol (2ml), and potassium acetate (36mg, 0.369mmol), palladium acetate (20mg, 0.092mmol), n-butylbis(1-adamantyl)phosphine (92mg, 0.184 mmol), slowly raise the temperature to 120°C and stir for 16 hours under a nitrogen atmosphere. Add 10mL of water to quench, extract with EA (10mL Model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), 1.6 mg of the title compound was obtained as a white solid, yield: 3.8%.
LC-MS：m/z＝461[M+H]+。LC-MS: m/z=461[M+H] + .
实施例8：(5R)-3-氟-5,20-二甲基-14(三氟甲基)-13,14,15,16,18,20-六氢-5H-7,11-(亚甲基)苯并[l]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,15-j][1]氧杂[4]氮杂环十四碳烯-8-胺(8)的制备
Example 8: (5R)-3-fluoro-5,20-dimethyl-14(trifluoromethyl)-13,14,15,16,18,20-hexahydro-5H-7,11-( Methylene)benzo[l]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,15-j][1 Preparation of ]oxa[4]azacyclotetradecene-8-amine (8)
步骤1：6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-甲醛(8a)的制备Step 1: Preparation of 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxaldehyde (8a)
于室温，将6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-羧酸乙酯(2.50g，9.54mmol)溶于THF(50ml)中。于-78℃，滴加DIBAL-H(9.5ml，1M，9.54mmol)，继续搅拌4h。将反应液加水淬灭，EA萃取(50mL x 5)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1-1:1)，得黄色固体标题化合物1.80g，收率：54.9％。Dissolve ethyl 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylate (2.50g, 9.54mmol) in THF at room temperature. (50ml). At -78°C, DIBAL-H (9.5ml, 1M, 9.54mmol) was added dropwise, and stirring was continued for 4h. The reaction solution was quenched with water, extracted with EA (50mL -1:1), 1.80g of the title compound was obtained as a yellow solid, yield: 54.9%.
LC-MS：m/z＝219[M+H]+。LC-MS: m/z=219[M+H] + .
步骤2：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基)甲醇(8b)的制备Step 2: (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo Preparation of [1,2-a]pyridin-2-yl)methanol (8b)
于室温，将4,5-二溴-2-甲基-2H-1,2,3-三唑(2.71g，12.3mmol)溶于20ml THF中。于78℃，滴加正丁基锂溶液(4.90ml，2.5M，12.3mmol)，继续搅拌0.5h，加入6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-甲醛(8a)(1.80g，8.21mmol)。于0℃搅拌2h，加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物1.10g，收率：54.9％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (2.71g, 12.3mmol) in 20ml THF at room temperature. At 78°C, add n-butyllithium solution (4.90ml, 2.5M, 12.3mmol) dropwise, continue stirring for 0.5h, and add 6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[ 1,2-a]pyridine-2-carboxaldehyde (8a) (1.80 g, 8.21 mmol). Stir at 0°C for 2 hours, add water to quench, extract with EA (50mL 1:1-2:1), 1.10g of the title compound was obtained as a yellow solid, yield: 54.9%.
LC-MS：m/z＝380[M+H]+。LC-MS: m/z=380[M+H] + .
步骤3：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶(8c)的制备Step 3: 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)-5,6,7, Preparation of 8-tetrahydroimidazo[1,2-a]pyridine (8c)
于室温，将(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基)甲醇(8b)(1.10g，2.89mmol)溶于三氟乙酸(5ml)中，加入 三乙基硅烷(2ml)，于60℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物510mg，收率：48.6％。At room temperature, (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazole And [1,2-a]pyridin-2-yl)methanol (8b) (1.10g, 2.89mmol) was dissolved in trifluoroacetic acid (5ml), and added Triethylsilane (2ml), stir at 60°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 510 mg of the title compound as a yellow solid, yield: 48.6%.
LC-MS：m/z＝364[M+H]+。LC-MS: m/z=364[M+H] + .
步骤4：(1R)-1-(5-氟-2-(2-甲基-5-((6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙-1-醇(8d)的制备Step 4: (1R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))-5,6,7,8-tetrahydroimidazo[1, Preparation of 2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (8d)
于室温，将2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶(8c)(400mg，1.09mmol)、(R)-5-氟-3-甲基苯并[c][1,2]氧杂硼酸-1(3H)-醇(218mg，1.31mmol)、四三苯基膦钯(125mg，0.109mmol)、碳酸钠(577mg，5.45mmol)溶于10ml甲苯/EtOH/H2O(2:1:0.4)中，于95℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物150mg，收率：32.5％。At room temperature, 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)-5,6,7 ,8-tetrahydroimidazo[1,2-a]pyridine (8c) (400mg, 1.09mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaboric acid -1(3H)-alcohol (218mg, 1.31mmol), tetrakis triphenylphosphine palladium (125mg, 0.109mmol), sodium carbonate (577mg, 5.45mmol) were dissolved in 10ml toluene/EtOH/H2O (2:1:0.4) medium and stir at 95°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 150 mg of the title compound as a yellow solid, yield: 32.5%.
LC-MS：m/z＝424[M+H]+。LC-MS: m/z=424[M+H] + .
步骤5：2-((5-(2-((R)-1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-4-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶(8e)的制备Step 5: 2-((5-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 -Methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a ] Preparation of pyridine (8e)
于室温，将(1R)-1-(5-氟-2-(2-甲基-5-((6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙-1-醇(8d)(150mg，0.354mmol)溶于10ml THF中。于0℃加入NaH(42mg，1.06mmol)，继续搅拌0.5h，加入5-溴-3-氟-2-硝基吡啶(85mg，0.389mmol)。于室温搅拌过夜。将反应液用冰水淬灭，EA萃取，合并有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物80mg，收率：36.3％。At room temperature, (1R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (8d) (150mg, 0.354mmol) dissolved in 10ml THF. NaH (42 mg, 1.06 mmol) was added at 0°C, stirring was continued for 0.5 h, and 5-bromo-3-fluoro-2-nitropyridine (85 mg, 0.389 mmol) was added. Stir at room temperature overnight. The reaction solution was quenched with ice water, extracted with EA, the combined organic phases were concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain a yellow solid Title compound 80 mg, yield: 36.3%.
LC-MS：m/z＝624[M+H]+。LC-MS: m/z=624[M+H] + .
步骤6：5-溴-3-((1R)-1-(5-氟-2-(2-甲基-5-((6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙氧基)吡啶-2-胺(8f)的制备Step 6: 5-bromo-3-((1R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))-5,6,7,8- Tetrahydroimidazo[1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (8f ) preparation
于室温，将2-((5-(2-((R)-1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-4-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)-5,6,7,8-四氢咪唑并[1,2-a]吡啶(8e)(70mg，0.112mmol)溶于5ml EtOH和1ml H2O中，依次加入Fe粉(25mg，0.448mmol)和氯化铵(48mg，0.896mmol)，于70℃搅拌2h。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物50mg，收率：75.7％。At room temperature, 2-((5-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)- 2-Methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2- a] Pyridine (8e) (70 mg, 0.112 mmol) was dissolved in 5 ml EtOH and 1 ml H 2 O. Fe powder (25 mg, 0.448 mmol) and ammonium chloride (48 mg, 0.896 mmol) were added in sequence, and stirred at 70°C for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 50 mg of the title compound as a yellow solid, yield: 75.7%.
LC-MS：m/z＝594[M+H]+。LC-MS: m/z=594[M+H] + .
步骤7：(5R)-3-氟-5,20-二甲基-14(三氟甲基)-13,14,15,16,18,20-六氢-5H-7,11-(亚甲基)苯并[l]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,15-j][1]氧杂[4]氮杂环十四碳烯-8-胺(8)的制备Step 7: (5R)-3-fluoro-5,20-dimethyl-14(trifluoromethyl)-13,14,15,16,18,20-hexahydro-5H-7,11-(methyl Methyl)benzo[l]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,15-j][1] Preparation of oxa[4]azacyclotetradecene-8-amine (8)
于室温，将5-溴-3-((1R)-1-(5-氟-2-(2-甲基-5-((6-(三氟甲基)-5,6,7,8-四氢咪唑并 [1,2-a]吡啶-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙氧基)吡啶-2-胺(8f)(50mg，0.084mmol)溶于2ml叔戊醇中，加入乙酸钾(63mg，0.645mmol)、醋酸钯(29mg，0.129mmol)、正丁基二(1-金刚烷基)膦(92mg，0.258mmol)，氮气氛下，于120℃搅拌16小时。加10mL水淬灭，EA萃取(10mL x 3)，饱和食盐水洗涤(10mL x 1)，无水硫酸钠干燥，过滤，减压浓缩，残余物通过高效制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物4mg，收率：9.3％。At room temperature, 5-bromo-3-((1R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))-5,6,7,8 -Tetrahydroimidazo [1,2-a]pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (8f) (50 mg, 0.084mmol) was dissolved in 2 ml of tert-amyl alcohol, potassium acetate (63mg, 0.645mmol), palladium acetate (29mg, 0.129mmol), n-butylbis(1-adamantyl)phosphine (92mg, 0.258mmol), nitrogen Under the atmosphere, stir at 120°C for 16 hours. Add 10mL of water to quench, extract with EA (10mL : Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), 4 mg of the title compound was obtained as a white solid, yield: 9.3%.
LC-MS：m/z＝514[M+H]+。LC-MS: m/z=514[M+H] + .
实施例9：(R)-3-氟-5,20-二甲基-14,15,18,20-四氢-5H,13H-7,11-(亚甲基)[1,3]噁嗪并[3',2':1,5]吡唑并[4,3-g]苯并[l][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(9)的制备
Example 9: (R)-3-fluoro-5,20-dimethyl-14,15,18,20-tetrahydro-5H,13H-7,11-(methylene)[1,3]oxane Azino[3',2':1,5]pyrazolo[4,3-g]benzo[l][1,2,3]triazolo[4,5-j][1]oxa [4] Preparation of nitrogen heterocyclic tetradecene-8-amine (9)
步骤1：6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-甲酸乙酯(9a)的制备Step 1: Preparation of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid ethyl ester (9a)
于室温，向5-羟基-1H-吡唑-3-甲酸乙酯(3.1g，19.8mmol)的乙腈(40.0mL)溶液中加入1,3-二溴丙烷(4.41g，21.8mmol)、碳酸钾(10.96g，79.4mmol)，于85℃搅拌16小时。过滤，滤液直接减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物3.00g。收率77.3％。To a solution of 5-hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (3.1g, 19.8mmol) in acetonitrile (40.0mL) at room temperature, 1,3-dibromopropane (4.41g, 21.8mmol) and carbonic acid were added. Potassium (10.96g, 79.4mmol), stirred at 85°C for 16 hours. Filter, and the filtrate is directly concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 3.00 g of the title compound as a white solid. The yield is 77.3%.
LC-MS：m/z 197[M+H]+。LC-MS: m/z 197[M+H] + .
步骤2：6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-甲醛(9b)的制备 Step 2: Preparation of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carbaldehyde (9b)
氮气氛下，于-78℃向6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-甲酸乙酯(9a)(2.75g，14.0mmol)的二氯甲烷(30.0mL)溶液中加入二异丁基氢化铝(42.0mL，42.0mmol)，搅拌1.5小时。缓慢加入甲醇淬灭，加入1M盐酸调节PH～7，将反应液用二氯甲烷萃取(50mL x 2)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物1.70g。收率73.1％。Under nitrogen atmosphere, add 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid ethyl ester (9a) (2.75g, 14.0mmol) at -78°C. ) in dichloromethane (30.0 mL), add diisobutylaluminum hydride (42.0 mL, 42.0 mmol), and stir for 1.5 hours. Slowly add methanol to quench, add 1M hydrochloric acid to adjust the pH to 7, and extract the reaction solution with dichloromethane (50mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 1.70 g of the title compound as a white solid. The yield is 73.1%.
LC-MS：m/z 152[M+H]+。LC-MS: m/z 152[M+H] + .
步骤3：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-基)甲醇(9c)的制备Step 3: (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6,7-dihydro-5H-pyrazolo[5,1-b][1 ,3] Preparation of oxazin-2-yl)methanol (9c)
氮气氛下，于-78℃向4,5-二溴-2-甲基-2H-1,2,3-三唑(3.14g，13.15mmol)的四氢呋喃(30.0mL)溶液中加入正丁基锂(5.26mL，13.15mmol)，搅拌1小时，加入6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-甲醛(9b)(1.0g，6.57mmol)再搅拌1小时。加入饱和氯化铵溶液淬灭，EA萃取，合并有机相，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝10:1)，得到白色固体状的标题化合物900mg。收率41.9％。Under a nitrogen atmosphere, n-butyl was added to a solution of 4,5-dibromo-2-methyl-2H-1,2,3-triazole (3.14g, 13.15mmol) in tetrahydrofuran (30.0mL) at -78°C. Lithium (5.26mL, 13.15mmol), stir for 1 hour, add 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carbaldehyde (9b) (1.0g , 6.57mmol) and stir for another 1 hour. Add saturated ammonium chloride solution to quench, extract with EA, combine the organic phases, and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=10:1) to obtain 900 mg of the title compound as a white solid. Yield 41.9%.
LC-MS：m/z 314[M+H]+。LC-MS: m/z 314[M+H] + .
步骤4：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(9d)的制备Step 4: 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-5H-pyrazolo[5, Preparation of 1-b][1,3]oxazine (9d)
于室温，向(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-基)甲醇(9c)(1.70g，5.43mmol)的三氟乙酸(20.0mL)溶液中加入三乙基硅烷(2.50g，21.7mmol)，于60℃搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)，得到淡黄色油状的标题化合物1.1g。收率65.1％。To (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6,7-dihydro-5H-pyrazolo[5,1-b][ Add triethylsilane (2.50g, 21.7mmol) to a solution of 1,3]oxazin-2-yl)methanol (9c) (1.70g, 5.43mmol) in trifluoroacetic acid (20.0mL), and stir at 60°C overnight. . The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 1.1 g of the title compound as a light yellow oil. Yield 65.1%.
LC-MS：m/z 298[M+H]+。LC-MS: m/z 298[M+H] + .
步骤5：(R)-1-(2-(5-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙烷-1-醇(9e)的制备Step 5: (R)-1-(2-(5-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl)methyl Preparation of )-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethane-1-ol (9e)
氮气氛下，于室温，向2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(9d)(500mg，1.68mmol)的甲苯(10.0mL)、乙醇(2.00mL)和水(2.00mL)混合溶液中加入四三苯基膦钯(194mg，1.85mmol)，碳酸钠(713mg，6.73mmol)和(R)-5-氟-3-甲基苯并[c][1,2]噁硼烷-1(3H)-醇(307mg，1.85mmol)。氮气氛下，于70℃搅拌过夜。将反应液用水稀释，乙酸乙酯萃取(50mL x 2)。合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到黄色固体状的标题化合物300mg。收率45.9％。Under nitrogen atmosphere, at room temperature, add 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-5H-pyridine. To a mixed solution of azolo[5,1-b][1,3]oxazine (9d) (500 mg, 1.68 mmol) in toluene (10.0 mL), ethanol (2.00 mL) and water (2.00 mL) was added tetraphenyl Palladium phosphine (194 mg, 1.85 mmol), sodium carbonate (713 mg, 6.73 mmol) and (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborane-1(3H)- Alcohol (307 mg, 1.85 mmol). Under nitrogen atmosphere, stir at 70°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate (50mL x 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 300 mg of the title compound as a yellow solid. Yield 45.9%.
LC-MS：m/z 358[M+H]+。LC-MS: m/z 358[M+H] + .
步骤6：(R)-2-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-5-氟苯基)-2-甲基 -2H-1,2,3-三唑-4-基)甲基)-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(9f)的制备Step 6: (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2 -methyl -2H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (9f) preparation
于0℃，向(R)-1-(2-(5-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙烷-1-醇(9e)(280mg，0.784mmol)的四氢呋喃(7.0mL)溶液中加入NaH(47mg，1.17mmol)，于室温搅拌1小时，加入5-溴-3-氟-2-硝基吡啶(207mg，0.941mmol)，室温搅拌过夜。将反应液加水淬灭，乙酸乙酯萃取，合并有机相，减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)，得到黄色固体状的标题化合物260mg。收率58.0％。To (R)-1-(2-(5-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-2-yl) Methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethane-1-ol (9e) (280 mg, 0.784 mmol) in tetrahydrofuran (7.0 mL) solution, add NaH (47 mg, 1.17 mmol), stir at room temperature for 1 hour, add 5-bromo-3-fluoro-2-nitropyridine (207 mg, 0.941 mmol), and stir at room temperature overnight. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 260 mg of the title compound as a yellow solid. The yield is 58.0%.
LC-MS：m/z 558[M+H]+。LC-MS: m/z 558[M+H] + .
步骤7：(R)-5-溴-3-(1-(2-(5-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙氧基)吡啶-2-胺(9g)的制备Step 7: (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine Preparation of -2-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (9g)
将(R)-2-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-5-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(9f)(250mg，0.448mmol)溶于乙醇(5.00mL)和水(1.00mL)的混合溶液中，加入铁粉(125mg，2.24mmol)和氯化铵(193mg，3.59mmol)，于70℃搅拌2小时。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)。得到淡黄色固体的标题化合物40mg。收率16.9％。(R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2-methyl Base-2H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (9f) (250mg, 0.448mmol) was dissolved in a mixed solution of ethanol (5.00mL) and water (1.00mL), add iron powder (125mg, 2.24mmol) and ammonium chloride (193mg, 3.59mmol), and stir at 70°C for 2 hours. . The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1). 40 mg of the title compound was obtained as a pale yellow solid. Yield 16.9%.
LC-MS：m/z 528[M+H]+。LC-MS: m/z 528[M+H] + .
步骤8：(R)-3-氟-5,20-二甲基-14,15,18,20-四氢-5H,13H-7,11-(亚甲基)[1,3]噁嗪并[3',2':1,5]吡唑并[4,3-g]苯并[l][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(9)的制备Step 8: (R)-3-fluoro-5,20-dimethyl-14,15,18,20-tetrahydro-5H,13H-7,11-(methylene)[1,3]oxazine And[3',2':1,5]pyrazolo[4,3-g]benzo[l][1,2,3]triazolo[4,5-j][1]oxa[ 4] Preparation of nitrogen heterocyclic tetradecene-8-amine (9)
于室温，向(R)-5-溴-3-(1-(2-(5-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙氧基)吡啶-2-胺(9g)(40mg，0.075mmol)的叔戊醇(3.00mL)溶液中加入醋酸钯(17mg，0.075mmol)、正丁基二(1-金刚烷基)膦(54mg，0.15mmol)和醋酸钾(37mg，0.379mmol)。氮气氛下，于120℃搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝20:1)，得到粗品。粗品通过高效液相色谱法纯化(色谱柱型号：XBridge Prep OBD C18 Column，30*150mm，5μm；流动相A：水(10mmol/L碳酸氢铵+0.1％氨水)，流动相B：乙腈；流速：60mL/min；梯度：47％B至74％B，在8min内，74％B)，得到白色固体状的标题化合物0.500mg。收率14.7％。At room temperature, add (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]ox Azin-2-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (9g) ( To a solution of 40 mg, 0.075 mmol) in tert-amyl alcohol (3.00 mL) were added palladium acetate (17 mg, 0.075 mmol), n-butyldi(1-adamantyl)phosphine (54 mg, 0.15 mmol) and potassium acetate (37 mg, 0.379 mmol). Under nitrogen atmosphere, stir at 120°C overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=20:1) to obtain a crude product. The crude product was purified by high performance liquid chromatography (column model: : 60 mL/min; gradient: 47% B to 74% B, within 8 min, 74% B) to obtain 0.500 mg of the title compound as a white solid. Yield 14.7%.
LC-MS：m/z 448[M+H]+。LC-MS: m/z 448[M+H] + .
实施例10：(R)-3-氟-5,20-二甲基-12,13,18,20-四氢-5H,15H-7,11-(亚甲基)[1,3]噁嗪并[3',4':1,5]吡唑并[4,3-g]苯并[1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(10)的制备
Example 10: (R)-3-fluoro-5,20-dimethyl-12,13,18,20-tetrahydro-5H,15H-7,11-(methylene)[1,3]oxane Azino[3',4':1,5]pyrazolo[4,3-g]benzo[1,2,3]triazolo[4,5-j][1]oxa[4] Preparation of nitrogen heterocyclic tetradecene-8-amine (10)
步骤1：4-亚硝基吗啉-3-羧酸(10a)的制备Step 1: Preparation of 4-nitrosomorpholine-3-carboxylic acid (10a)
将吗啉-3-羧酸(8.00g，61.0mmol)溶于50mL水中的溶液中，加入8mL浓盐酸，然后于0℃缓慢地加入亚硝酸钠(NaNO2)(6.73g，97.6mmol)溶于80mL H2O中的溶液。继续搅拌1小时，将反应液减压浓缩，得到白色固体状的标题化合物9.00g，收率：90.0％。Dissolve morpholine-3-carboxylic acid (8.00g, 61.0mmol) in 50mL of water, add 8mL of concentrated hydrochloric acid, and then slowly add sodium nitrite (NaNO 2 ) (6.73g, 97.6mmol) at 0°C. Solution in 80 mL H 2 O. Stirring was continued for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain 9.00 g of the title compound as a white solid, yield: 90.0%.
LC-MS：m/z＝161[M+H]+。LC-MS: m/z=161[M+H] + .
步骤2：3-氧代-6,7-二氢-3H-[1,2,3]噁二唑并[4,3-c][1,4]噁嗪-8(4H)-鎓-3a-盐(10b)的制备Step 2: 3-Oxo-6,7-dihydro-3H-[1,2,3]oxadiazolo[4,3-c][1,4]oxazine-8(4H)-onium- Preparation of 3a-salt (10b)
将化合物10a(9.00g，49.6mmol)溶于90ml二氯甲烷中，于0℃缓慢滴加三氟甲磺酸酐(TFAA)(10.4g，49.6mmol)，继续搅拌0.5h。加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/THF＝1:1-2:1)，得白色固体状标题化合物7.90g，收率：100％。Compound 10a (9.00g, 49.6mmol) was dissolved in 90ml of methylene chloride, trifluoromethanesulfonic anhydride (TFAA) (10.4g, 49.6mmol) was slowly added dropwise at 0°C, and stirring was continued for 0.5h. Add water to quench, extract with EA (50mL 1), 7.90g of the title compound was obtained as a white solid, yield: 100%.
LC-MS：m/z＝143[M+H]+。LC-MS: m/z=143[M+H] + .
步骤3：(6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-2-羧酸甲酯(10c)的制备Step 3: Preparation of: (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid methyl ester (10c)
将化合物10b(10.0g，69.9mmol)溶于100ml二甲苯中，再加入丙炔酸甲酯(17.6g，209mmol)，于120℃搅拌过夜，加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动:DCM/MeOH＝1:1-2:1)，得白色固体标题化合物6.00g，收率：46.8％。Dissolve compound 10b (10.0g, 69.9mmol) in 100ml xylene, then add methyl propiolate (17.6g, 209mmol), stir at 120°C overnight, add water to quench, EA extraction (50mL x 3), no Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile: DCM/MeOH=1:1-2:1) to obtain 6.00g of the title compound as a white solid, yield: 46.8%.
LC-MS：m/z＝183[M+H]+。LC-MS: m/z=183[M+H] + .
步骤4：(6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-2-基)甲醇(10d)的制备Step 4 Preparation of: (6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)methanol (10d)
将化合物10c(6.00g，32.7mmol)溶于100ml四氢呋喃中，于0℃，分批加 入氢化铝锂(LAH)(2.47g，65.4mmol)，室温搅拌0.5h。将反应液加水淬灭，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得黄色油状标题化合物6.00g，直接用于下一步反应。Compound 10c (6.00g, 32.7mmol) was dissolved in 100ml tetrahydrofuran, and added in batches at 0°C. Lithium aluminum hydride (LAH) (2.47g, 65.4mmol) was added and stirred at room temperature for 0.5h. The reaction solution was quenched with water and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:1-2:1) to obtain 6.00g of the title compound as a yellow oil, which was used directly. Next reaction.
LC-MS：m/z＝155[M+H]+。LC-MS: m/z=155[M+H] + .
步骤5：4,5-二氢-7H-吡唑并[1,5-c][1,3]噁嗪-2-甲醛(10e)的制备Step 5: Preparation of 4,5-dihydro-7H-pyrazolo[1,5-c][1,3]oxazine-2-carbaldehyde (10e)
将化合物10d(3.00g，19.3mmol)溶于30ml 1,2-二氯甲烷中，加入二氧化锰(MnO2)(3.36g，38.7mmol)，于80℃搅拌过夜。将反应液加水淬灭，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得黄色固体标题化合物1.80g，收率：59.8％。Compound 10d (3.00g, 19.3mmol) was dissolved in 30ml of 1,2-dichloromethane, manganese dioxide (MnO 2 ) (3.36g, 38.7mmol) was added, and the mixture was stirred at 80° C. overnight. The reaction solution was quenched with water and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:1-2:1) to obtain 1.80g of the title compound as a yellow solid, yield: 59.8%.
LC-MS：m/z＝153[M+H]+。LC-MS: m/z=153[M+H] + .
步骤6：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(4,5-二氢-7H-吡唑并[1,5-c][1,3]噁嗪-2-基)甲醇(10f)的制备Step 6: (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(4,5-dihydro-7H-pyrazolo[1,5-c][1 ,3] Preparation of oxazin-2-yl)methanol (10f)
将4,5-二溴-2-甲基-2H-1,2,3-三唑(4.05g，16.7mmol)溶于100ml THF中，于-78℃，滴加正丁基锂(在己烷中)(9.25ml,1.60M，14.8mmol)，继续搅拌0.5h。加入化合物10e(1.50g，9.86mmol)，继续搅拌2h。加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物550mg，收率：18.0％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (4.05g, 16.7mmol) in 100ml THF, and add n-butyllithium (in hexane) dropwise at -78°C. alkane) (9.25ml, 1.60M, 14.8mmol), and continued stirring for 0.5h. Compound 10e (1.50g, 9.86mmol) was added and stirring was continued for 2h. Add water to quench, extract with EA (50mL x 3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-2:1) to obtain 550 mg of the title compound as a yellow solid, yield: 18.0%.
LC-MS：m/z＝314[M+H]+。LC-MS: m/z=314[M+H] + .
步骤7：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-4,5-二氢-7H-吡唑并[1,5-c][1,3]噁嗪(10g)的制备Step 7: 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-4,5-dihydro-7H-pyrazolo[1, Preparation of 5-c][1,3]oxazine (10g)
将化合物10f(550mg，1.75mmol)溶于10ml三氟乙酸(TFA)中，加入三乙基硅烷(Et3SiH)(2ml)，于70℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得黄色油状标题化合物450mg，收率：70.1％。Compound 10f (550 mg, 1.75 mmol) was dissolved in 10 ml of trifluoroacetic acid (TFA), triethylsilane (Et 3 SiH) (2 ml) was added, and the mixture was stirred at 70° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:1-2:1) to obtain 450 mg of the title compound as a yellow oil, yield: 70.1%.
LC-MS：m/z＝298[M+H]+。LC-MS: m/z=298[M+H] + .
步骤8：(R)-1-(2-(5-((4,5-二氢-7H-吡唑并[1,5-c][1,3]噁嗪-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙-1-醇(10h)的制备Step 8: (R)-1-(2-(5-((4,5-dihydro-7H-pyrazolo[1,5-c][1,3]oxazin-2-yl)methyl Preparation of )-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethan-1-ol (10h)
将化合物10g(450mg，1.51mmol)、(R)-5-氟-3-甲基苯并[c][1,2]氧杂硼酸-1(3H)-醇(326mg，1.81mmol)、四三苯基膦钯(189mg，0.151mmol)、碳酸钠(695mg，6.04mmol)溶于10ml甲苯/EtOH/H2O(2:1:0.4)中，于95℃搅拌过夜，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物550mg，直接用于下一步反应。Compound 10g (450mg, 1.51mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborate-1(3H)-ol (326mg, 1.81mmol), tetrakis Triphenylphosphine palladium (189 mg, 0.151 mmol) and sodium carbonate (695 mg, 6.04 mmol) were dissolved in 10 ml toluene/EtOH/H2O (2:1:0.4), stirred at 95°C overnight, and the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 550 mg of the title compound as a yellow solid, which was directly used in the next reaction.
LC-MS：m/z＝358[M+H]+。LC-MS: m/z=358[M+H] + .
步骤9：(R)-2-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-4-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪(10i)的制备 Step 9: (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 -Methyl-2H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine ( Preparation of 10i)
将化合物10g(450mg，1.25mmol)溶于10ml四氢呋喃中，于0℃加入钠氢(NaH)(147mg，3.68mmol，60％在油中)。于0℃搅拌0.5h，加入5-溴-3-氟-2-硝基吡啶(270mg，1.23mmol)，继续搅拌1小时。将反应液用冰水淬灭，EA萃取，合并有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物330mg，收率：47.0％。Compound 10g (450mg, 1.25mmol) was dissolved in 10ml tetrahydrofuran, and sodium hydrogen (NaH) (147mg, 3.68mmol, 60% in oil) was added at 0°C. Stir at 0°C for 0.5 h, add 5-bromo-3-fluoro-2-nitropyridine (270 mg, 1.23 mmol), and continue stirring for 1 hour. The reaction solution was quenched with ice water, extracted with EA, the combined organic phases were concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain a yellow solid Title compound 330 mg, yield: 47.0%.
LC-MS：m/z＝558[M+H]+。LC-MS: m/z=558[M+H] + .
步骤10：(R)-5-溴-3-(1-(2-(5-((6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-5-氟苯基)乙氧基)吡啶-2-胺(10j)的制备Step 10: (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine Preparation of -2-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)-5-fluorophenyl)ethoxy)pyridin-2-amine (10j)
将化合物10i(330mg，0.591mmol)溶于5ml乙醇和1ml水中，依次加入铁粉(132mg，2.36mmol)和氯化铵(273mg，4.72mmol)，于70℃搅拌2h，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物220mg，收率：70.5％。Compound 10i (330 mg, 0.591 mmol) was dissolved in 5 ml of ethanol and 1 ml of water, iron powder (132 mg, 2.36 mmol) and ammonium chloride (273 mg, 4.72 mmol) were added in sequence, stirred at 70°C for 2 h, and the reaction solution was concentrated under reduced pressure. , the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 220 mg of the title compound as a yellow solid, yield: 70.5%.
LC-MS：m/z＝528[M+H]+。LC-MS: m/z=528[M+H] + .
步骤11：(R)-3-氟-5,20-二甲基-12,13,18,20-四氢-5H,15H-7,11-(亚甲基)[1,3]噁嗪并[3',4':1,5]吡唑并[4,3-g]苯并[1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(10)的制备Step 11: (R)-3-fluoro-5,20-dimethyl-12,13,18,20-tetrahydro-5H,15H-7,11-(methylene)[1,3]oxazine And[3',4':1,5]pyrazolo[4,3-g]benzo[1,2,3]triazolo[4,5-j][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (10)
将化合物10j(220mg，0.416mmol)溶于2ml叔戊醇中，加入乙酸钾(290mg，2.02mmol)、醋酸钯(90.0mg，0.416mmol)、正丁基二(1-金刚烷基)膦(cataCXium A)(290mg，0.832mmol)，氮气氛下，于120℃搅拌16小时。加10mL水淬灭，EA萃取(10mL x 3)，饱和食盐水洗涤(10mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高效制备液相色谱法分离(色谱柱型号：Daisogei30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物10.0mg，收率：8.30％。Compound 10j (220 mg, 0.416 mmol) was dissolved in 2 ml of tert-amyl alcohol, and potassium acetate (290 mg, 2.02 mmol), palladium acetate (90.0 mg, 0.416 mmol), n-butylbis(1-adamantyl)phosphine ( cataCXium A) (290 mg, 0.832 mmol), stir at 120°C for 16 hours under nitrogen atmosphere. Add 10 mL of water to quench, extract with EA (10 mL Model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), 10.0 mg of the title compound was obtained as a white solid, yield: 8.30%.
LC-MS：m/z＝448[M+H]+。LC-MS: m/z=448[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.71(dd,J＝10.3,2.7Hz,1H),7.31(dd,J＝8.6,5.9Hz,1H),7.28–7.12(m,2H),6.01(d,J＝1.9Hz,1H),5.77(s,2H),5.13(dd,J＝6.5,2.1Hz,1H),4.97(d,J＝14.9Hz,1H),4.53(d,J＝14.9Hz,1H),4.35–4.02(m,6H),4.04–3.90(m,2H),3.23(d,J＝15.3Hz,1H),1.71(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.71 (dd, J＝10.3, 2.7Hz, 1H), 7.31 (dd, J＝8.6, 5.9Hz, 1H), 7.28–7.12 (m, 2H), 6.01(d,J＝1.9Hz,1H),5.77(s,2H),5.13(dd,J＝6.5,2.1Hz,1H),4.97(d,J＝14.9Hz,1H),4.53(d,J ＝14.9Hz,1H),4.35–4.02(m,6H),4.04–3.90(m,2H),3.23(d,J＝15.3Hz,1H),1.71(d,J＝6.2Hz,3H).
实施例11：(R)-3-氟-5,19-二甲基-5,12,13,15,17,19-六氢-7,11-(亚甲基)苯并[1]吡喃并[4',3':4,5]噻吩并[3,2-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(11)的制备

Example 11: (R)-3-fluoro-5,19-dimethyl-5,12,13,15,17,19-hexahydro-7,11-(methylene)benzo[1]pyridine Prando[4',3':4,5]thieno[3,2-g][1,2,3]triazolo[4,5-j][1]oxa[4]azeterocycle Preparation of tetradecene-8-amine (11)

步骤1：4-氯-5,6-二氢2H-吡喃-3-甲醛(11a)的制备Step 1: Preparation of 4-chloro-5,6-dihydro2H-pyran-3-carboxaldehyde (11a)
将4H-吡喃-4-酮(10.0g，100mmol)溶于50ml N,N-二甲基甲酰胺(DMF)中。于0℃缓慢地加入三氯氧磷(POCl3)(24.4g，160mmol)。继续搅拌3小时，将反应液加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物11.0g，收率：74.8％。4H-pyran-4-one (10.0 g, 100 mmol) was dissolved in 50 ml N,N-dimethylformamide (DMF). Phosphorus oxychloride (POCl 3 ) (24.4 g, 160 mmol) was added slowly at 0°C. Continue stirring for 3 hours, quench the reaction solution with water, extract with EA (50 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 11.0 g of the title compound as a yellow oil, yield: 74.8%.
LC-MS：m/z＝147[M+H]+。LC-MS: m/z=147[M+H] + .
步骤2：6,7-二氢-4H-噻吩并[3,2-c]吡喃-2-羧酸乙酯(11b)的制备Step 2: Preparation of 6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxylic acid ethyl ester (11b)
将化合物11a(11.0g，74.8mmol)溶于110ml二氯甲烷中。于0℃缓慢滴加三乙胺(9.44g,93.5mmol)和巯基乙酸乙酯(11.2g，93.5mmol)。于40℃搅拌3h，加水淬灭，二氯甲烷萃取(100mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得无色油状标题化合物12.0g，收率：76.0％。Compound 11a (11.0 g, 74.8 mmol) was dissolved in 110 ml dichloromethane. Triethylamine (9.44g, 93.5mmol) and ethyl thioglycolate (11.2g, 93.5mmol) were slowly added dropwise at 0°C. Stir at 40°C for 3 hours, add water to quench, extract with dichloromethane (100mL EA=1:1-1:2), 12.0g of the title compound was obtained as colorless oil, yield: 76.0%.
LC-MS：m/z＝213[M+H]+。LC-MS: m/z=213[M+H] + .
步骤3：(6,7-二氢-4H-噻吩并[3,2-c]吡喃-2-基)甲醇(11c)的制备Step 3 Preparation of: (6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methanol (11c)
将化合物11b(6.00g，69.9mmol)溶于60ml四氢呋喃中，于0℃，分批加入氢化铝锂(LAH)(2.47g，69.9mmol)，于室温搅拌0.5h。加水淬灭，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得黄色油状标题化合物5.00g，直接用于下一步反应。Compound 11b (6.00g, 69.9mmol) was dissolved in 60ml tetrahydrofuran, lithium aluminum hydride (LAH) (2.47g, 69.9mmol) was added in batches at 0°C, and stirred at room temperature for 0.5h. Add water to quench, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:1-2:1) to obtain 5.00g of the title compound as a yellow oil, which is directly used in the next reaction. .
LC-MS：m/z＝171[M+H]+。LC-MS: m/z=171[M+H] + .
步骤4：(6,7-二氢-4H-噻吩并[3,2-c]吡喃-2-甲醛(11d)的制备Step 4: Preparation of: (6,7-dihydro-4H-thieno[3,2-c]pyran-2-carboxaldehyde (11d)
将化合物11c(5.00g，29.4mmol)溶于30ml 1,2-二氯甲烷中，加二氧化锰(MnO2)(5.11g，58.8mmol)，于80℃搅拌过夜。将反应液加水淬灭，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝1:1-2:1)，得黄色固体标题化合物4.00g，收率：80.0％。Compound 11c (5.00g, 29.4mmol) was dissolved in 30ml of 1,2-dichloromethane, manganese dioxide (MnO 2 ) (5.11g, 58.8mmol) was added, and the mixture was stirred at 80°C overnight. The reaction solution was quenched with water and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: EA/PE=1:1-2:1) to obtain 4.00g of the title compound as a yellow solid, yield: 80.0%.
LC-MS：m/z＝169[M+H]+。 LC-MS: m/z=169[M+H]+.
步骤5：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6,7-二氢-4H-噻吩并[3,2-c]吡喃-2-基)甲醇(11e)的制备Step 5: (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6,7-dihydro-4H-thieno[3,2-c]pyran- Preparation of 2-yl)methanol (11e)
将4,5-二溴-2-甲基-2H-1,2,3-三唑(4.05g，16.7mmol)溶于100ml四氢呋喃中，于-78℃滴加正丁基锂(在己烷中)(9.25ml，1.60M，14.8mmol),-78℃搅拌0.5h，加入化合物11d(1.50g，8.87mmol)，继续搅拌2h。加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物1.80g，收率：62.1％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (4.05g, 16.7mmol) in 100ml tetrahydrofuran, add n-butyllithium (in hexane) dropwise at -78°C Medium) (9.25ml, 1.60M, 14.8mmol), stir at -78°C for 0.5h, add compound 11d (1.50g, 8.87mmol), and continue stirring for 2h. Add water to quench, extract with EA (50mL 1), 1.80g of the title compound was obtained as a yellow solid, yield: 62.1%.
LC-MS：m/z＝330[M+H]+。LC-MS: m/z=330[M+H] + .
步骤6：4-溴-5-((6,7-二氢-4H-噻吩并[3,2-c]吡喃-2-基)甲基)-2-甲基-2H-1,2,3-三唑(11f)的制备Step 6: 4-bromo-5-((6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl)-2-methyl-2H-1,2 , Preparation of 3-triazole (11f)
将化合物11e(1.80g，5.45mmol)溶于10ml三氟乙酸(TFA)中，加入三乙基硅烷(Et3SiH)(2ml)，于50℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得黄色油状标题化合物1.50g，收率：88.2％。Compound 11e (1.80g, 5.45mmol) was dissolved in 10ml of trifluoroacetic acid (TFA), triethylsilane ( Et3SiH ) (2ml) was added, and the mixture was stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:1-2:1) to obtain 1.50g of the title compound as a yellow oil, yield: 88.2%.
LC-MS：m/z＝314[M+H]+。LC-MS: m/z=314[M+H] + .
步骤7：(R)-1-(2-(5-((6,7-二氢-4H-噻吩并[3,2-c]吡喃-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙-1-醇(11g)的制备Step 7: (R)-1-(2-(5-((6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl)-2-methyl Preparation of -2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethan-1-ol (11g)
将化合物11f(500mg，1.59mmol)、(R)-5-氟-3-甲基苯并[c][1,2]氧杂硼酸-1(3H)-醇(296mg，1.64mmol)、四三苯基膦钯(171mg，0.159mmol)、碳酸钠(695mg，6.04mmol)溶于10ml甲苯/EtOH/H2O(2:1:0.4)中，于95℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物650mg，直接用于下一步反应。Compound 11f (500 mg, 1.59 mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborate-1(3H)-ol (296 mg, 1.64 mmol), tetrakis Triphenylphosphine palladium (171 mg, 0.159 mmol) and sodium carbonate (695 mg, 6.04 mmol) were dissolved in 10 ml of toluene/EtOH/H 2 O (2:1:0.4), and stirred at 95°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 650 mg of the title compound as a yellow solid, which was directly used in the next reaction.
LC-MS：m/z＝374[M+H]+。LC-MS: m/z=374[M+H] + .
步骤8：(R)-5-溴-3-(1-(2-(5-((6,7-二氢-4H-噻吩并[3,2-c]吡喃-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙氧基)-2-硝基吡啶(11h)的制备Step 8: (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl Preparation of (11h)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)-2-nitropyridine (11h)
将化合物11g(100mg，0.174mmol)溶于10ml四氢呋喃中，于0℃加入钠氢(NaH)(21.0mg，0.522mmol)，于0℃搅拌0.5h，加入5-溴-3-氟-2-硝基吡啶(46.0mg，0.208mmol)，继续搅拌1小时。将反应液用冰水淬灭，EA萃取，合并有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色油状标题化合物70.0mg，收率：47.0％。Dissolve compound 11g (100mg, 0.174mmol) in 10ml tetrahydrofuran, add sodium hydrogen (NaH) (21.0mg, 0.522mmol) at 0°C, stir at 0°C for 0.5h, add 5-bromo-3-fluoro-2- Nitropyridine (46.0 mg, 0.208 mmol), continue stirring for 1 hour. The reaction solution was quenched with ice water, extracted with EA, the combined organic phases were concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain a yellow oil. Title compound 70.0 mg, yield: 47.0%.
LC-MS：m/z＝574[M+H]+。LC-MS: m/z=574[M+H] + .
步骤9：(R)-5-溴-3-(1-(2-(5-((6,7-二氢-4H-噻吩并[3,2-c]吡喃-2-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)-4-氟苯基)乙氧基)吡啶-2-胺(11i)的制备Step 9: (R)-5-bromo-3-(1-(2-(5-((6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)methyl) Preparation of (1,2,3-triazol-4-yl)-2-methyl-2H-1,2,3-triazol-4-yl)-4-fluorophenyl)ethoxy)pyridin-2-amine (11i)
将化合物11h(70.0mg，0.122mmol)溶于5ml乙醇和1ml水中，依次加入铁粉(Fe)(13.2mg，0.236mmol)和氯化铵(27.7mg，0.472mmol)，于70℃ 搅拌2h，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物65.0mg，粗品。Compound 11h (70.0 mg, 0.122 mmol) was dissolved in 5 ml ethanol and 1 ml water, iron powder (Fe) (13.2 mg, 0.236 mmol) and ammonium chloride (27.7 mg, 0.472 mmol) were added in sequence, and the mixture was heated at 70°C. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 65.0 mg of the title compound as a yellow solid, crude product.
LC-MS：m/z＝544[M+H]+。LC-MS: m/z=544[M+H] + .
步骤10：(R)-3-氟-5,19-二甲基-5,12,13,15,17,19-六氢-7,11-(亚甲基)苯并[1]吡喃并[4',3':4,5]噻吩并[3,2-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(11)的制备Step 10: (R)-3-fluoro-5,19-dimethyl-5,12,13,15,17,19-hexahydro-7,11-(methylene)benzo[1]pyran And[4',3':4,5]thieno[3,2-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacycloten Preparation of tetracarben-8-amine (11)
将化合物11i(65.0mg，0.119mmol)溶于2ml叔戊醇中，加入乙酸钾(59.7mg，0.597mmol)、醋酸钯(29.0mg，0.119mmol)、正丁基二(1-金刚烷基)膦(cataCXium A)(43.4mg，0.119mmol)。氮气氛下，于120℃搅拌16小时。加10mL水淬灭，EA萃取(10mL x 3)，饱和食盐水洗涤(10mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高效制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物7.00mg，收率：12.7％。Compound 11i (65.0 mg, 0.119 mmol) was dissolved in 2 ml of tert-amyl alcohol, and potassium acetate (59.7 mg, 0.597 mmol), palladium acetate (29.0 mg, 0.119 mmol), n-butylbis(1-adamantyl) were added. Phosphine (cataCXium A) (43.4 mg, 0.119 mmol). Under nitrogen atmosphere, stir at 120°C for 16 hours. Add 10 mL of water to quench, extract with EA (10 mL Model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), 7.00 mg of the title compound was obtained as a white solid, yield: 12.7%.
LC-MS：m/z＝463[M+H]+。LC-MS: m/z=463[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.71(dd,J＝10.3,2.7Hz,1H),7.31(dd,J＝8.6,5.9Hz,1H),7.28–7.12(m,2H),6.01(d,J＝1.9Hz,1H),5.77(s,2H),5.13(dd,J＝6.5,2.1Hz,1H),4.97(d,J＝14.9Hz,1H),4.53(d,J＝14.9Hz,1H),4.35–4.02(m,6H),4.04–3.90(m,2H),3.23(d,J＝15.3Hz,1H),1.71(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.71 (dd, J＝10.3, 2.7Hz, 1H), 7.31 (dd, J＝8.6, 5.9Hz, 1H), 7.28–7.12 (m, 2H), 6.01(d,J＝1.9Hz,1H),5.77(s,2H),5.13(dd,J＝6.5,2.1Hz,1H),4.97(d,J＝14.9Hz,1H),4.53(d,J ＝14.9Hz,1H),4.35–4.02(m,6H),4.04–3.90(m,2H),3.23(d,J＝15.3Hz,1H),1.71(d,J＝6.2Hz,3H).
实施例12：(R)-3-氟-5,20-二甲基-14-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(12)的制备
Example 12: (R)-3-fluoro-5,20-dimethyl-14-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo[ l]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (12)
步骤1：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲醇(12a)的制备 Step 1: (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-(trifluoromethyl)imidazo[1,2-a]pyridine-2- Preparation of methanol (12a)
于室温，将4,5-二溴-2-甲基-2H-1,2,3-三唑(801mg，2.80mmol)溶于20ml THF中。于-78℃，滴加正丁基锂溶液(2.15ml,1.3M,2.80mmol)，于0℃搅拌0.5h，加入6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(500mg，2.33mmol)，继续搅拌2h。加10ml冰水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物480mg，收率：54.9％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (801 mg, 2.80 mmol) in 20 ml THF at room temperature. At -78°C, add n-butyllithium solution (2.15ml, 1.3M, 2.80mmol) dropwise, stir at 0°C for 0.5h, and add 6-(trifluoromethyl)imidazo[1,2-a]pyridine- 2-Formaldehyde (500mg, 2.33mmol), continue stirring for 2h. Add 10 ml of ice water to quench, extract with EA (50 mL -2:1), 480 mg of the title compound was obtained as a yellow solid, yield: 54.9%.
LC-MS：m/z＝376[M+H]+。LC-MS: m/z=376[M+H] + .
步骤2：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)的制备Step 2: 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2- a] Preparation of pyridine (12b)
于室温，将(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲醇(12a)(480mg，1.27mmol)溶于三氟乙酸(5ml)中，加入三乙基硅烷(2ml)，于60℃搅拌过夜，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物420mg，收率：88.0％。At room temperature, (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-(trifluoromethyl)imidazo[1,2-a]pyridine-2 -Methanol (12a) (480 mg, 1.27 mmol) was dissolved in trifluoroacetic acid (5 ml), added triethylsilane (2 ml), stirred at 60°C overnight, the reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column Separate and purify by chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 420 mg of the title compound as a yellow solid, yield: 88.0%.
LC-MS：m/z＝360[M+H]+。LC-MS: m/z=360[M+H] + .
步骤3：(R)-1-(5-氟-2-(2-甲基-5-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙-1-醇(12c)的制备Step 3: (R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl) Preparation of (12c)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (12c)
于室温，将2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)(420mg，1.17mmol)、(R)-5-氟-3-甲基苯并[c][1,2]氧杂硼酸-1(3H)-醇(233mg，1.40mmol)、四三苯基膦钯(135mg，0.117mmol)、碳酸钠(496mg，4.68mmol)溶于甲苯/EtOH/H2O(10ml)(2:1:0.4)中。于95℃搅拌过夜，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物160mg，收率：41.7％。At room temperature, 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine (12b) (420mg, 1.17mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaboric acid-1(3H)-ol (233mg, 1.40 mmol), tetrakis triphenylphosphine palladium (135 mg, 0.117 mmol), and sodium carbonate (496 mg, 4.68 mmol) were dissolved in toluene/EtOH/H 2 O (10 ml) (2:1:0.4). Stir overnight at 95°C, and concentrate the reaction solution under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 160 mg of the title compound as a yellow solid, yield :41.7%.
LC-MS：m/z＝420[M+H]+。LC-MS: m/z=420[M+H] + .
步骤4：(R)-2-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-4-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12d)的制备Step 4: (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-2 Preparation of -methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (12d)
于室温，将(R)-1-(5-氟-2-(2-甲基-5-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙-1-醇(12c)(160mg，0.380mmol)溶于THF(10ml)中。于0℃加入NaH(45mg，1.14mmol，60％在油中)。于0℃搅拌0.5h，加入5-溴-3-氟-2-硝基吡啶(92mg，0.418mmol)。于60℃搅拌过夜，将反应液用冰水淬灭，EA萃取，合并有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物70mg，收率：29.7％。At room temperature, (R)-1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl) Methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethan-1-ol (12c) (160 mg, 0.380 mmol) was dissolved in THF (10 ml). NaH (45 mg, 1.14 mmol, 60% in oil) was added at 0°C. Stir at 0°C for 0.5h, and add 5-bromo-3-fluoro-2-nitropyridine (92 mg, 0.418 mmol). Stir overnight at 60°C, quench the reaction solution with ice water, extract with EA, combine the organic phases and concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1: 2), 70 mg of the title compound was obtained as a yellow solid, yield: 29.7%.
LC-MS：m/z＝620[M+H]+。LC-MS: m/z=620[M+H] + .
步骤5：(R)-5-溴-3-(1-(5-氟-2-(2-甲基-5-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙氧基)吡啶-2-胺(12e)的制备Step 5: (R)-5-bromo-3-(1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))imidazo[1,2-a] Preparation of pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (12e)
于室温，将(R)-2-((5-(2-(1-((5-溴-2-硝基吡啶-3-基)氧基)乙基)-4-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12d)(70mg，0.113 mmol)溶于5ml EtOH和1ml H2O中，依次加入Fe粉(30mg，0.565mmol)和氯化铵(48mg，0.904mmol)，于70℃搅拌2h，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物50mg，收率：75.7％。At room temperature, (R)-2-((5-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)- 2-Methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (12d) (70 mg, 0.113 mmol) was dissolved in 5 ml EtOH and 1 ml H2O, Fe powder (30 mg, 0.565 mmol) and ammonium chloride (48 mg, 0.904 mmol) were added in sequence, stirred at 70°C for 2 h, the reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column Separate and purify by chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 50 mg of the title compound as a yellow solid, yield: 75.7%.
LC-MS：m/z＝590[M+H]+。LC-MS: m/z=590[M+H] + .
步骤6：(R)-3-氟-5,20-二甲基-14-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(12)的制备Step 6: (R)-3-fluoro-5,20-dimethyl-14-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo[l ]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]aza Preparation of cyclotetradecen-8-amine (12)
于室温，将(R)-5-溴-3-(1-(5-氟-2-(2-甲基-5-((6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲基)-2H-1,2,3-三唑-4-基)苯基)乙氧基)吡啶-2-胺(12e)(50mg，0.085mmol)溶于2ml叔戊醇中，加入乙酸钾(63mg，0.645mmol)、醋酸钯(29mg，0.129mmol)、cataCXium A(92mg，0.258mmol)。氮气氛下，于120℃搅拌16小时。将反应液加10mL水淬灭，EA萃取(10mL x 3)，饱和食盐水洗涤(10mL x 1)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过高效制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物1.3mg，收率：3％。At room temperature, (R)-5-bromo-3-(1-(5-fluoro-2-(2-methyl-5-((6-(trifluoromethyl))imidazo[1,2-a ]pyridin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)phenyl)ethoxy)pyridin-2-amine (12e) (50mg, 0.085mmol) dissolved in 2ml To tert-amyl alcohol, add potassium acetate (63 mg, 0.645 mmol), palladium acetate (29 mg, 0.129 mmol), and cataCXium A (92 mg, 0.258 mmol). Under nitrogen atmosphere, stir at 120°C for 16 hours. Quench the reaction solution with 10mL of water, extract with EA (10mL (Column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), 1.3 mg of the title compound was obtained as a white solid, yield: 3% .
LC-MS：m/z＝510[M+H]+。LC-MS: m/z=510[M+H] + .
实施例13：(R)-3-氟-5,20-二甲基-16-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(13)的制备
Example 13: (R)-3-fluoro-5,20-dimethyl-16-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo[ l]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (13)
步骤1：8-(三氟甲基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(13a)的制备Step 1: Preparation of ethyl 8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (13a)
于室温，将2-氨基-3-三氟甲基吡啶(5.00g，30.8mmol)、3-溴丙酮酸乙酯(8.38 g，43.2mmol)溶于DMF(150ml)，于50℃搅拌6h。将反应液加水淬灭，EA萃取，饱和氯化钠溶液洗涤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-1:1)，得黄色固体标题化合物6.00g，收率：75.5％。At room temperature, 2-amino-3-trifluoromethylpyridine (5.00g, 30.8mmol), ethyl 3-bromopyruvate (8.38 g, 43.2 mmol) was dissolved in DMF (150 ml), and stirred at 50°C for 6 h. The reaction solution was quenched with water, extracted with EA, washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=10:1-1:1) to obtain 6.00g of the title compound was obtained as a yellow solid, yield: 75.5%.
LC-MS：m/z＝259[M+H]+。LC-MS: m/z=259[M+H] + .
步骤2：8-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(13b)的制备Step 2: Preparation of 8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (13b)
于室温，将8-(三氟甲基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(13a)(2.70g，10.4mmol)溶于DCM(60ml)中。于-78℃，滴加DIBAL-H(15.6ml,15.6mmol)，继续搅拌2h。将反应液用饱和氯化铵溶液淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物1.50g，收率：67.2％。8-(Trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (13a) (2.70 g, 10.4 mmol) was dissolved in DCM (60 ml) at room temperature. At -78°C, DIBAL-H (15.6 ml, 15.6 mmol) was added dropwise, and stirring was continued for 2 h. The reaction solution was quenched with saturated ammonium chloride solution, extracted with EA (50mL EA=1:1-1:2), 1.50g of the title compound was obtained as a yellow solid, yield: 67.2%.
LC-MS：m/z＝215[M+H]+。LC-MS: m/z=215[M+H] + .
其余步骤与实施例12相同，除了用8-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(13b)代替步骤1的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物13。The remaining steps are the same as in Example 12, except that 8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (13b) is used instead of 6-(trifluoromethyl)imidazo[ 1,2-a]pyridine-2-carboxaldehyde to prepare compound 13.
LC-MS：m/z＝510[M+H]+。LC-MS: m/z=510[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.58(d,J＝6.9Hz,1H),7.80(dd,J＝10.4,2.8Hz,1H),7.73-7.66(m,2H),7.31(dd,J＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.99(t,J＝7.0Hz,1H),6.23-6.13(m,3H),5.30(td,J＝7.0,4.9Hz,1H),4.19–4.10(m,4H),3.48(d,J＝15.2Hz,1H),1.74(d,J＝6.2Hz,3H)。1H NMR(400MHz, DMSO-d6)δ8.58(d,J＝6.9Hz,1H),7.80(dd,J＝10.4,2.8Hz,1H),7.73-7.66(m,2H),7.31(dd, J＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.99(t,J＝7.0Hz,1H),6.23-6.13(m,3H),5.30(td,J ＝7.0,4.9Hz,1H),4.19–4.10(m,4H),3.48(d,J＝15.2Hz,1H),1.74(d,J＝6.2Hz,3H).
实施例14：((R)-3-氟-5,20-二甲基-14-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(14)的制备
Example 14: ((R)-3-fluoro-5,20-dimethyl-14-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo [l]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene -Preparation of 8-amine (14)
步骤1：3-溴-4-碘-1-甲基-1H-吡唑(14a)的制备Step 1: Preparation of 3-bromo-4-iodo-1-methyl-1H-pyrazole (14a)
于室温，将3-溴-1-甲基吡唑(19.0g，118mmol)溶于DMF(200ml)，分批 加入NIS(40.0g，178mmol)，于50℃搅拌过夜。加水淬灭，EA萃取，饱和氯化钠溶液洗涤三次，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1/10)，得黄色固体标题化合物25.0g，收率：41.6％。Dissolve 3-bromo-1-methylpyrazole (19.0g, 118mmol) in DMF (200ml) at room temperature, batchwise Add NIS (40.0g, 178mmol) and stir at 50°C overnight. Add water to quench, extract with EA, wash with saturated sodium chloride solution three times, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1/10) to obtain 25.0g of the title compound as a yellow solid. , Yield: 41.6%.
LC-MS：m/z＝287[M+H]+。LC-MS: m/z=287[M+H] + .
步骤2：(3-溴-1-甲基-1H-吡唑-4-基)(6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲醇(14b)的制备Step 2: (3-bromo-1-methyl-1H-pyrazol-4-yl)(6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol (14b) Preparation
于室温，将3-溴-4-碘-1-甲基-1H-吡唑(14a)(801mg，2.80mmol)溶于20ml THF中。于0℃，滴加异丙基氯化镁氯化锂复合物溶液(2.15ml,2.80mmol)，继续搅拌0.5h，加入6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(500mg，2.33mmol)，于0℃搅拌2h。加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤。滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物700mg，收率：80.2％。Dissolve 3-bromo-4-iodo-1-methyl-1H-pyrazole (14a) (801 mg, 2.80 mmol) in 20 ml THF at room temperature. At 0°C, add isopropylmagnesium chloride lithium chloride complex solution (2.15ml, 2.80mmol) dropwise, continue stirring for 0.5h, and add 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2 -Formaldehyde (500 mg, 2.33 mmol), stir at 0°C for 2 h. Add water to quench, extract with EA (50mL x 3), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-2:1) to obtain 700 mg of the title compound as a yellow solid, yield: 80.2%.
LC-MS：m/z＝375[M+H]+。LC-MS: m/z=375[M+H] + .
其余步骤与实施例12相同，除了用(3-溴-1-甲基-1H-吡唑-4-基)(6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲醇(14b)代替步骤2中的(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲醇(12a)，制得化合物14。The remaining steps are the same as in Example 12, except that (3-bromo-1-methyl-1H-pyrazol-4-yl)(6-(trifluoromethyl)imidazo[1,2-a]pyridine-2 is used -yl)methanol (14b) instead of (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-(trifluoromethyl)imidazo[1 ,2-a]pyridin-2-yl)methanol (12a) to prepare compound 14.
LC-MS：m/z＝509[M+H]+。LC-MS: m/z=509[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.62(d,J＝2.3Hz,1H),7.86-7.76(m,2H),7.71(dd,J＝10.4,2.7Hz,1H),7.58(s,1H),7.45(dd,J＝9.5,1.9Hz,1H),7.28-7.14(m,2H),6.34(d,J＝2.0Hz,1H),6.18(s,2H),5.35(dd,J＝6.5,2.1Hz,1H),3.92(d,J＝15.0Hz,1H),3.82(s,3H),3.19(d,J＝14.9Hz,1H),1.73(d,J＝6.3Hz,3H)。1H NMR(400MHz,DMSO-d6)δ8.62(d,J＝2.3Hz,1H),7.86-7.76(m,2H),7.71(dd,J＝10.4,2.7Hz,1H),7.58(s, 1H),7.45(dd,J＝9.5,1.9Hz,1H),7.28-7.14(m,2H),6.34(d,J＝2.0Hz,1H),6.18(s,2H),5.35(dd,J ＝6.5,2.1Hz,1H),3.92(d,J＝15.0Hz,1H),3.82(s,3H),3.19(d,J＝14.9Hz,1H),1.73(d,J＝6.3Hz,3H ).
实施例15：(R)-3-氟-5,14,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四烷-8-胺(15)的制备

Example 15: (R)-3-fluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecane-8 - Preparation of amine (15)

步骤1：6-甲基咪唑并[1,2-a]吡啶-2-羧酸乙酯(15a)的制备Step 1: Preparation of ethyl 6-methylimidazo[1,2-a]pyridine-2-carboxylate (15a)
于室温，将5-甲基吡啶-2-胺(3.00g，27.7mmol)、3-溴丙酮酸乙酯(8.06g，41.55mmol)溶于二甲基甲酰胺(30ml)，于50℃搅拌6h。加水淬灭，EA萃取，饱和氯化钠溶液洗涤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-1:1)，得黄色固体标题化合物5.00g，收率：89.2％。Dissolve 5-methylpyridin-2-amine (3.00g, 27.7mmol) and ethyl 3-bromopyruvate (8.06g, 41.55mmol) in dimethylformamide (30ml) at room temperature, and stir at 50°C. 6h. Add water to quench, extract with EA, wash with saturated sodium chloride solution, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=10:1-1:1) to obtain the yellow solid title Compound 5.00g, yield: 89.2%.
LC-MS：m/z＝205[M+H]+。LC-MS: m/z=205[M+H] + .
步骤2：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-甲基咪唑并[1,2-a]吡啶-2-基)甲酮(15b)的制备Step 2: (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-methylimidazo[1,2-a]pyridin-2-yl)methanone Preparation of (15b)
将4,5-二溴-2-甲基-2H-1,2,3-三唑(10.0g，42.1mmol)溶于100ml THF中。于-78℃，滴加正丁基锂(n-BuLi)(15.0ml,37.1mmol)，于-78℃搅拌0.5h。加入化合物15a(5.00g，24.5mmol)，继续搅拌2h。加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物2.10g，收率：26.9％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (10.0g, 42.1mmol) in 100ml THF. At -78°C, n-butyllithium (n-BuLi) (15.0 ml, 37.1 mmol) was added dropwise, and stirred at -78°C for 0.5 h. Compound 15a (5.00g, 24.5mmol) was added and stirring was continued for 2h. Add water to quench, extract with EA (50mL ) to obtain 2.10g of the title compound as a yellow solid, yield: 26.9%.
LC-MS：m/z＝320[M+H]+。LC-MS: m/z=320[M+H] + .
步骤3：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-甲基咪唑并[1,2-a]吡啶-2-基)甲醇(15c)的制备Step 3: (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-methylimidazo[1,2-a]pyridin-2-yl)methanol ( Preparation of 15c)
将化合物15b(2.10g，6.58mmol)溶于50ml甲醇中，于0℃，分批加入硼氢化钠(NaBH4)(0.490g，13.1mmol)，室温搅拌0.5h。加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得白色固体标题化合物1.20g，收率：57.1％。Compound 15b (2.10g, 6.58mmol) was dissolved in 50 ml of methanol, and sodium borohydride (NaBH 4 ) (0.490g, 13.1mmol) was added in batches at 0°C, and stirred at room temperature for 0.5h. Add water to quench, extract with EA (50mL ) to obtain 1.20g of the title compound as a white solid, yield: 57.1%.
LC-MS：m/z＝322[M+H]+。LC-MS: m/z=322[M+H] + .
其余步骤与实施例12相同，除了用(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-甲基咪唑并[1,2-a]吡啶-2-基)甲醇(15c)代替步骤1的(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-(三氟甲基)咪唑并[1,2-a]吡啶-2-基)甲醇(12a)，得到化合物15。The remaining steps are the same as in Example 12, except that (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-methylimidazo[1,2-a]pyridine is used -2-yl)methanol (15c) instead of (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-2-yl)methanol (12a) gave compound 15.
LC-MS：m/z＝456[M+H]+。 LC-MS: m/z=456[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.12(d,J＝1.6Hz,1H),7.79(dd,J＝10.3,2.7Hz,1H),7.68(d,J＝1.7Hz,1H),7.48(d,J＝9.1Hz,1H),7.31(dd,J＝8.6,5.8Hz,1H),7.22(td,J＝8.4,2.7Hz,1H),7.08(dd,J＝9.2,1.6Hz,1H),6.10(s,2H),5.27(dd,J＝6.5,2.1Hz,1H),4.14(s,3H),4.03(d,J＝15.1Hz,1H),2.24(s,3H),1.73(d,J＝6.2Hz,3H)。1H NMR (400MHz, DMSO-d6) δ8.40(s,1H),8.12(d,J＝1.6Hz,1H),7.79(dd,J＝10.3,2.7Hz,1H),7.68(d,J＝ 1.7Hz,1H),7.48(d,J＝9.1Hz,1H),7.31(dd,J＝8.6,5.8Hz,1H),7.22(td,J＝8.4,2.7Hz,1H),7.08(dd, J＝9.2,1.6Hz,1H),6.10(s,2H),5.27(dd,J＝6.5,2.1Hz,1H),4.14(s,3H),4.03(d,J＝15.1Hz,1H), 2.24(s,3H),1.73(d,J=6.2Hz,3H).
实施例16：(R)-3-氟-5,14,20-三甲基-18,20-二氢-5H-7,16-(亚甲基)苯并[1]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(16)的制备
Example 16: (R)-3-fluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,16-(methylene)benzo[1]pyrazolo[4 ,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (16) preparation
步骤1：2-(二氯甲基)-6-甲基-1,2,3,8a-四氢咪唑并[1,2-a]吡啶-2-醇(16a)的制备Step 1: Preparation of 2-(dichloromethyl)-6-methyl-1,2,3,8a-tetrahydroimidazo[1,2-a]pyridin-2-ol (16a)
于室温，将3-甲基吡啶-2-胺(10.0g，92.2mmol)、1,1,3-三氯丙酮(37.0g，138mmol)溶于乙二醇二甲醚(100ml)，于室温搅拌6h。过滤，将滤饼烘干，得白色固体标题化合物18.0g，直接用于下一步反应。Dissolve 3-methylpyridin-2-amine (10.0g, 92.2mmol) and 1,1,3-trichloroacetone (37.0g, 138mmol) in ethylene glycol dimethyl ether (100ml) at room temperature. Stir for 6h. Filter and dry the filter cake to obtain 18.0 g of the title compound as a white solid, which is directly used in the next reaction.
LC-MS：m/z＝233[M+H]+。LC-MS: m/z=233[M+H] + .
步骤2：2-二氯甲基-6-甲基咪唑并[1,2-a]吡啶(16b)的制备Step 2: Preparation of 2-dichloromethyl-6-methylimidazo[1,2-a]pyridine (16b)
将化合物16a(18.0g，77.2mmol)溶于100ml乙醇中，于80℃搅拌16h，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色状标题化合物10.0g，两步收率：50.0％。Compound 16a (18.0g, 77.2mmol) was dissolved in 100ml ethanol, stirred at 80°C for 16h, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1: 1-1:2), 10.0g of the title compound was obtained as white, two-step yield: 50.0%.
LC-MS：m/z＝215[M+H]+。LC-MS: m/z=215[M+H] + .
步骤3：6-甲基咪唑并[1,2-a]吡啶-2-甲醛(16c)的制备Step 3: Preparation of 6-methylimidazo[1,2-a]pyridine-2-carboxaldehyde (16c)
将化合物16b(10.0g，21.2mmol)溶于50ml水和50ml二氧六环中，加入碳酸钙(8.48g，84.8mmol)，于70℃搅拌4h。将反应液加水淬灭，EA萃取，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得淡黄色固体标题化合物5.00g，收率：67.0％。Compound 16b (10.0g, 21.2mmol) was dissolved in 50ml water and 50ml dioxane, calcium carbonate (8.48g, 84.8mmol) was added, and stirred at 70°C for 4h. The reaction solution was quenched with water, extracted with EA, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-2:1) to obtain 5.00g of the title compound as a light yellow solid. , Yield: 67.0%.
LC-MS：m/z＝161[M+H]+。 LC-MS: m/z=161[M+H] + .
其余步骤与实施例14相同，除了用6-甲基咪唑并[1,2-a]吡啶-2-甲醛(16c)代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物16。The remaining steps are the same as in Example 14, except that 6-methylimidazo[1,2-a]pyridine-2-carboxaldehyde (16c) is used instead of 6-(trifluoromethyl)imidazo[1,2 -a]pyridine-2-carboxaldehyde to obtain compound 16.
LC-MS：m/z＝456[M+H]+。LC-MS: m/z=456[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.15(q,J＝1.3Hz,1H),7.77–7.65(m,2H),7.57(s,1H),7.51–7.43(m,1H),7.29–7.13(m,2H),7.08(dd,J＝9.2,1.6Hz,1H),6.33(d,J＝1.8Hz,1H),6.07(s,2H),5.40–5.27(m,1H),3.82(s,4H),3.13(d,J＝14.9Hz,1H),2.25(d,J＝1.1Hz,3H),1.72(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.15 (q, J＝1.3Hz, 1H), 7.77–7.65 (m, 2H), 7.57 (s, 1H), 7.51–7.43 (m, 1H), 7.29–7.13(m,2H),7.08(dd,J＝9.2,1.6Hz,1H),6.33(d,J＝1.8Hz,1H),6.07(s,2H),5.40–5.27(m,1H) ,3.82(s,4H),3.13(d,J＝14.9Hz,1H),2.25(d,J＝1.1Hz,3H),1.72(d,J＝6.2Hz,3H).
实施例17：(R)-3-氟-5,16,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(17)的制备
Example 17: (R)-3-fluoro-5,16,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (17)
步骤1：2-(二氯甲基)-8-甲基-2,3-二氢咪唑并[1,2-a]吡啶-2-醇(17a)的制备Step 1: Preparation of 2-(dichloromethyl)-8-methyl-2,3-dihydroimidazo[1,2-a]pyridin-2-ol (17a)
于室温，将3-甲基吡啶-2-胺(5.00g，46.1mmol)、1,1,3-三氯丙酮(18.5g，69.4mmol)溶于乙二醇二甲醚(50ml)，于室温搅拌6h。过滤，将滤饼烘干，得白色固体标题化合物6.00g，收率：55.6％。Dissolve 3-methylpyridin-2-amine (5.00g, 46.1mmol) and 1,1,3-trichloroacetone (18.5g, 69.4mmol) in ethylene glycol dimethyl ether (50ml) at room temperature. Stir at room temperature for 6h. Filter and dry the filter cake to obtain 6.00g of the title compound as a white solid, yield: 55.6%.
LC-MS：m/z＝233[M+H]+。LC-MS: m/z=233[M+H] + .
步骤2：2-(二乙氧基甲基)-8-甲基咪唑并[1,2-a]吡啶(17b)的制备Step 2: Preparation of 2-(diethoxymethyl)-8-methylimidazo[1,2-a]pyridine (17b)
将化合物17a(6.00g，25.8mmol)溶于100ml乙醇中，于80℃，搅拌4h。将反应液降至室温，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得无色油状标题化合物5.00g，收率：83.0％。Compound 17a (6.00g, 25.8mmol) was dissolved in 100ml of ethanol, and stirred at 80°C for 4h. The reaction solution was lowered to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 5.00g of the title compound as a colorless oil, yield :83.0%.
LC-MS：m/z＝235[M+H]+。 LC-MS: m/z=235[M+H] + .
步骤3：8-甲基咪唑并[1,2-a]吡啶-2-甲醛(17c)的制备Step 3: Preparation of 8-methylimidazo[1,2-a]pyridine-2-carboxaldehyde (17c)
将化合物17b(5.0g，21.2mmol)溶于50ml HCl的二氧六环溶液(4M)中，于0℃搅拌4h。加水淬灭，EA萃取，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得淡黄色固体标题化合物3.00g，收率：88.0％。Compound 17b (5.0g, 21.2mmol) was dissolved in 50ml HCl dioxane solution (4M) and stirred at 0°C for 4h. Add water to quench, extract with EA, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-2:1) to obtain 3.00g of the title compound as a light yellow solid, yield :88.0%.
LC-MS：m/z＝160[M+H]+。LC-MS: m/z=160[M+H] + .
其余步骤与实施例12相同，除了用8-甲基咪唑并[1,2-a]吡啶-2-甲醛(17c)代替6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物17。The remaining steps were the same as in Example 12, except that 8-methylimidazo[1,2-a]pyridine-2-carboxaldehyde (17c) was used instead of 6-(trifluoromethyl)imidazo[1,2-a]pyridine -2-carboxaldehyde to obtain compound 17.
LC-MS：m/z＝456[M+H]+。LC-MS: m/z=456[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝6.9Hz,1H),7.79(dd,J＝10.3,2.7Hz,1H),7.64(d,J＝1.8Hz,1H),7.31(dd,J＝8.5,5.8Hz,1H),7.23(td,J＝8.4,2.7Hz,1H),7.04(dt,J＝6.8,1.2Hz,1H),6.77(t,J＝6.9Hz,1H),6.24–6.04(m,3H),5.28(dd,J＝6.4,2.2Hz,1H),4.11(d,J＝29.5Hz,4H),3.44(d,J＝15.2Hz,1H),2.54(s,3H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.16 (d, J = 6.9 Hz, 1H), 7.79 (dd, J = 10.3, 2.7 Hz, 1H), 7.64 (d, J = 1.8 Hz, 1H) ,7.31(dd,J＝8.5,5.8Hz,1H),7.23(td,J＝8.4,2.7Hz,1H),7.04(dt,J＝6.8,1.2Hz,1H),6.77(t,J＝6.9 Hz,1H),6.24–6.04(m,3H),5.28(dd,J＝6.4,2.2Hz,1H),4.11(d,J＝29.5Hz,4H),3.44(d,J＝15.2Hz,1H ), 2.54 (s, 3H), 1.74 (d, J = 6.2Hz, 3H).
实施例18：(R)-3-氟-5,15,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(18)的制备
Example 18: (R)-3-fluoro-5,15,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (18)
与实施例17的制备方法相同，除了用4-甲基吡啶-2-胺代替3-甲基吡啶-2-胺，得到化合物18。The preparation method was the same as in Example 17, except that 4-methylpyridin-2-amine was used instead of 3-methylpyridin-2-amine to obtain compound 18.
LC-MS：m/z＝456[M+H]+。 LC-MS: m/z=456[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝7.1Hz,1H),7.78(dd,J＝10.4,2.7Hz,1H),7.65(d,J＝1.8Hz,1H),7.36–7.26(m,2H),7.23(td,J＝8.4,2.8Hz,1H),6.70(dd,J＝7.1,1.8Hz,1H),6.18–6.00(m,3H),5.26(dt,J＝6.9,3.5Hz,1H),4.14(s,3H),4.03(d,J＝15.1Hz,1H),3.41(d,J＝15.2Hz,1H),2.46–2.29(m,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.20(d,J＝7.1Hz,1H),7.78(dd,J＝10.4,2.7Hz,1H),7.65(d,J＝1.8Hz,1H) ,7.36–7.26(m,2H),7.23(td,J＝8.4,2.8Hz,1H),6.70(dd,J＝7.1,1.8Hz,1H),6.18–6.00(m,3H),5.26(dt ,J＝6.9,3.5Hz,1H),4.14(s,3H),4.03(d,J＝15.1Hz,1H),3.41(d,J＝15.2Hz,1H),2.46–2.29(m,3H) ,1.73(d,J=6.2Hz,3H).
实施例19：(R)-3,14-二氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(19)的制备
Example 19: (R)-3,14-difluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrido[2 ',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene Preparation of -8-amine (19)
步骤1：1,1-二氯-3-((5-氟吡啶-2-基)氨基)丙-2-酮(19a)的制备Step 1: Preparation of 1,1-dichloro-3-((5-fluoropyridin-2-yl)amino)propan-2-one (19a)
于室温，2-氨基-5-氟吡啶(5.00g，44.6mmol)、1,1,3-三氯丙酮(10.7g，466.9mmol)溶于DME(100ml)，于室温搅拌过夜，过滤，收集滤饼，得白色固体标题化合物6.50g，收率：61.7％。Dissolve 2-amino-5-fluoropyridine (5.00g, 44.6mmol) and 1,1,3-trichloroacetone (10.7g, 466.9mmol) in DME (100ml) at room temperature, stir at room temperature overnight, filter and collect Filter the cake to obtain 6.50g of the title compound as a white solid, yield: 61.7%.
LC-MS：m/z＝237[M+H]+。LC-MS: m/z=237[M+H] + .
步骤2：2-(二氯甲基)-6-氟咪唑并[1,2-a]吡啶(19b)的制备Step 2: Preparation of 2-(dichloromethyl)-6-fluoroimidazo[1,2-a]pyridine (19b)
于室温，将1,1-二氯-3-((5-氟吡啶-2-基)氨基)丙-2-酮(19a)(6.50，27.5mmol)溶于100ml EtOH中，于80℃搅拌4h。将反应液降至室温，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物2.50g，收率：41.6％。Dissolve 1,1-dichloro-3-((5-fluoropyridin-2-yl)amino)propan-2-one (19a) (6.50, 27.5mmol) in 100ml EtOH at room temperature, and stir at 80°C 4h. The reaction solution was lowered to room temperature, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 2.50g of the title compound as a yellow solid, yield: 41.6%.
LC-MS：m/z＝219[M+H]+。LC-MS: m/z=219[M+H] + .
步骤3：6-氟咪唑并[1,2-a]吡啶-2-甲醛(19c)的制备Step 3: Preparation of 6-fluoroimidazo[1,2-a]pyridine-2-carboxaldehyde (19c)
于室温，将2-(二氯甲基)-6-氟咪唑并[1,2-a]吡啶(19b)(2.50g，1.14mmol)溶于THF(20ml)和H2O(100ml)中，于100℃搅拌4h。将反应液用EA萃取，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物500mg，收率：26.4％。Dissolve 2-(dichloromethyl)-6-fluoroimidazo[1,2-a]pyridine (19b) (2.50g, 1.14mmol) in THF (20ml) and H 2 O (100ml) at room temperature. , stirred at 100℃ for 4h. The reaction solution was extracted with EA, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-2:1) to obtain 500 mg of the title compound as a yellow solid, yield: 26.4 %.
LC-MS：m/z＝165[M+H]+。 LC-MS: m/z=165[M+H] + .
其余步骤与实施例12相同，除了用6-氟咪唑并[1,2-a]吡啶-2-甲醛(19c)代替6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物19。The remaining steps are the same as in Example 12, except that 6-fluoroimidazo[1,2-a]pyridine-2-carboxaldehyde (19c) is used instead of 6-(trifluoromethyl)imidazo[1,2-a]pyridine- 2-Formaldehyde gave compound 19.
LC-MS：m/z＝460[M+H]+。LC-MS: m/z=460[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.78-7.68(m,2H),7.56(dd,J＝10.4,2.8Hz,1H),7.37(dd,J＝9.7,4.5Hz,1H),7.28(t,J＝9.5Hz,1H),7.17(td,J＝8.4,2.9Hz,1H),7.02(d,J＝2.0Hz,1H),6.91(s,1H),6.66(s,2H),5.60-5.50(m,1H),4.55(d,J＝16.4Hz,1H),4.11(s,3H),4.07(s,1H),1.88(d,J＝6.2Hz,3H)。1H NMR (400MHz, DMSO-d6) δ7.78-7.68(m,2H),7.56(dd,J＝10.4,2.8Hz,1H),7.37(dd,J＝9.7,4.5Hz,1H),7.28( t,J＝9.5Hz,1H),7.17(td,J＝8.4,2.9Hz,1H),7.02(d,J＝2.0Hz,1H),6.91(s,1H),6.66(s,2H), 5.60-5.50(m,1H),4.55(d,J＝16.4Hz,1H),4.11(s,3H),4.07(s,1H),1.88(d,J＝6.2Hz,3H).
实施例20：(R)-3,14-二氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(20)的制备
Example 20: (R)-3,14-difluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazolo[ 4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (20) Preparation
与实施例15的制备方法相同，除了用5-氟吡啶-2-胺代替步骤1中的5-甲基吡啶-2-胺，并用3-溴-4-碘-1-甲基-1H-吡唑代替步骤2中的4,5-二溴-2-甲基-2H-1,2,3-三唑，制得化合物20。The preparation method is the same as in Example 15, except that 5-fluoropyridin-2-amine is used instead of 5-methylpyridin-2-amine in step 1, and 3-bromo-4-iodo-1-methyl-1H- Pyrazole replaced 4,5-dibromo-2-methyl-2H-1,2,3-triazole in step 2 to prepare compound 20.
LC-MS：m/z＝459[M+H]+。LC-MS: m/z=459[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.44(dd,J＝4.9,2.3Hz,1H),7.77-7.60(m,3H),7.57(s,1H),7.29(ddd,J＝10.3,8.1,2.4Hz,1H),7.21(qd,J＝8.5,5.9Hz,2H),6.33(d,J＝1.9Hz,1H),6.12(s,2H),5.38-5.28(m,1H),3.87(d,J＝15.2Hz,1H),3.82(s,3H),3.15(d,J＝15.0Hz,1H),1.72(d,J＝6.2Hz,3H)。1H NMR(400MHz, DMSO-d6)δ8.44(dd,J＝4.9,2.3Hz,1H),7.77-7.60(m,3H),7.57(s,1H),7.29(ddd,J＝10.3,8.1 ,2.4Hz,1H),7.21(qd,J＝8.5,5.9Hz,2H),6.33(d,J＝1.9Hz,1H),6.12(s,2H),5.38-5.28(m,1H),3.87 (d,J=15.2Hz,1H),3.82(s,3H),3.15(d,J=15.0Hz,1H),1.72(d,J=6.2Hz,3H).
实施例21：(R)-14-(环丙基)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(21)的制备

Example 21: (R)-14-(cyclopropyl)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l ]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]aza Preparation of cyclotetradecen-8-amine (21)

步骤1：6-溴咪唑并[1,2-a]吡啶-2-甲酸乙酯(21a)的制备Step 1: Preparation of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (21a)
于室温，将2-氨基-5-溴吡啶(5.00g，29.0mmol)、3-溴丙酮酸乙酯(8.38g，43.2mmol)溶于二氧六环(100ml)中，加入碳酸氢钠(5.16g，58.0mmol)，于100℃搅拌过夜。将反应液加水淬灭，EA萃取，饱和氯化钠溶液洗涤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-1:1)，得黄色固体标题化合物6.00g，收率：77.1％。Dissolve 2-amino-5-bromopyridine (5.00g, 29.0mmol) and ethyl 3-bromopyruvate (8.38g, 43.2mmol) in dioxane (100ml) at room temperature, and add sodium bicarbonate ( 5.16g, 58.0mmol), stirred at 100°C overnight. The reaction solution was quenched with water, extracted with EA, washed with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=10:1-1:1) to obtain 6.00g of the title compound was obtained as a yellow solid, yield: 77.1%.
LC-MS：m/z＝269[M+H]+。LC-MS: m/z=269[M+H] + .
步骤2：6-环丙基咪唑并[1,2-a]吡啶-2-甲酸乙酯(21b)的制备Step 2: Preparation of 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (21b)
于室温，将6-溴咪唑并[1,2-a]吡啶-2-甲酸乙酯(21a)(5.00g，18.6mmol)、磷酸钾(7.91g，37.3mmol)、Pd(dppf)Cl2.CH2Cl2(1.51g，0.186mmol)、环丙硼酸(2.40g，27.9mmol)溶于100ml二氧六环中，于100℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物2.50g，收率：58.4％。At room temperature, 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (21a) (5.00g, 18.6mmol), potassium phosphate (7.91g, 37.3mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (1.51g, 0.186mmol) and cyclopropylboronic acid (2.40g, 27.9mmol) were dissolved in 100ml dioxane and stirred at 100°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 2.50g of the title compound as a white solid, yield: 58.4%.
LC-MS：m/z＝231[M+H]+。LC-MS: m/z=231[M+H] + .
其余步骤与实施例13相同，除了用6-环丙基咪唑并[1,2-a]吡啶-2-甲酸乙酯(21b)代替步骤2中的8-(三氟甲基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(13a)，得到化合物21。The remaining steps are the same as in Example 13, except that 6-cyclopropylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (21b) is used instead of 8-(trifluoromethyl)imidazo[ 1,2-a]pyridine-2-carboxylic acid ethyl ester (13a) to obtain compound 21.
LC-MS：m/z＝482[M+H]+。LC-MS: m/z=482[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.08(d,J＝1.5Hz,1H),7.79(dd,J＝10.3,2.8Hz,1H),7.70(d,J＝1.8Hz,1H),7.47(dd,J＝9.3,0.8Hz,1H),7.30(dd,J＝8.6,5.9Hz,1H),7.22(td,J＝8.4,2.7Hz,1H),6.91(dd,J＝9.4,1.7Hz,1H),6.10(d,J＝2.2Hz,3H),5.28(dt,J＝6.4,3.5Hz,1H),4.13(s,3H),4.03(d,J＝15.2Hz,1H),2.04-1.93(m,1H),1.73(d,J＝6.2Hz,3H),1.24(s,1H),0.88(ddd,J＝7.9,4.6,3.0Hz,2H),0.64(qd,J＝3.8,2.0Hz,2H)。 1 H NMR (400MHz, DMSO-d6) δ8.08(d,J＝1.5Hz,1H),7.79(dd,J＝10.3,2.8Hz,1H),7.70(d,J＝1.8Hz,1H), 7.47(dd,J＝9.3,0.8Hz,1H),7.30(dd,J＝8.6,5.9Hz,1H),7.22(td,J＝8.4,2.7Hz,1H),6.91(dd,J＝9.4, 1.7Hz,1H),6.10(d,J＝2.2Hz,3H),5.28(dt,J＝6.4,3.5Hz,1H),4.13(s,3H),4.03(d,J＝15.2Hz,1H) ,2.04-1.93(m,1H),1.73(d,J＝6.2Hz,3H),1.24(s,1H),0.88(ddd,J＝7.9,4.6,3.0Hz,2H),0.64(qd,J =3.8,2.0Hz,2H).
实施例22：(R)-14-环丙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(22)的制备
Example 22: (R)-14-cyclopropyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyridine Azolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine Preparation of (22)
与实施例21的制备方法相同，除了用3-溴-4-碘-1-甲基-1H-吡唑代替4,5-二溴-2-甲基-2H-1,2,3-三唑，制得化合物22。The preparation method is the same as that of Example 21, except that 3-bromo-4-iodo-1-methyl-1H-pyrazole is used instead of 4,5-dibromo-2-methyl-2H-1,2,3-triazole. azole to prepare compound 22.
LC-MS：m/z＝481[M+H]+。LC-MS: m/z=481[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.76–7.66(m,2H),7.56(s,1H),7.47(d,J＝9.3Hz,1H),7.20(qd,J＝8.4,5.9Hz,2H),6.90(dd,J＝9.3,1.7Hz,1H),6.32(d,J＝1.8Hz,1H),6.07(s,2H),5.33(dt,J＝6.9,3.5Hz,1H),3.82(s,4H),3.12(d,J＝14.9Hz,1H),1.99(tt,J＝8.5,5.1Hz,1H),1.72(d,J＝6.2Hz,3H),0.88(ddt,J＝8.7,4.2,2.5Hz,2H),0.64(dt,J＝5.9,2.9Hz,2H)。1H NMR (400MHz, DMSO-d6)δ8.11(s,1H),7.76–7.66(m,2H),7.56(s,1H),7.47(d,J＝9.3Hz,1H),7.20(qd, J＝8.4,5.9Hz,2H),6.90(dd,J＝9.3,1.7Hz,1H),6.32(d,J＝1.8Hz,1H),6.07(s,2H),5.33(dt,J＝6.9 ,3.5Hz,1H),3.82(s,4H),3.12(d,J＝14.9Hz,1H),1.99(tt,J＝8.5,5.1Hz,1H),1.72(d,J＝6.2Hz,3H ), 0.88 (ddt, J = 8.7, 4.2, 2.5 Hz, 2H), 0.64 ( dt, J = 5.9, 2.9 Hz, 2H).
实施例23：(R)-3-氟-5，20-二甲基-18，20-二氢-5H-7，11-(亚甲基)苯并[1]吡唑并[4，3-j]嘧啶并[2'，1':2，3]咪唑并[4，5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(23)的制备

Example 23: (R)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazolo[4,3 Preparation of -j]pyrimido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (23)

步骤1：咪唑并[1,2-a]嘧啶-2-甲醛(23a)的制备Step 1: Preparation of imidazo[1,2-a]pyrimidine-2-carboxaldehyde (23a)
将咪唑并[1,2-a]嘧啶-2-羧酸乙酯(2.00g，10.4mmol)溶于二氯甲烷(80mL)中，然后在-78℃，慢慢地加入二异丁基氢化铝(DIBAL-H)(20.8ml，1M，20.8mmol)，继续搅拌3小时。将反应液加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物600mg，收率：40.0％。Imidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester (2.00g, 10.4mmol) was dissolved in dichloromethane (80mL), and then diisobutyl hydrogenation was slowly added at -78°C. Aluminum (DIBAL-H) (20.8ml, 1M, 20.8mmol), continue stirring for 3 hours. The reaction solution was quenched with water, extracted with EA (50mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 600 mg of the title compound as a yellow oil, yield: 40.0%.
LC-MS：m/z＝148[M+H]+。LC-MS: m/z=148[M+H] + .
其余步骤与实施例14相同，除了用咪唑并[1,2-a]嘧啶-2-甲醛(23a)代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物23。The remaining steps are the same as in Example 14, except that imidazo[1,2-a]pyrimidine-2-carboxaldehyde (23a) is used instead of 6-(trifluoromethyl)imidazo[1,2-a]pyridine in step 2 -2-carboxaldehyde to obtain compound 23.
LC-MS：m/z＝442[M+H]+。LC-MS: m/z=442[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.15(q,J＝1.3Hz,1H),7.79–7.63(m,2H),7.57(s,1H),7.50–7.42(m,1H),7.26–7.13(m,2H),7.08(dd,J＝9.2,1.6Hz,1H),6.33(d,J＝1.8Hz,1H),6.07(s,2H),5.39–5.23(m,1H),3.82(s,4H),3.13(d,J＝14.9Hz,1H),2.25(d,J＝1.1Hz,3H),1.72(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.15 (q, J＝1.3Hz, 1H), 7.79–7.63 (m, 2H), 7.57 (s, 1H), 7.50–7.42 (m, 1H), 7.26–7.13(m,2H),7.08(dd,J＝9.2,1.6Hz,1H),6.33(d,J＝1.8Hz,1H),6.07(s,2H),5.39–5.23(m,1H) ,3.82(s,4H),3.13(d,J＝14.9Hz,1H),2.25(d,J＝1.1Hz,3H),1.72(d,J＝6.2Hz,3H).
实施例24：(R)-3-氟-5,14,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]嘧啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(24)的制备

Example 24: (R)-3-fluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazolo[4 ,3-j]pyrimido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (24) preparation

与实施例16的制备方法相同，除了用5-甲基嘧啶-2-胺代替步骤1中的3-甲基吡啶-2-胺，制得化合物24。Compound 24 was prepared by the same preparation method as Example 16, except that 5-methylpyrimidin-2-amine was used instead of 3-methylpyridin-2-amine in step 1.
LC-MS：m/z＝457[M+H]+。LC-MS: m/z=457[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.26–8.14(m,1H),7.78(dd,J＝10.3,2.7Hz,1H),7.65(d,J＝1.8Hz,1H),7.41–7.14(m,3H),6.71(dd,J＝7.1,1.8Hz,1H),6.18–5.98(m,3H),5.26(dt,J＝6.6,3.4Hz,1H),4.14(s,3H),4.03(d,J＝15.2Hz,1H),3.41(d,J＝15.2Hz,1H),2.35(d,J＝1.1Hz,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.26–8.14(m,1H),7.78(dd,J＝10.3,2.7Hz,1H),7.65(d,J＝1.8Hz,1H),7.41– 7.14(m,3H),6.71(dd,J＝7.1,1.8Hz,1H),6.18–5.98(m,3H),5.26(dt,J＝6.6,3.4Hz,1H),4.14(s,3H) ,4.03(d,J＝15.2Hz,1H), 3.41(d,J＝15.2Hz,1H), 2.35(d,J＝1.1Hz,3H), 1.73(d,J＝6.2Hz,3H).
实施例25：(R)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[1',2'：1,5]吡唑并[4,3-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(25)的制备
Example 25: (R)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrido[1',2 '：1,5]pyrazolo[4,3-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene-8 - Preparation of amine (25)
步骤1：吡唑并[1,5-a]吡啶-2-甲醛(25a)的制备Step 1: Preparation of pyrazolo[1,5-a]pyridine-2-carboxaldehyde (25a)
将吡唑并[1,5-a]吡啶-2-羧酸(1.00g，6.17mmol)溶于二氯甲烷(80mL)中， 然后于-78℃缓慢滴加二异丁基氢化铝(DIBAL-H)(12.3ml，1.00M，12.3mmol)，继续搅拌3小时。将反应液加入50mL水淬灭，EA(50mL x 3)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物400mg，收率：40.0％。Dissolve pyrazolo[1,5-a]pyridine-2-carboxylic acid (1.00g, 6.17mmol) in dichloromethane (80mL). Then diisobutylaluminum hydride (DIBAL-H) (12.3ml, 1.00M, 12.3mmol) was slowly added dropwise at -78°C, and stirring was continued for 3 hours. The reaction solution was quenched by adding 50 mL of water, extracted with EA (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 400 mg of the title compound as a yellow oil, yield: 40.0%.
LC-MS：m/z＝147[M+H]+。LC-MS: m/z=147[M+H] + .
其余步骤与实施例12相同，除了用吡唑并[1,5-a]吡啶-2-甲醛(25a)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物25。The remaining steps are the same as in Example 12, except that pyrazolo[1,5-a]pyridine-2-carboxaldehyde (25a) is used instead of 6-(trifluoromethyl)imidazo[1,2-a] in step 1. Pyridine-2-carboxaldehyde gave compound 25.
LC-MS：m/z＝442.17[M+H]+。LC-MS: m/z=442.17[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.26(d,J＝2.0Hz,1H),7.97(d,J＝2.0Hz,1H),7.68(dd,J＝8.7,5.7Hz,1H),7.55–7.40(m,2H),7.20–7.03(m,3H),6.55(s,1H),6.37(s,2H),5.64–5.50(m,1H),4.48(d,J＝15.7Hz,1H),4.27(d,J＝15.8Hz,1H),4.13(s,3H),1.86(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.26(d,J＝2.0Hz,1H),7.97(d,J＝2.0Hz,1H),7.68(dd,J＝8.7,5.7Hz,1H) ,7.55–7.40(m,2H),7.20–7.03(m,3H),6.55(s,1H),6.37(s,2H),5.64–5.50(m,1H),4.48(d,J＝15.7Hz ,1H),4.27(d,J＝15.8Hz,1H),4.13(s,3H),1.86(d,J＝6.2Hz,3H).
实施例26：(R)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[1',2':1,5]吡唑并[4,3-g][1]氧杂[4]氮杂环十四碳烯-8-胺(26)的制备
Example 26: (R)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazolo[4,3 Preparation of -j]pyrido[1',2':1,5]pyrazolo[4,3-g][1]oxa[4]azacyclotetradecen-8-amine (26)
与实施例25的制备方法相同，除了用3-溴-4-碘-1-甲基-1H-吡唑代替步骤2中的4,5-二溴-2-甲基-2H-1,2,3-三唑，制得化合物26。The preparation method is the same as that of Example 25, except that 3-bromo-4-iodo-1-methyl-1H-pyrazole is used instead of 4,5-dibromo-2-methyl-2H-1,2 in step 2. ,3-triazole to prepare compound 26.
LC-MS：m/z＝441[M+H]+。LC-MS: m/z=441[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝2.0Hz,1H),7.97(d,J＝2.0Hz,1H),7.65(s,1H),7.57(dd,J＝8.6,5.9Hz,1H),7.46–7.37(m,2H),7.16–6.98(m,3H),6.45(s,1H),6.32(s,2H),5.72–5.61(m,1H),4.22(d,J＝15.8Hz,1H),4.02(d,J＝15.9Hz,1H),3.82(s,3H),1.88(d,J＝6.1Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.37 (d, J＝2.0Hz, 1H), 7.97 (d, J＝2.0Hz, 1H), 7.65 (s, 1H), 7.57 (dd, J＝ 8.6,5.9Hz,1H),7.46–7.37(m,2H),7.16–6.98(m,3H),6.45(s,1H),6.32(s,2H),5.72–5.61(m,1H),4.22 (d, J = 15.8 Hz, 1H), 4.02 (d, J = 15.9 Hz, 1H), 3.82 (s, 3H), 1.88 (d, J = 6.1 Hz, 3H).
实施例27：(R)-3,13-二氟-11,17-二甲基-17,19-二氢-11H-5,9-(亚甲基)苯并[1]吡啶并[3,2-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(27)的制备
Example 27: (R)-3,13-difluoro-11,17-dimethyl-17,19-dihydro-11H-5,9-(methylene)benzo[1]pyrido[3 Preparation of ,2-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecen-8-amine (27)
步骤1：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(5-氟-2-甲氧基吡啶-3-基)甲醇(27a)的制备Step 1 Preparation of: (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(5-fluoro-2-methoxypyridin-3-yl)methanol (27a)
将4,5-二溴-2-甲基-2H-1,2,3-三唑(3.09g，12.9mmol)溶于100ml四氢呋喃中，于-78℃滴加正丁基锂(在己烷中)(6.05ml，1.60M，9.67mmol),于-78℃搅拌0.5h，加入5-氟-2-甲氧基烟醛(1.00g，6.45mmol)，继续搅拌2h。将反应液加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物1.50g，收率：73.8％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (3.09g, 12.9mmol) in 100ml tetrahydrofuran, add n-butyllithium (in hexane) dropwise at -78°C Medium) (6.05ml, 1.60M, 9.67mmol), stir at -78°C for 0.5h, add 5-fluoro-2-methoxynicotinic aldehyde (1.00g, 6.45mmol), and continue stirring for 2h. The reaction solution was quenched with water, extracted with EA (50mL -2:1), 1.50g of the title compound was obtained as a yellow solid, yield: 73.8%.
LC-MS：m/z＝317[M+H]+。LC-MS: m/z=317[M+H] + .
步骤2：3-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-5-氟-2-甲氧基吡啶(27b)的制备Step 2: Preparation of 3-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-fluoro-2-methoxypyridine (27b)
将化合物27a(1.50g，4.73mmol)溶于10ml三氟乙酸(TFA)中，加入三乙基硅烷(Et3SiH)(2ml)，于50℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得黄色油状标题化合物1.30g，收率：91.5％。Compound 27a (1.50g, 4.73mmol) was dissolved in 10ml of trifluoroacetic acid (TFA), triethylsilane ( Et3SiH ) (2ml) was added, and the mixture was stirred at 50°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:1-2:1) to obtain 1.30g of the title compound as a yellow oil, yield: 91.5%.
LC-MS：m/z＝301[M+H]+。LC-MS: m/z=301[M+H] + .
步骤3：3-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-5-氟吡啶-2-醇(27c)的制备Step 3: Preparation of 3-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-5-fluoropyridin-2-ol (27c)
将化合物27b(1.30g，4.32mmol)溶于10ml乙醇，加入10ml 4mol/L盐酸的1,4-二氧六环溶液，于60℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得黄色油状标题化合物1.20g，收率：91.5％。Dissolve compound 27b (1.30g, 4.32mmol) in 10ml of ethanol, add 10ml of 4mol/L hydrochloric acid in 1,4-dioxane, and stir at 60°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=1:1-2:1) to obtain 1.20g of the title compound as a yellow oil, yield: 91.5%.
LC-MS：m/z＝287[M+H]+。LC-MS: m/z=287[M+H] + .
步骤4：(5-((5-氟-2-羟基吡啶-3-基)甲基)-2-甲基-2H-1,2,3-三唑-4-基)硼酸(27d)的制备 Step 4: (5-((5-fluoro-2-hydroxypyridin-3-yl)methyl)-2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (27d) preparation
将化合物27c(1.00g，3.48mmol)溶于100ml四氢呋喃中，于-78℃滴加正丁基锂(在己烷中)(5.44ml，1.6M，7.71mmol)，继续搅拌0.5h，加入硼酸三甲酯(1.09g，10.4mmol)，继续搅拌2h。将反应液加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物450mg，收率：51.1％。Dissolve compound 27c (1.00g, 3.48mmol) in 100ml tetrahydrofuran, add n-butyllithium (in hexane) (5.44ml, 1.6M, 7.71mmol) dropwise at -78°C, continue stirring for 0.5h, and add boric acid Trimethyl ester (1.09g, 10.4mmol), continue stirring for 2h. The reaction solution was quenched with water, extracted with EA (50mL -2:1), 450 mg of the title compound was obtained as a yellow solid, yield: 51.1%.
LC-MS：m/z＝253[M+H]+。LC-MS: m/z=253[M+H] + .
步骤5：(R)-3-((5-(2-(1-((2-氨基-5-溴吡啶-3-基)氧基)乙基)-5-氟苯基)-2-甲基-2H-1.2.3-三唑-4-基)甲基)-5-氟吡啶-2-醇(27e)的制备Step 5: (R)-3-((5-(2-(1-((2-Amino-5-bromopyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2- Preparation of methyl-2H-1.2.3-triazol-4-yl)methyl)-5-fluoropyridin-2-ol (27e)
将化合物27d(450mg，1.78mmol)、(R)-5-溴-3-(1-(4-氟-2-碘苯基)乙氧基)吡啶-2-胺(931mg，2.14mmol)、四三苯基膦钯(103mg，0.089mmol)、碳酸钠(768mg，7.12mmol)溶于10ml甲苯/EtOH/H2O(2:1:0.4)中，于70℃搅拌过夜。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物120mg，收率：13.0％。Compound 27d (450 mg, 1.78 mmol), (R)-5-bromo-3-(1-(4-fluoro-2-iodophenyl)ethoxy)pyridin-2-amine (931 mg, 2.14 mmol), Tetrakis triphenylphosphine palladium (103 mg, 0.089 mmol) and sodium carbonate (768 mg, 7.12 mmol) were dissolved in 10 ml of toluene/EtOH/H2O (2:1:0.4), and stirred at 70°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 120 mg of the title compound as a yellow solid, yield: 13.0%.
LC-MS：m/z＝517[M+H]+。LC-MS: m/z=517[M+H] + .
步骤6：(R)-3-((5-(2-(1-((2-氨基-5-溴吡啶-3-基)氧基)乙基)-5-氟苯基)-2-甲基-2H-1,2,3-三唑-4-基)甲基)-5-氟吡啶-2-基三氟甲磺酸酯(27f)的制备Step 6: (R)-3-((5-(2-(1-((2-Amino-5-bromopyridin-3-yl)oxy)ethyl)-5-fluorophenyl)-2- Preparation of methyl-2H-1,2,3-triazol-4-yl)methyl)-5-fluoropyridin-2-yl triflate (27f)
将化合物27e(110mg，0.174mmol)溶于10ml四氢呋喃中，于0℃加入三乙胺(35.2mg，0.348mmol)、N-苯基双(三氟甲烷磺酰)亚胺(80.7mg，0.226mmol)，于室温搅拌过夜。将反应液用冰水淬灭，EA萃取，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色油状标题化合物70.0mg，收率：50.7％。Compound 27e (110 mg, 0.174 mmol) was dissolved in 10 ml of tetrahydrofuran, and triethylamine (35.2 mg, 0.348 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (80.7 mg, 0.226 mmol) were added at 0°C. ) and stir at room temperature overnight. The reaction solution was quenched with ice water, extracted with EA, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain the title compound 70.0 as a yellow oil. mg, yield: 50.7%.
LC-MS：m/z＝649[M+H]+。LC-MS: m/z=649[M+H] + .
步骤7：(R)-3,13-二氟-11,17-二甲基-17,19-二氢-11H-5,9-(亚甲基)苯并[1]吡啶并[3,2-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(27)的制备Step 7: (R)-3,13-difluoro-11,17-dimethyl-17,19-dihydro-11H-5,9-(methylene)benzo[1]pyrido[3, Preparation of 2-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecen-8-amine (27)
将化合物27f(70.0mg，0.108mmol)、双联频哪醇硼酸酯(41.2mg，0.162mmol)、1,1-双(二苯基膦)二茂铁二氯化钯(78mg，0.108mmol)、磷酸钾(45.8mg，0.216mmol)、乙酸钾(21.6mg，0.216mmol)溶于10ml 1,4-二氧六环中，于70℃搅拌过夜，将反应液减压浓缩，残余物通过高效制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物1.00mg，收率：2.20％。Compound 27f (70.0 mg, 0.108 mmol), bis-pinacol boronic acid ester (41.2 mg, 0.162 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (78 mg, 0.108 mmol) ), potassium phosphate (45.8mg, 0.216mmol), potassium acetate (21.6mg, 0.216mmol) were dissolved in 10ml of 1,4-dioxane, stirred at 70°C overnight, the reaction solution was concentrated under reduced pressure, and the residue was passed through High-efficiency preparative liquid chromatography separation (chromatographic column model: Daisogei 30mm*250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), the title compound 1.00 was obtained as a white solid mg, yield: 2.20%.
LC-MS：m/z＝421[M+H]+。LC-MS: m/z=421[M+H] + .
实施例28：(R)-3-氟-5,20-二甲基-14-(四氢-2H-吡喃-4-基)-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(28)的制备
Example 28: (R)-3-fluoro-5,20-dimethyl-14-(tetrahydro-2H-pyran-4-yl)-18,20-dihydro-5H-7,11-( Methylene)benzo[1]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (28)
步骤1：6-(3,6-二氢-2H-吡喃-4-基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(28a)的制备Step 1: Preparation of ethyl 6-(3,6-dihydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-2-carboxylate (28a)
于室温，6-溴咪唑并[1,2-a]吡啶-2-羧酸乙酯(1.00g，3.73mmol)、(3,6-二氢-2H-吡喃-4-基)硼酸(573mg，4.47mmol)、碳酸钠(806mg，7.46mmol)、DPPF二氯化钯(324mg，0.477mmol)溶于1,4-二氧六环(10ml)，于90℃搅拌6h。加水淬灭，EA萃取，饱和氯化钠溶液洗涤，合并有机相减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝10:1-1:1)，得黄色固体状标题化合物700mg，收率：70.1％。At room temperature, 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.00g, 3.73mmol), (3,6-dihydro-2H-pyran-4-yl)boronic acid ( 573 mg, 4.47 mmol), sodium carbonate (806 mg, 7.46 mmol), and DPPF palladium dichloride (324 mg, 0.477 mmol) were dissolved in 1,4-dioxane (10 ml), and stirred at 90°C for 6 hours. Add water to quench, extract with EA, wash with saturated sodium chloride solution, combine the organic phases and concentrate under reduced pressure, and use silica gel column chromatography to separate and purify the residue (mobile phase: PE/EA=10:1-1:1) to obtain The title compound was a yellow solid, 700 mg, yield: 70.1%.
LC-MS：m/z＝272[M+H]+。LC-MS: m/z=272[M+H] + .
步骤2：(6-(四氢-2H-吡喃-4-基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(28b)的制备Step 2: Preparation of: (6-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (28b)
将化合物28a(700mg，2.57mmol)溶于50ml甲醇中，于室温加入140mg的10％含水钯碳，氢气氛下，继续室温搅拌0.5h，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝1:1-2:1)，得白色固体状标题化合物600mg，收率：85.7％。Dissolve compound 28a (700 mg, 2.57 mmol) in 50 ml of methanol, add 140 mg of 10% aqueous palladium on carbon at room temperature, continue stirring at room temperature for 0.5 h under a hydrogen atmosphere, filter, and concentrate the filtrate under reduced pressure. The residue is subjected to silica gel column chromatography. Separate and purify by chromatography (mobile phase: DCM/MeOH=1:1-2:1) to obtain 600 mg of the title compound as a white solid, yield: 85.7%.
LC-MS：m/z＝275[M+H]+。LC-MS: m/z=275[M+H] + .
其他步骤与实施例15的制备方法相同，除了用(6-(四氢2H-吡喃-4-基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(28b)代替步骤2中的6-甲基咪唑并[1,2-a]吡啶-2-羧酸乙酯(15a)，并用3-溴-4-碘-1-甲基-1H-吡唑代替步骤2中的4,5-二溴-2-甲基-2H-1,2,3-三唑，制得化合物28。Other steps are the same as the preparation method of Example 15, except that (6-(tetrahydro2H-pyran-4-yl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (28b) is used instead of step 6-methylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (15a) in step 2 and replace it with 3-bromo-4-iodo-1-methyl-1H-pyrazole in step 2 4,5-dibromo-2-methyl-2H-1,2,3-triazole was used to prepare compound 28.
LC-MS：m/z＝525[M+H]+。LC-MS: m/z=525[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.14(d,J＝1.9Hz,1H),7.85-7.65(m,2H),7.56(d,J＝7.9Hz,2H),7.35-7.08(m,3H),6.33(d,J＝1.9Hz,1H),6.14(s,2H),5.40-5.22(m,1H),3.97-3.91(m,1H),3.83(d,J＝7.9Hz,3H),3.41(m,4H),3.15(d,J＝15.0Hz,1H),2.83(tt,J＝10.1,5.6Hz,1H),1.84-1.54(m,7H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.14 (d, J = 1.9 Hz, 1H), 7.85-7.65 (m, 2H), 7.56 (d, J = 7.9 Hz, 2H), 7.35-7.08 ( m,3H),6.33(d,J＝1.9Hz,1H),6.14(s,2H),5.40-5.22(m,1H),3.97-3.91(m,1H),3.83(d,J＝7.9Hz ,3H),3.41(m,4H),3.15(d,J＝15.0Hz,1H),2.83(tt,J＝10.1,5.6Hz,1H),1.84-1.54(m,7H).
实施例29：(R)-3-氟-5,20-二甲基-14-(1-甲基-1H-吡唑-3-基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(29)的制备
Example 29: (R)-3-fluoro-5,20-dimethyl-14-(1-methyl-1H-pyrazol-3-yl)-18,20-dihydro-5H-7,11 -(Methylene)benzo[l]pyrazole[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4] Preparation of nitrogen heterocyclic tetradecene-8-amine (29)
步骤1：6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(29a)的制备Step 1: Preparation of ethyl 6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate (29a)
于室温，将6-溴咪唑并[1,2-a]吡啶-2-羧酸乙酯(1.85g，6.90mmol)、(1-甲基-1H-吡唑-4-基)硼酸(1.04g，8.28mmol)、Pd(dppf)Cl2(504mg，0.690mmol)溶于二氧六环/H2O(40ml/10mL)，加入碳酸钠(1.46g，13.8mmol)，于100℃搅拌过夜。加水淬灭，EA萃取，饱和氯化钠溶液洗涤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:2-1:3)，得黄棕色固体标题化合物1.10g，收率：61.1％。At room temperature, 6-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.85g, 6.90mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (1.04 g, 8.28mmol), Pd(dppf)Cl2 (504mg, 0.690mmol) were dissolved in dioxane/H 2 O (40ml/10mL), sodium carbonate (1.46g, 13.8mmol) was added, and stirred at 100°C overnight. Add water to quench, extract with EA, wash with saturated sodium chloride solution, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:2-1:3) to obtain a yellow-brown solid. 1.10 g of the title compound, yield: 61.1%.
LC-MS：m/z＝271[M+H]+。LC-MS: m/z=271[M+H] + .
其他步骤与实施例15的制备方法相同，除了用6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(29a)代替步骤2中的6-甲基咪唑并[1,2-a]吡啶-2-羧酸乙酯(15a)，并用3-溴-4-碘-1-甲基-1H-吡唑代替步骤2中的4,5-二溴-2-甲基-2H-1,2,3-三唑，制得化合物29。Other steps are the same as the preparation method of Example 15, except that ethyl 6-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-2-carboxylate (29a) is used Replace ethyl 6-methylimidazo[1,2-a]pyridine-2-carboxylate (15a) in step 2 with 3-bromo-4-iodo-1-methyl-1H-pyrazole 4,5-dibromo-2-methyl-2H-1,2,3-triazole in 2 was used to prepare compound 29.
LC-MS：m/z＝521[M+H]+。LC-MS: m/z=521[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.38(t,J＝1.3Hz,1H),8.18(s,1H),7.86(s,1H),7.79(d,J＝1.7Hz,1H),7.72(dd,J＝10.4,2.7Hz,1H),7.63-7.53(m,2H),7.46(dd,J＝9.3,1.7Hz,1H),7.21(qd,J＝8.4,5.8Hz,2H),6.35(d,J＝1.8Hz,1H),6.08(s,2H),5.35(dd,J＝6.5,2.1Hz,1H),3.92–3.79(m,7H),3.14(d,J＝14.9Hz,1H),1.73(d,J＝6.2Hz,3H)。1H NMR (400MHz, DMSO-d6) δ8.38(t,J＝1.3Hz,1H),8.18(s,1H),7.86(s,1H),7.79(d,J＝1.7Hz,1H),7.72 (dd,J＝10.4,2.7Hz,1H),7.63-7.53(m,2H),7.46(dd,J＝9.3,1.7Hz,1H),7.21(qd,J＝8.4,5.8Hz,2H), 6.35(d,J＝1.8Hz,1H),6.08(s,2H),5.35(dd,J＝6.5,2.1Hz,1H),3.92–3.79(m,7H),3.14(d,J＝14.9Hz ,1H),1.73(d,J=6.2Hz,3H).
实施例30：(R)-3-氟-5,20-二甲基-14-(甲磺酰基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(30)的制备
Example 30: (R)-3-fluoro-5,20-dimethyl-14-(methanesulfonyl)-18,20-dihydro-5H-7,11-(methylene)benzo[l ]pyrazole[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene-8- Preparation of amine (30)
步骤1：5-(甲基磺酰基)吡啶-2-胺(30a)的制备Step 1: Preparation of 5-(methylsulfonyl)pyridin-2-amine (30a)
于室温，向5-碘吡啶-2-胺(10.0g，45.45mmol，1.00equiv)的DMSO(80.0mL)溶液中加入甲烷亚磺酸钠(9.45g，90.90mmol，2.0equiv)、四甲基乙二胺(2.63g，22.7mmol，0.500equiv)、碘化亚铜(1.08g，9.09mmol，0.200equiv)和碳酸钾(6.27g，45.4mmol，1.00equiv)。氮气氛围下，100℃搅拌16h。加水淬灭，EA萃取。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物6.0g，收率76.43％。To a solution of 5-iodopyridin-2-amine (10.0g, 45.45mmol, 1.00equiv) in DMSO (80.0mL) at room temperature, add sodium methane sulfinate (9.45g, 90.90mmol, 2.0equiv), tetramethyl Ethylenediamine (2.63g, 22.7mmol, 0.500equiv), copper iodide (1.08g, 9.09mmol, 0.200equiv) and potassium carbonate (6.27g, 45.4mmol, 1.00equiv). Under nitrogen atmosphere, stir at 100°C for 16 hours. Add water to quench and extract with EA. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 6.0 g of the title compound as a white solid, with a yield of 76.43%.
LC-MS：m/z 173.05[M+H]+。LC-MS: m/z 173.05[M+H] + .
其他步骤与实施例16的制备方法相同，除了用5-(甲基磺酰基)吡啶-2-胺(30a)代替步骤1中的3-甲基吡啶-2-胺，制得化合物30。Other steps were the same as the preparation method in Example 16, except that 5-(methylsulfonyl)pyridin-2-amine (30a) was used instead of 3-methylpyridin-2-amine in step 1 to prepare compound 30.
LC-MS：m/z 519.10[M+H]+。LC-MS: m/z 519.10[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.74(dd,J＝1.9,0.9Hz,1H),7.87-7.76(m,2H),7.71(dd,J＝10.4,2.7Hz,1H),7.63-7.56(m,2H),7.29-7.15(m,2H),6.35(d,J＝1.9Hz,1H),6.20(s,2H),5.35(dd,J＝6.6,2.1Hz,1H),3.93(d,J＝15.0Hz,1H),3.82(s,3H),3.28(s,3H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.74 (dd, J＝1.9, 0.9Hz, 1H), 7.87-7.76 (m, 2H), 7.71 (dd, J＝10.4, 2.7Hz, 1H), 7.63-7.56(m,2H),7.29-7.15(m,2H),6.35(d,J＝1.9Hz,1H),6.20(s,2H),5.35(dd,J＝6.6,2.1Hz,1H) ,3.93(d,J＝15.0Hz,1H),3.82(s,3H),3.28(s,3H),1.74(d,J＝6.2Hz,3H).
实施例31：(R)-3-氟-5,20-二甲基-15-(2,2,2-三氟乙氧基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(30)的制备
Example 31: (R)-3-fluoro-5,20-dimethyl-15-(2,2,2-trifluoroethoxy)-18,20-dihydro-5H-7,11-( Methylene)benzo[l]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (30)
步骤1：6-羟基咪唑并[1,2-a]吡啶-2-羧酸乙酯(31a)的制备Step 1: Preparation of ethyl 6-hydroxyimidazo[1,2-a]pyridine-2-carboxylate (31a)
于室温，向6-氨基吡啶-3-醇(4.85g，44.09mmol，1.00equiv)的DME(50.00mL)和甲醇(50.00mL)溶液中加入80％溴丙酮酸乙酯(16.0g，66.1mmol，1.50equiv)，于氮气氛围下80℃搅拌16h。直接浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物2.1g，收率23.12％。To a solution of 6-aminopyridin-3-ol (4.85 g, 44.09 mmol, 1.00 equiv) in DME (50.00 mL) and methanol (50.00 mL) was added 80% ethyl bromopyruvate (16.0 g, 66.1 mmol) at room temperature. , 1.50equiv), stirred at 80°C for 16h under nitrogen atmosphere. Concentrate directly. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 2.1 g of the title compound as a white solid, with a yield of 23.12%.
LC-MS：m/z 207.05[M+H]+。LC-MS: m/z 207.05[M+H] + .
步骤2：6-(2,2,2-三氟乙氧基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(31b)的制备Step 2: Preparation of ethyl 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-2-carboxylate (31b)
于0℃，向6-羟基咪唑并[1,2-a]吡啶-2-羧酸乙酯(1.00g，4.85mmol，1.00equiv)的DMF(10.00mL)溶液中加入氢化钠(388mg，9.70mmol，2.00equiv)，搅拌5分钟，加入2,2,2-三氟乙基三氟甲磺酸酯(2.25g，9.70mmol，2.00equiv)，于氮气氛围下80℃搅拌1h。加水淬灭，EA萃取。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物950mg，收率68.01％。To a solution of ethyl 6-hydroxyimidazo[1,2-a]pyridine-2-carboxylate (1.00g, 4.85mmol, 1.00equiv) in DMF (10.00mL) at 0°C was added sodium hydride (388mg, 9.70 mmol, 2.00 equiv), stir for 5 minutes, add 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.25g, 9.70 mmol, 2.00 equiv), and stir at 80°C for 1 hour under nitrogen atmosphere. Add water to quench and extract with EA. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 950 mg of the title compound as a white solid, with a yield of 68.01%.
LC-MS：m/z 289.05[M+H]+。LC-MS: m/z 289.05[M+H] + .
步骤3：6-(2,2,2-三氟乙氧基)咪唑并[1,2-a]吡啶-2-甲醛(31c)的制备Step 3: Preparation of 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-2-carboxaldehyde (31c)
氮气氛围下，于-78℃向6-(2,2,2-三氟乙氧基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(950mg，3.29mmol，1.00equiv)的二氯甲烷(15.00mL)溶液中加入二异丁基氢化铝(6.59mL，6.59mmol，2.00equiv)，继续搅拌1.5小时。缓慢加入甲醇淬灭，加入1M盐酸调节PH～7，反应混合物用二氯甲烷萃取(3X50毫升)。合并有机相，硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物500mg。收率62.28％。 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (950mg, 3.29mmol, 1.00equiv) at -78°C under nitrogen atmosphere Diisobutylaluminum hydride (6.59 mL, 6.59 mmol, 2.00 equiv) was added to the dichloromethane (15.00 mL) solution, and stirring was continued for 1.5 hours. Methanol was slowly added to quench, 1M hydrochloric acid was added to adjust the pH to ~7, and the reaction mixture was extracted with dichloromethane (3X50 ml). The organic phases were combined and dried over sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 500 mg of the title compound as a white solid. The yield is 62.28%.
LC-MS：m/z 245.05[M+H]+。LC-MS: m/z 245.05[M+H] + .
其他步骤与实施例16的制备方法相同，除了用6-(2,2,2-三氟乙氧基)咪唑并[1,2-a]吡啶-2-甲醛(31c)代替步骤4中的6-甲基咪唑并[1,2-a]吡啶-2-甲醛(16c)，制得化合物31。Other steps are the same as the preparation method of Example 16, except that 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-2-carboxaldehyde (31c) is used instead of step 4 6-methylimidazo[1,2-a]pyridine-2-carboxaldehyde (16c) gave compound 31.
LC-MS：m/z 539.05[M+H]+。LC-MS: m/z 539.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝2.6Hz,1H),7.72(dt,J＝10.4,2.6Hz,1H),7.55(dd,J＝10.0,2.6Hz,2H),7.21(tq,J＝8.3,2.7Hz,2H),7.17-7.07(m,1H),6.33(d,J＝2.2Hz,1H),6.09(s,1H),5.34(d,J＝6.6Hz,1H),4.90-4.70(m,2H),3.86(s,1H),3.32(d,J＝2.7Hz,3H),3.12(dd,J＝15.0,2.6Hz,1H),1.73(dd,J＝6.2,2.6Hz,3H),1.24(s,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.03 (d, J = 2.6 Hz, 1H), 7.72 (dt, J = 10.4, 2.6 Hz, 1H), 7.55 (dd, J = 10.0, 2.6 Hz, 2H),7.21(tq,J＝8.3,2.7Hz,2H),7.17-7.07(m,1H),6.33(d,J＝2.2Hz,1H),6.09(s,1H),5.34(d,J ＝6.6Hz,1H),4.90-4.70(m,2H),3.86(s,1H),3.32(d,J＝2.7Hz,3H),3.12(dd,J＝15.0,2.6Hz,1H),1.73 (dd,J=6.2,2.6Hz,3H),1.24(s,1H).
实施例32：(R)-3,14-二氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]嘧啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(32)的制备
Example 32: (R)-3,14-difluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazolo[ 4,3-j]pyrimido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (32) Preparation
步骤1：6-氟咪唑并[1,2-a]嘧啶-2-羧酸乙酯(32a)的制备Step 1: Preparation of ethyl 6-fluoroimidazo[1,2-a]pyrimidine-2-carboxylate (32a)
于室温，将5-氟嘧啶-2-胺(2.00g，18.4mmol)、3-溴丙酮酸乙酯(5.35g，27.6mmol)溶于二氧六环(50ml)，加入碳酸氢钠(3.90g，36.8mmol)，于100℃搅拌过夜。加水淬灭，EA萃取，饱和氯化钠溶液洗涤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：MeOH/DCM＝1:50-1:20)，得白色固体标题化合物2.00g，收率：55.2％。Dissolve 5-fluoropyrimidin-2-amine (2.00g, 18.4mmol) and ethyl 3-bromopyruvate (5.35g, 27.6mmol) in dioxane (50ml) at room temperature, and add sodium bicarbonate (3.90 g, 36.8 mmol), stirred at 100°C overnight. Add water to quench, extract with EA, wash with saturated sodium chloride solution, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: MeOH/DCM=1:50-1:20) to obtain the title white solid Compound 2.00g, yield: 55.2%.
LC-MS：m/z＝210[M+H]+。LC-MS: m/z=210[M+H] + .
步骤2：6-氟咪唑并[1,2-a]嘧啶-2-甲醛(32b)的制备Step 2: Preparation of 6-fluoroimidazo[1,2-a]pyrimidine-2-carboxaldehyde (32b)
于室温，将6-氟咪唑并[1,2-a]嘧啶-2-羧酸乙酯(2.00g，9.52mmol)溶于二氯甲烷(15ml)。于-78℃，加入二异丁基氢化铝(19.0ml，1M，19.0mmol)，继续搅拌2h，加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，减压浓缩， 残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-2:1)，得黄色固体标题化合物300mg，收率：18.9％。6-Fluoroimidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester (2.00 g, 9.52 mmol) was dissolved in dichloromethane (15 ml) at room temperature. At -78°C, add diisobutylaluminum hydride (19.0ml, 1M, 19.0mmol), continue stirring for 2 hours, add water to quench, extract with EA (50mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-2:1) to obtain 300 mg of the title compound as a yellow solid, yield: 18.9%.
其他步骤与实施例16的制备方法相同，除了用6-氟咪唑并[1,2-a]嘧啶-2-甲醛(32b)代替步骤4中的6-甲基咪唑并[1,2-a]吡啶-2-甲醛(16c)，制得化合物32。Other steps are the same as the preparation method of Example 16, except that 6-fluoroimidazo[1,2-a]pyrimidine-2-carboxaldehyde (32b) is used instead of 6-methylimidazo[1,2-a in step 4 ]pyridine-2-carboxaldehyde (16c) to prepare compound 32.
LC-MS：m/z＝460[M+H]+。LC-MS: m/z=460[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.99(dd,J＝4.6,2.8Hz,1H),8.64(d,J＝2.8Hz,1H),7.77(d,J＝1.8Hz,1H),7.70(dd,J＝10.4,2.6Hz,1H),7.61(s,1H),7.27-7.15(m,2H),6.35(d,J＝1.9Hz,1H),6.16(s,2H),5.33(tt,J＝6.8,3.3Hz,1H),3.93(dd,J＝14.9,1.1Hz,1H),3.83(s,3H),3.18(d,J＝14.9Hz,1H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.99 (dd, J = 4.6, 2.8Hz, 1H), 8.64 (d, J = 2.8Hz, 1H), 7.77 (d, J = 1.8Hz, 1H) ,7.70(dd,J＝10.4,2.6Hz,1H),7.61(s,1H),7.27-7.15(m,2H),6.35(d,J＝1.9Hz,1H),6.16(s,2H), 5.33(tt,J＝6.8,3.3Hz,1H),3.93(dd,J＝14.9,1.1Hz,1H),3.83(s,3H),3.18(d,J＝14.9Hz,1H),1.73(d ,J=6.2Hz,3H).
实施例33：(R)-14-环丙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]嘧啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯8-胺(33)的制备
Example 33: (R)-14-cyclopropyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyridine Azolo[4,3-j]pyrimido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene 8-amine ( 33) Preparation
步骤1：5-环丙基嘧啶-2-胺(33a)的制备Step 1: Preparation of 5-cyclopropylpyrimidin-2-amine (33a)
于室温，2-氨基-5-溴嘧啶(5.00g，28.9mmol)、环丙基硼酸(7.45g，86.7mmol)、Pd(dppf)Cl2(1.00g，1.45mmol)溶于THF/H2O(5:1)(100ml)，加入碳酸钾(9.97g，72.0mmol)，于80℃搅拌过夜。加水淬灭，EA萃取，饱和氯化钠溶液洗涤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1-1:1)，得黄色固体标题化合物2.20g，收率：38.7％。At room temperature, 2-amino-5-bromopyrimidine (5.00g, 28.9mmol), cyclopropylboronic acid (7.45g, 86.7mmol), and Pd(dppf)Cl 2 (1.00g, 1.45mmol) were dissolved in THF/H 2 O(5:1) (100ml), add potassium carbonate (9.97g, 72.0mmol), and stir at 80°C overnight. Add water to quench, extract with EA, wash with saturated sodium chloride solution, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=2:1-1:1) to obtain the yellow solid title Compound 2.20g, yield: 38.7%.
LC-MS：m/z＝136[M+H]+。LC-MS: m/z=136[M+H] + .
其他步骤与实施例16的制备方法相同，除了用5-环丙基嘧啶-2-胺(33a)代替步骤1中的3-甲基吡啶-2-胺，制得化合物33。The other steps were the same as the preparation method in Example 16, except that 5-cyclopropylpyrimidin-2-amine (33a) was used instead of 3-methylpyridin-2-amine in step 1 to prepare compound 33.
LC-MS：m/z＝482[M+H]+。LC-MS: m/z=482[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.43(d,J＝2.4Hz,1H),8.32-8.22(m,1H), 7.78-7.66(m,2H),7.59(s,1H),7.21(qd,J＝8.4,5.8Hz,2H),6.33(d,J＝1.8Hz,1H),6.11(s,2H),5.32(dt,J＝6.9,3.5Hz,1H),3.88(d,J＝15.0Hz,1H),3.82(s,3H),3.16(d,J＝14.9Hz,1H),2.02(tt,J＝8.5,5.1Hz,1H),1.72(d,J＝6.2Hz,3H),0.93(ddd,J＝8.3,4.2,2.5Hz,2H),0.78(ddd,J＝9.3,4.6,2.9Hz,2H)。 1 H NMR (400MHz, DMSO-d6) δ8.43 (d, J = 2.4Hz, 1H), 8.32-8.22 (m, 1H), 7.78-7.66(m,2H),7.59(s,1H),7.21(qd,J＝8.4,5.8Hz,2H),6.33(d,J＝1.8Hz,1H),6.11(s,2H),5.32 (dt,J＝6.9,3.5Hz,1H),3.88(d,J＝15.0Hz,1H),3.82(s,3H),3.16(d,J＝14.9Hz,1H),2.02(tt,J＝ 8.5,5.1Hz,1H),1.72(d,J＝6.2Hz,3H),0.93(ddd,J＝8.3,4.2,2.5Hz,2H),0.78(ddd,J＝9.3,4.6,2.9Hz,2H ).
实施例34：(R)-3-氟-5,14,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(34)的制备
Example 34: (R)-3-fluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazino[2 ',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecen-8-amine (34) Preparation
步骤1：(3-溴-1,5-二甲基-1H-吡唑-4-基)(6-甲基咪唑并[1,2-a]吡嗪-2-基)甲醇(34a)的制备Step 1: (3-bromo-1,5-dimethyl-1H-pyrazol-4-yl)(6-methylimidazo[1,2-a]pyrazin-2-yl)methanol (34a) Preparation
于室温，将3-溴-4-碘-1,5-二甲基1H-吡唑(1.11g，3.71mmol)溶于250ml THF中，于0℃，滴加异丙基溴化镁溶液(1.85ml,，2M，3.71mmol)，继续搅拌0.5h，加入6-甲基咪唑并[1,2-a]吡嗪-2-甲醛(500mg，3.09mmol)，升至室温搅拌4h，将反应液加水淬灭，乙酸乙酯萃取(100mL x 3)，无水硫酸钠干燥，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄棕色固体标题化合物900mg，收率：90.1％。Dissolve 3-bromo-4-iodo-1,5-dimethyl 1H-pyrazole (1.11g, 3.71mmol) in 250ml THF at room temperature, and add isopropyl magnesium bromide solution ( 1.85ml, 2M, 3.71mmol), continue stirring for 0.5h, add 6-methylimidazo[1,2-a]pyrazine-2-carbaldehyde (500mg, 3.09mmol), raise to room temperature and stir for 4h, then react The liquid was quenched with water, extracted with ethyl acetate (100mL The title compound was a yellow-brown solid, 900 mg, yield: 90.1%.
LC-MS：m/z＝336[M+H]+。LC-MS: m/z=336[M+H] + .
其他步骤与实施例12的制备方法相同，除了用6-甲基咪唑并[1,2-a]吡嗪-2-甲醛代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，并用3-溴-4-碘-1,5-二甲基代替3-溴-4-碘-1-甲基1H-吡唑得到化合物34。Other steps are the same as the preparation method of Example 12, except that 6-methylimidazo[1,2-a]pyrazine-2-carboxaldehyde is used instead of 6-(trifluoromethyl)imidazo[1, 2-a]pyridine-2-carboxaldehyde, and replacing 3-bromo-4-iodo-1,5-dimethyl with 3-bromo-4-iodo-1-methyl 1H-pyrazole gave compound 34.
LC-MS：m/z＝470[M+H]+。LC-MS: m/z=470[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝1.4Hz,1H),8.25(t,J＝1.3Hz,1H),7.76(d,J＝1.8Hz,1H),7.70(dd,J＝10.4,2.7Hz,1H),7.58(s,1H),7.30–7.11(m,2H),6.35(d,J＝1.8Hz,1H),6.18(s,2H),5.33(tt,J＝6.7,3.3Hz,1H),3.94(d,J＝ 15.1Hz,1H),3.82(s,3H),3.29(s,6H),3.20(d,J＝15.0Hz,1H),2.75(s,3H)2.45–2.31(m,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.93 (d, J = 1.4Hz, 1H), 8.25 (t, J = 1.3Hz, 1H), 7.76 (d, J = 1.8Hz, 1H), 7.70 (dd,J＝10.4,2.7Hz,1H),7.58(s,1H),7.30–7.11(m,2H),6.35(d,J＝1.8Hz,1H),6.18(s,2H),5.33( tt,J＝6.7,3.3Hz,1H),3.94(d,J＝ 15.1Hz,1H),3.82(s,3H),3.29(s,6H),3.20(d,J＝15.0Hz,1H),2.75(s,3H)2.45–2.31(m,3H),1.73(d ,J=6.2Hz,3H).
实施例35：(R)-3-氟-5,20-二甲基-14-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(35)的制备
Example 35: (R)-3-fluoro-5,20-dimethyl-14-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo[ 1]pyrazino[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4] Preparation of azacyclotetradecene-8-amine (35)
与实施例15的制备方法相同，除了用5-(三氟甲基)吡嗪-2-胺代替步骤1中的3-甲基吡啶-2-胺，制得化合物35。Compound 35 was prepared by the same preparation method as Example 15, except that 5-(trifluoromethyl)pyrazin-2-amine was used instead of 3-methylpyridin-2-amine in step 1.
LC-MS：m/z＝511[M+H]+。LC-MS: m/z=511[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.19(d,J＝1.3Hz,1H),8.72(t,J＝1.1Hz,1H),7.88-7.76(m,2H),7.35(dd,J＝8.5,5.8Hz,1H),7.25(td,J＝8.4,2.8Hz,1H),6.32(s,2H),6.13(d,J＝1.9Hz,1H),5.28(tt,J＝6.7,3.3Hz,1H),4.23(d,J＝15.2Hz,1H),4.14(s,3H),3.53(d,J＝15.2Hz,1H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.19(d,J＝1.3Hz,1H),8.72(t,J＝1.1Hz,1H),7.88-7.76(m,2H),7.35(dd,J ＝8.5,5.8Hz,1H),7.25(td,J＝8.4,2.8Hz,1H),6.32(s,2H),6.13(d,J＝1.9Hz,1H),5.28(tt,J＝6.7, 3.3Hz, 1H), 4.23 (d, J = 15.2Hz, 1H), 4.14 (s, 3H), 3.53 (d, J = 15.2Hz, 1H), 1.74 (d, J = 6.2Hz, 3H).
实施例36：(R)-14-(环丙基)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(36)的制备

Example 36: (R)-14-(cyclopropyl)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l ]pyrazino[2',1':2,3]imidazole[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]aza Preparation of cyclotetradecen-8-amine (36)

步骤1：5-环丙基吡嗪-2-胺(36a)的制备Step 1: Preparation of 5-cyclopropylpyrazin-2-amine (36a)
于室温，将2-氨基-5-溴吡嗪(50.0g，0.289mol)、2-环丙基-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(97.0g，0.433mol)溶于二氧六环(500ml)和H2O(100ml)，加入碳酸铯(235g，0.722mol)，于100℃搅拌过夜。加水淬灭，EA萃取，饱和氯化钠溶液洗涤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝5:1-5:2)，得白色固体标题化合物21g，收率：38.2％。At room temperature, 2-amino-5-bromopyrazine (50.0g, 0.289mol), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (97.0g, 0.433mol) was dissolved in dioxane (500ml) and H 2 O (100ml), added cesium carbonate (235g, 0.722mol), and stirred at 100°C overnight. Add water to quench, extract with EA, wash with saturated sodium chloride solution, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=5:1-5:2) to obtain the title white solid. Compound 21g, yield: 38.2%.
LC-MS：m/z＝136[M+H]+。LC-MS: m/z=136[M+H] + .
其他步骤与实施例15的制备方法相同，除了用5-环丙基吡嗪-2-胺(36a)代替步骤1中的3-甲基吡啶-2-胺，制得化合物36。The other steps were the same as the preparation method in Example 15, except that 5-cyclopropylpyrazin-2-amine (36a) was used instead of 3-methylpyridin-2-amine in step 1 to prepare compound 36.
LC-MS:m/z＝483[M+H]+。LC-MS: m/z=483[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.91(d,J＝1.4Hz,1H),8.30(d,J＝1.4Hz,1H),7.83-7.73(m,2H),7.33(dd,J＝8.5,5.8Hz,1H),7.24(td,J＝8.4,2.8Hz,1H),6.22(s,2H),6.12(d,J＝1.9Hz,1H),5.28(tt,J＝6.5,3.9Hz,1H),4.12(d,J＝12.1Hz,4H),3.47(d,J＝15.2Hz,1H),2.15(td,J＝7.3,3.9Hz,1H),1.73(d,J＝6.2Hz,3H),0.86(ddd,J＝8.6,6.4,4.1Hz,4H)。 1 H NMR (400MHz, DMSO-d6) δ8.91(d,J＝1.4Hz,1H),8.30(d,J＝1.4Hz,1H),7.83-7.73(m,2H),7.33(dd,J ＝8.5,5.8Hz,1H),7.24(td,J＝8.4,2.8Hz,1H),6.22(s,2H),6.12(d,J＝1.9Hz,1H),5.28(tt,J＝6.5, 3.9Hz,1H),4.12(d,J＝12.1Hz,4H),3.47(d,J＝15.2Hz,1H),2.15(td,J＝7.3,3.9Hz,1H),1.73(d,J＝ 6.2Hz, 3H), 0.86 (ddd, J = 8.6, 6.4, 4.1Hz, 4H).
实施例37：(R)-3-氟-5,13,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]嘧啶并[1'，2':1,5]吡唑并[4,3-g][1]氧杂[4]氮杂环十四碳烯-8胺(37)的制备

Example 37: (R)-3-fluoro-5,13,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazolo[4 ,3-j]pyrimido[1',2':1,5]pyrazolo[4,3-g][1]oxa[4]azacyclotetradecene-8amine (37) preparation

步骤1：5-甲基吡唑并[1,5-a]嘧啶-2-羧酸乙酯(37a)的制备Step 1: Preparation of ethyl 5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (37a)
于室温，向5-氨基-1H-吡唑-3-羧酸乙酯(1.00g，6.45mmol，1.00equiv)的DMF(10.00mL)溶液中加入4,4-二甲氧基丁-2-酮(1.70g，13.0mmol，2.00equiv)和醋酸(0.370g，6.45mmol，1.00equiv)。氮气氛围下，于110℃搅拌过夜。加水淬灭，EA萃取。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物1.2g，收率90.8％。To a solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (1.00 g, 6.45 mmol, 1.00 equiv) in DMF (10.00 mL) at room temperature was added 4,4-dimethoxybut-2- Ketone (1.70g, 13.0mmol, 2.00equiv) and acetic acid (0.370g, 6.45mmol, 1.00equiv). Under nitrogen atmosphere, stir at 110°C overnight. Add water to quench and extract with EA. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 1.2 g of the title compound as a white solid, with a yield of 90.8%.
LC-MS:m/z 206.05[M+H]+。LC-MS: m/z 206.05[M+H] + .
其他步骤与实施例15的制备方法相同，除了用5-甲基吡唑并[1,5-a]嘧啶-2-羧酸乙酯(37b)代替步骤2中的6-甲基咪唑并[1,2-a]吡啶-2-羧酸乙酯(15a)，并用3-溴-4-碘-1-甲基-1H-吡唑代替步骤2中的4,5-二溴-2-甲基-2H-1,2,3-三唑，制得化合物37。Other steps are the same as the preparation method of Example 15, except that 5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester (37b) is used instead of 6-methylimidazo[ 1,2-a]pyridine-2-carboxylic acid ethyl ester (15a) and replacing 4,5-dibromo-2- in step 2 with 3-bromo-4-iodo-1-methyl-1H-pyrazole Methyl-2H-1,2,3-triazole, prepared compound 37.
LC-MS：m/z 536.05[M+H]+。LC-MS: m/z 536.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.70(d,J＝2.0Hz,1H),8.28(d,J＝2.0Hz,1H),7.69(s,1H),7.60(dd,J＝8.6,5.8Hz,1H),7.33(dd,J＝10.4,2.9Hz,1H),7.26(s,1H),7.05(td,J＝8.4,2.9Hz,1H),6.64(s,2H),6.34(s,1H),5.68-5.58(m,1H),4.27(d,J＝16.3Hz,1H),4.09(d,J＝16.4Hz,1H),3.32(s,3H),2.45(s,3H),1.89(d,J＝6.1Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.70 (d, J＝2.0Hz, 1H), 8.28 (d, J＝2.0Hz, 1H), 7.69 (s, 1H), 7.60 (dd, J＝ 8.6,5.8Hz,1H),7.33(dd,J＝10.4,2.9Hz,1H),7.26(s,1H),7.05(td,J＝8.4,2.9Hz,1H),6.64(s,2H), 6.34(s,1H),5.68-5.58(m,1H),4.27(d,J＝16.3Hz,1H),4.09(d,J＝16.4Hz,1H),3.32(s,3H),2.45(s ,3H),1.89(d,J=6.1Hz,3H).
实施例38：(R)-14-环丙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基苯并[1]哒嗪并[6',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(38)的制备

Example 38: (R)-14-cyclopropyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylenebenzo[1]pyridazine And[6',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclodeca Preparation of tetracarben-8-amine (38)

步骤1：6-环丙基咪唑并[1,2-b]哒嗪-2-羧酸甲酯(38a)的制备Step 1: Preparation of 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (38a)
将6-氯咪唑并[1,2-b]哒嗪-2-羧酸甲酯(2.00g，9.48mmol)、环丙基硼酸(978mg，11.4mmol)、四三苯基膦钯(109mg，0.0950mmol)、碳酸铯(6.18g，18.9mmol)溶于10ml二氧六环中，于95℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物1.71g，收率：82.5％。6-Chloroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (2.00g, 9.48mmol), cyclopropylboronic acid (978mg, 11.4mmol), tetrakistriphenylphosphine palladium (109mg, 0.0950mmol) and cesium carbonate (6.18g, 18.9mmol) were dissolved in 10ml dioxane, stirred at 95°C overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA =1:1-1:2), 1.71g of the title compound was obtained as a yellow solid, yield: 82.5%.
LC-MS：m/z＝218[M+H]+。LC-MS: m/z=218[M+H] + .
步骤2：(6-环丙基咪唑并[1,2-b]哒嗪-2-基)甲醇(38b)的制备Step 2 Preparation of: (6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanol (38b)
将6-环丙基咪唑并[1,2-b]哒嗪-2-羧酸甲酯(38a)(1.30g，5.96mmol)溶于甲醇(80mL)中。于0℃，分批加入硼氢化锂(262mg，11.9mmol)。将反应混合物于室温搅拌3小时，加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，过滤，滤液减压浓缩，得黄色油状标题化合物800mg，收率：70.7％。6-Cyclopropylimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (38a) (1.30 g, 5.96 mmol) was dissolved in methanol (80 mL). Lithium borohydride (262 mg, 11.9 mmol) was added in portions at 0°C. The reaction mixture was stirred at room temperature for 3 hours, quenched with water, extracted with EA (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 800 mg of the title compound as a yellow oil, yield: 70.7%.
LC-MS：m/z＝190[M+H]+。LC-MS: m/z=190[M+H] + .
步骤3：6-环丙基咪唑并[1,2-b]哒嗪-2-甲醛(38c)的制备Step 3: Preparation of 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxaldehyde (38c)
将(6-环丙基咪唑并[1,2-b]哒嗪-2-基)甲醇(38b)(350mg，5.96mmol)溶于二氧六环(80mL)中，加入二氧化锰(2.07g，23.8mmol)。将反应混合物于室温搅拌3小时，加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，减压浓缩，得黄色油状标题化合物280mg，收率：80.1％。Dissolve (6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanol (38b) (350 mg, 5.96 mmol) in dioxane (80 mL), and add manganese dioxide (2.07 g, 23.8mmol). The reaction mixture was stirred at room temperature for 3 hours, quenched with water, extracted with EA (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 280 mg of the title compound as a yellow oil, yield: 80.1%.
LC-MS：m/z＝188[M+H]+。LC-MS: m/z=188[M+H] + .
其他步骤与实施例12的制备方法相同，除了用6-环丙基咪唑并[1,2-b]哒嗪-2-甲醛(38c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物38。Other steps are the same as the preparation method of Example 12, except that 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxaldehyde (38c) is used instead of 6-(trifluoromethyl)imidazole in step 1 and [1,2-a]pyridine-2-carboxaldehyde to prepare compound 38.
LC-MS：m/z＝483[M+H]+。LC-MS: m/z=483[M+H] + .
实施例39：(R)-14-环丙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(39)的制备
Example 39: (R)-14-cyclopropyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyridine Azino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene-8- Preparation of amine (39)
步骤1：6-溴咪唑并[1,2-a]吡嗪-2-羧酸乙酯(39a)的制备Step 1: Preparation of 6-bromoimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (39a)
于室温，将2-氨基-5-溴吡嗪(10.0g，57.8mmol)、3-溴丙酮酸乙酯(16.8g，86.7mmol)溶于二氧六环(100ml)，加入碳酸氢钠(9.71g，115mmol)，于100℃搅拌过夜。加水淬灭，EA萃取，饱和氯化钠溶液洗涤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物6.00g，收率：38.7％。Dissolve 2-amino-5-bromopyrazine (10.0g, 57.8mmol) and ethyl 3-bromopyruvate (16.8g, 86.7mmol) in dioxane (100ml) at room temperature, and add sodium bicarbonate ( 9.71g, 115mmol), stirred at 100°C overnight. Add water to quench, extract with EA, wash with saturated sodium chloride solution, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain the yellow solid title Compound 6.00g, yield: 38.7%.
LC-MS：m/z＝270[M+H]+。LC-MS: m/z=270[M+H] + .
步骤2：6-环丙基咪唑并[1,2-a]吡嗪-2-羧酸乙酯(39b)的制备Step 2: Preparation of 6-cyclopropylimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (39b)
于室温，将6-溴咪唑并[1,2-a]吡嗪-2-羧酸乙酯(39a)(6.00g，22.3mmol)、磷酸钾(9.46g，44.6mmol)、Pd(dppf)Cl2.CH2Cl2(903mg，1.11mmol)、环丙硼酸(2.87g，33.4mmol)溶于100ml二氧六环中。于100℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物1.80g，收率：35.2％。At room temperature, 6-bromoimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (39a) (6.00g, 22.3mmol), potassium phosphate (9.46g, 44.6mmol), Pd (dppf) Cl2.CH2Cl2 (903mg, 1.11mmol) and cyclopropylboronic acid (2.87g, 33.4mmol) were dissolved in 100ml dioxane. Stir overnight at 100°C and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 1.80g of the title compound as a white solid. Yield: 35.2 %.
LC-MS：m/z＝232[M+H]+。LC-MS: m/z=232[M+H] + .
其他步骤与实施例15的制备方法相同，除了用6-环丙基咪唑并[1,2-a]吡嗪-2-羧酸乙酯(39b)代替步骤2中的6-甲基咪唑并[1,2-a]吡啶-2-羧酸乙酯，并用3-溴-4-碘-1-甲基-1H-吡唑代替步骤2中的4,5-二溴-2-甲基-2H-1,2,3-三唑，制得化合物39。Other steps are the same as the preparation method of Example 15, except that 6-cyclopropylimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester (39b) is used instead of 6-methylimidazo in step 2. [1,2-a]pyridine-2-carboxylic acid ethyl ester and replace 4,5-dibromo-2-methyl in step 2 with 3-bromo-4-iodo-1-methyl-1H-pyrazole -2H-1,2,3-triazole to prepare compound 39.
LC-MS：m/z＝482[M+H]+。LC-MS: m/z=482[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.90(d,J＝1.4Hz,1H),8.35-8.26(m,1H),7.79(d,J＝1.8Hz,1H),7.70(dd,J＝10.4,2.7Hz,1H),7.57(s,1H),7.29-7.14(m,2H),6.35(d,J＝1.9Hz,1H),6.19(s,2H),5.33(qd,J＝6.4,2.1Hz,1H),3.93(d,J＝15.1Hz,1H),3.82(s,3H),3.19(d,J＝15.0Hz,2H),2.21-2.10(m,1H),1.73(d,J＝6.2Hz,3H),0.86(dd,J＝10.3,6.3Hz,4H)。 1 H NMR (400MHz, DMSO-d6) δ8.90(d,J＝1.4Hz,1H),8.35-8.26(m,1H),7.79(d,J＝1.8Hz,1H),7.70(dd,J ＝10.4,2.7Hz,1H),7.57(s,1H),7.29-7.14(m,2H),6.35(d,J＝1.9Hz,1H),6.19(s,2H),5.33(qd,J＝ 6.4,2.1Hz,1H),3.93(d,J＝15.1Hz,1H),3.82(s,3H),3.19(d,J＝15.0Hz,2H),2.21-2.10(m,1H),1.73( d, J=6.2Hz, 3H), 0.86 (dd, J=10.3, 6.3Hz, 4H).
实施例40：(R)-3-氟-5,20-二甲基-14-(甲磺酰基)-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(40)的制备
Example 40: (R)-3-fluoro-5,20-dimethyl-14-(methanesulfonyl)-18,20-dihydro-5H-7,11-(methylene)benzo[1 ]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]aza Preparation of cyclotetradecen-8-amine (40)
与实施例12的制备方法相同，除了用6-(甲基磺酰基)咪唑并[1,2-a]吡啶-2-甲醛(30d)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物40。The preparation method is the same as in Example 12, except that 6-(methylsulfonyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (30d) is used instead of 6-(trifluoromethyl)imidazole in step 1 and [1,2-a]pyridine-2-carboxaldehyde to prepare compound 40.
LC-MS：m/z 520.10[M+H]+。LC-MS: m/z 520.10[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.70(dd,J＝1.9,0.9Hz,1H),7.84-7.75(m,3H),7.60(dd,J＝9.5,1.8Hz,1H),7.33(dd,J＝8.5,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.24(s,2H),6.12(d,J＝1.9Hz,1H),5.33-5.24(m,1H),4.18-4.09(m,4H),3.49(d,J＝15.2Hz,1H),3.28(s,2H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.70 (dd, J＝1.9, 0.9Hz, 1H), 7.84-7.75 (m, 3H), 7.60 (dd, J＝9.5, 1.8Hz, 1H), 7.33(dd,J＝8.5,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.24(s,2H),6.12(d,J＝1.9Hz,1H),5.33-5.24 (m,1H),4.18-4.09(m,4H),3.49(d,J＝15.2Hz,1H),3.28(s,2H),1.74(d,J＝6.2Hz,3H).
实施例41：(R)-14-(环丙基磺酰基)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(41)的制备

Example 41: (R)-14-(cyclopropylsulfonyl)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo [l]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene Preparation of -8-amine (41)

步骤1：6-(环丙基磺酰基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(41a)的制备Step 1: Preparation of 6-(cyclopropylsulfonyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (41a)
于室温，向6-溴咪唑并[1,2-a]吡啶-2-羧酸乙酯(1.00g，3.93mmol，1.00equiv)的DMSO(10.00mL)溶液中加入环丙基亚磺酸钠(2.03mg，15.7mmol，4.00equiv)和碘化亚铜(149mg，0.787mmol，0.200equiv)，氮气氛围下于140℃搅拌6h。加水淬灭，EA萃取。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物400mg，收率34.6％。To a solution of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (1.00g, 3.93mmol, 1.00equiv) in DMSO (10.00mL) at room temperature was added sodium cyclopropylsulfinate. (2.03mg, 15.7mmol, 4.00equiv) and copper iodide (149mg, 0.787mmol, 0.200equiv), stirred at 140°C for 6h under nitrogen atmosphere. Add water to quench and extract with EA. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 400 mg of the title compound as a white solid, with a yield of 34.6%.
LC-MS：m/z 295.05[M+H]+。LC-MS: m/z 295.05[M+H] + .
步骤2：6-(环丙基磺酰基)咪唑并[1,2-a]吡啶-2-甲醛(41b)的制备Step 2: Preparation of 6-(cyclopropylsulfonyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (41b)
氮气氛围下，于-78℃向6-(环丙基磺酰基)咪唑并[1,2-a]吡啶-2-羧酸乙酯(1.20g，4.08mmol，1.00equiv)的二氯甲烷(20.00mL)溶液中加入二异丁基氢化铝(8.16mL，8.16mmol，2.00equiv)，继续搅拌1.5小时。缓慢加入甲醇淬灭，加入1M盐酸调节PH～7，反应混合物用二氯甲烷萃取(3X50毫升)。合并有机相，硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物500mg。收率49.01％。Under nitrogen atmosphere, ethyl 6-(cyclopropylsulfonyl)imidazo[1,2-a]pyridine-2-carboxylate (1.20g, 4.08mmol, 1.00equiv) was added to dichloromethane ( Diisobutylaluminum hydride (8.16 mL, 8.16 mmol, 2.00 equiv) was added to the solution (20.00 mL), and stirring was continued for 1.5 hours. Methanol was slowly added to quench, 1M hydrochloric acid was added to adjust the pH to ~7, and the reaction mixture was extracted with dichloromethane (3X50 ml). The organic phases were combined and dried over sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 500 mg of the title compound as a white solid. The yield is 49.01%.
LC-MS：m/z 251.05[M+H]+。LC-MS: m/z 251.05[M+H] + .
其他步骤与实施例14的制备方法相同，除了用6-(环丙基磺酰基)咪唑并[1,2-a]吡啶-2-甲醛(41b)代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物41。Other steps are the same as the preparation method of Example 14, except that 6-(cyclopropylsulfonyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (41b) is used instead of 6-(trifluoromethyl) in step 2. base)imidazo[1,2-a]pyridine-2-carboxaldehyde to prepare compound 41.
LC-MS:m/z 545.05[M+H]+。LC-MS: m/z 545.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.72(d,J＝1.8Hz,1H),7.86-7.78(m,2H),7.71(dd,J＝10.3,2.7Hz,1H),7.61-7.53(m,2H),7.29-7.15(m,2H),6.35(d,J＝1.8Hz,1H),6.21(s,2H),5.40-5.30(m,1H),3.94(d,J＝15.0Hz,1H),3.83(s,3H),3.21(d,J＝14.9Hz,1H),3.01(td,J＝7.9,4.0Hz,1H),1.74(d,J＝6.2Hz,3H),1.15(dtd,J＝17.7,9.9,4.9Hz,2H),1.04(tdd,J＝8.4,5.4,2.6Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.72 (d, J＝1.8Hz, 1H), 7.86-7.78 (m, 2H), 7.71 (dd, J＝10.3, 2.7Hz, 1H), 7.61- 7.53(m,2H),7.29-7.15(m,2H),6.35(d,J＝1.8Hz,1H),6.21(s,2H),5.40-5.30(m,1H),3.94(d,J＝ 15.0Hz,1H),3.83(s,3H),3.21(d,J＝14.9Hz,1H),3.01(td,J＝7.9,4.0Hz,1H),1.74(d,J＝6.2Hz,3H) ,1.15(dtd,J＝17.7,9.9,4.9Hz,2H), 1.04(tdd,J＝8.4,5.4,2.6Hz,2H).
实施例42：(R)-14-(环丙基磺酰基)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四 碳烯-8-胺(42)的制备
Example 42: (R)-14-(cyclopropylsulfonyl)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo [1]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4] Nitrogen heterocycle fourteen Preparation of carbene-8-amine (42)
与实施例12的制备方法相同，除了用6-(环丙基磺酰基)咪唑并[1,2-a]吡啶-2-甲醛(41b)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物42。The preparation method is the same as in Example 12, except that 6-(cyclopropylsulfonyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (41b) is used instead of 6-(trifluoromethyl) in step 1 Imidazo[1,2-a]pyridine-2-carboxaldehyde gave compound 42.
LC-MS：m/z 546.05[M+H]+。LC-MS: m/z 546.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),7.84-7.76(m,3H),7.58(dd,J＝9.4,1.8Hz,1H),7.33(dd,J＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.24(s,2H),6.13(d,J＝1.8Hz,1H),5.28(dt,J＝6.9,3.5Hz,1H),4.13(d,J＝9.6Hz,4H),3.49(d,J＝15.2Hz,1H),3.00(td,J＝7.9,4.1Hz,1H),1.75(d,J＝6.2Hz,3H),1.26-0.96(m,5H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.68 (s, 1H), 7.84-7.76 (m, 3H), 7.58 (dd, J = 9.4, 1.8 Hz, 1H), 7.33 (dd, J = 8.6 ,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.24(s,2H),6.13(d,J＝1.8Hz,1H),5.28(dt,J＝6.9,3.5Hz ,1H),4.13(d,J＝9.6Hz,4H),3.49(d,J＝15.2Hz,1H),3.00(td,J＝7.9,4.1Hz,1H),1.75(d,J＝6.2Hz ,3H),1.26-0.96(m,5H).
实施例43：(R)-3-氟-5,20-二甲基-15-(2,2,2-三氟乙氧基)-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(43)的制备

Example 43: (R)-3-fluoro-5,20-dimethyl-15-(2,2,2-trifluoroethoxy)-18,20-dihydro-5H-7,11-( Methylene)benzo[1]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazole[4,5-j][1] Preparation of oxa[4]azacyclotetradecene-8-amine (43)

与实施例12的制备方法相同，除了用6-(2,2,2-三氟乙氧基)咪唑并[1,2-a]吡啶-2-甲醛(31c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物43。The preparation method is the same as in Example 12, except that 6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-2-carboxaldehyde (31c) is used instead of 6- in step 1 (Trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde gave compound 43.
LC-MS：m/z 540.05[M+H]+。LC-MS: m/z 540.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.00(d,J＝2.3Hz,1H),7.84-7.73(m,2H),7.55(d,J＝9.7Hz,1H),7.31(dd,J＝8.5,5.8Hz,1H),7.23(td,J＝8.4,2.7Hz,1H),7.11(dd,J＝9.7,2.4Hz,1H),6.11(d,J＝1.8Hz,2H),5.28(dd,J＝6.4,2.1Hz,1H),4.79(ddq,J＝35.8,11.9,8.9Hz,2H),4.04(d,J＝15.2Hz,1H),3.41(d,J＝15.2Hz,2H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.00 (d, J = 2.3Hz, 1H), 7.84-7.73 (m, 2H), 7.55 (d, J = 9.7Hz, 1H), 7.31 (dd, J＝8.5,5.8Hz,1H),7.23(td,J＝8.4,2.7Hz,1H),7.11(dd,J＝9.7,2.4Hz,1H),6.11(d,J＝1.8Hz,2H), 5.28(dd,J＝6.4,2.1Hz,1H),4.79(ddq,J＝35.8,11.9,8.9Hz,2H),4.04(d,J＝15.2Hz,1H),3.41(d,J＝15.2Hz ,2H),1.73(d,J=6.2Hz,3H).
实施例44：(R)-3-氟-5,13,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(44)的制备
Example 44: (R)-3-fluoro-5,13,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazino[2 ',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene Preparation of -8-amine (44)
步骤1：2-(二氯甲基)-5-甲基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(44a)的制备 Step 1: Preparation of 2-(dichloromethyl)-5-methyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (44a)
于室温，将6-甲基吡嗪-2-胺(4.00g，36.6mmol)、1,1,3-三氯丙酮(11.0g，55.0mmol)溶于THF(100ml)，于室温搅拌过夜，过滤，滤饼烘干，得淡黄色固体状标题化合2：2.6g，收率，30.3％。Dissolve 6-methylpyrazin-2-amine (4.00g, 36.6mmol) and 1,1,3-trichloroacetone (11.0g, 55.0mmol) in THF (100ml) at room temperature, and stir at room temperature overnight. Filter and dry the filter cake to obtain the title compound 2 as a light yellow solid: 2.6g, yield: 30.3%.
LC-MS：m/z＝234[M+H]+。LC-MS: m/z=234[M+H] + .
步骤2：2-(二氯甲基)-5-甲基咪唑并[1,2-a]吡嗪(44b)的制备Step 2: Preparation of 2-(dichloromethyl)-5-methylimidazo[1,2-a]pyrazine (44b)
于室温，将2-(二氯甲基)-5-甲基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(44a)(2.60g，11.1mmol)溶于乙醇(50ml)中，于75℃搅拌4h，将反应液减压浓缩得白色固体标题化合物2.20g，收率：91.6％。Dissolve 2-(dichloromethyl)-5-methyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (44a) (2.60g, 11.1mmol) at room temperature. in ethanol (50 ml), stirred at 75°C for 4 hours, and concentrated the reaction solution under reduced pressure to obtain 2.20 g of the title compound as a white solid, yield: 91.6%.
LC-MS：m/z＝216[M+H]+。LC-MS: m/z=216[M+H] + .
步骤3：5-甲基咪唑并[1,2-a]吡嗪-2-甲醛(44c)的制备Step 3: Preparation of 5-methylimidazo[1,2-a]pyrazine-2-carbaldehyde (44c)
于室温，将2-(二氯甲基)-5-甲基咪唑并[1,2-a]吡嗪(44b)(2.20g，10.1mmol)、碳酸钙(3.05g，30.5mmol)溶于THF/H2O(1:1)(100ml)中，于70℃搅拌4h，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物700mg，收率：85.1％。At room temperature, 2-(dichloromethyl)-5-methylimidazo[1,2-a]pyrazine (44b) (2.20g, 10.1mmol) and calcium carbonate (3.05g, 30.5mmol) were dissolved in THF/H 2 O (1:1) (100ml), stirred at 70°C for 4h, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1: 2), 700 mg of the title compound was obtained as a white solid, yield: 85.1%.
LC-MS：m/z＝162[M+H]+。LC-MS: m/z=162[M+H] + .
其他步骤与实施例12的制备方法相同，除了用5-甲基咪唑并[1,2-a]吡嗪-2-甲醛(44c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物44。Other steps are the same as the preparation method of Example 12, except that 5-methylimidazo[1,2-a]pyrazine-2-carboxaldehyde (44c) is used instead of 6-(trifluoromethyl)imidazo in step 1. [1,2-a]pyridine-2-carboxaldehyde to prepare compound 44.
LC-MS：m/z＝457[M+H]+。LC-MS: m/z=457[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝0.8Hz,1H),7.89(dd,J＝10.5,2.7Hz,1H),7.64(d,J＝1.1Hz,1H),7.50(d,J＝1.8Hz,1H),7.29-7.17(m,2H),6.30(d,J＝1.9Hz,1H),6.14(s,2H),5.40(dd,J＝6.4,2.2Hz,1H),4.11(s,3H),4.06(d,J＝15.0Hz,1H),3.35(s,1H),2.23–2.17(m,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.93 (d, J = 0.8Hz, 1H), 7.89 (dd, J = 10.5, 2.7Hz, 1H), 7.64 (d, J = 1.1Hz, 1H), 7.50(d,J＝1.8Hz,1H),7.29-7.17(m,2H),6.30(d,J＝1.9Hz,1H),6.14(s,2H),5.40(dd,J＝6.4,2.2Hz ,1H),4.11(s,3H),4.06(d,J＝15.0Hz,1H),3.35(s,1H),2.23–2.17(m,3H),1.73(d,J＝6.2Hz,3H) .
实施例45：(R)-14-环丙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(甲基)苯并[l]吡唑并[4,3-j]哒嗪并[6',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(45)的制备

Example 45: (R)-14-cyclopropyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methyl)benzo[l]pyrazole And[4,3-j]pyridazino[6',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine Preparation of (45)

步骤1：6-环丙基咪唑并[1,2-b]哒嗪-2-甲醛(45a)的制备Step 1: Preparation of 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxaldehyde (45a)
将6-环丙基咪唑并[1,2-b]哒嗪-2-羧酸乙酯(1.50g，6.49mmol)溶于二氯甲烷(15mL)中。于-78℃，缓慢滴加二异丁基氢化铝(DIBAL-H)(12.9ml，1M，12.9mmol)。继续搅拌3小时，加入50mL水淬灭，EA(50mL x 3)萃取，无水硫酸钠干燥，减压浓缩，得黄色油状标题化合物500mg，收率：41.0％。6-Cyclopropylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (1.50 g, 6.49 mmol) was dissolved in dichloromethane (15 mL). At -78°C, diisobutylaluminum hydride (DIBAL-H) (12.9 ml, 1 M, 12.9 mmol) was slowly added dropwise. Continue stirring for 3 hours, add 50 mL of water to quench, extract with EA (50 mL x 3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 500 mg of the title compound as a yellow oil, yield: 41.0%.
LC-MS：m/z＝188[M+H]+。LC-MS: m/z=188[M+H] + .
其他步骤与实施例14的制备方法相同，除了用6-环丙基咪唑并[1,2-b]哒嗪-2-甲醛(45a)代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物45。Other steps are the same as the preparation method of Example 14, except that 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxaldehyde (45a) is used instead of 6-(trifluoromethyl)imidazole in step 2. and [1,2-a]pyridine-2-carboxaldehyde to prepare compound 45.
LC-MS：m/z＝482.17[M+H]+。LC-MS: m/z=482.17[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.01(d,J＝1.7Hz,1H),7.96(d,J＝9.3Hz,1H),7.66(dd,J＝10.3,2.7Hz,1H),7.59(s,1H),7.24(dtt,J＝16.8,8.5,4.4Hz,2H),7.08(d,J＝9.3Hz,1H),6.45(d,J＝1.8Hz,1H),6.00(s,2H),5.22(dt,J＝6.6,3.8Hz,1H),3.92(d,J＝15.1Hz,1H),3.83(s,3H),3.22(d,J＝15.0Hz,1H),2.16(ddd,J＝12.8,8.3,5.0Hz,1H),1.72(d,J＝6.2Hz,3H),1.10-0.77(m,4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.01(d,J＝1.7Hz,1H),7.96(d,J＝9.3Hz,1H),7.66(dd,J＝10.3,2.7Hz,1H) ,7.59(s,1H),7.24(dtt,J＝16.8,8.5,4.4Hz,2H),7.08(d,J＝9.3Hz,1H),6.45(d,J＝1.8Hz,1H),6.00( s,2H),5.22(dt,J＝6.6,3.8Hz,1H),3.92(d,J＝15.1Hz,1H),3.83(s,3H),3.22(d,J＝15.0Hz,1H), 2.16(ddd,J＝12.8,8.3,5.0Hz,1H),1.72(d,J＝6.2Hz,3H),1.10-0.77(m,4H).
实施例46：(R)-3-氟-5,14,16,20-四甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(46)的制备

Example 46: (R)-3-fluoro-5,14,16,20-tetramethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazino [2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]aza Preparation of carbene-8-amine (46)

与实施例12的制备方法相同，除了用5-甲基咪唑并[1,2-a]吡嗪-2-甲醛(44c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物46。The preparation method is the same as in Example 12, except that 5-methylimidazo[1,2-a]pyrazine-2-carbaldehyde (44c) is used instead of 6-(trifluoromethyl)imidazo[1 ,2-a]pyridine-2-carboxaldehyde to prepare compound 46.
LC-MS：m/z＝457[M+H]+。LC-MS: m/z=457[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝0.8Hz,1H),7.89(dd,J＝10.5,2.7Hz,1H),7.64(d,J＝1.1Hz,1H),7.50(d,J＝1.8Hz,1H),7.29-7.17(m,2H),6.30(d,J＝1.9Hz,1H),6.14(s,2H),5.40(dd,J＝6.4,2.2Hz,1H),4.11(s,3H),4.06(d,J＝15.0Hz,1H),3.35(s,1H),2.23-2.17(m,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.93 (d, J = 0.8Hz, 1H), 7.89 (dd, J = 10.5, 2.7Hz, 1H), 7.64 (d, J = 1.1Hz, 1H), 7.50(d,J＝1.8Hz,1H),7.29-7.17(m,2H),6.30(d,J＝1.9Hz,1H),6.14(s,2H),5.40(dd,J＝6.4,2.2Hz ,1H),4.11(s,3H),4.06(d,J＝15.0Hz,1H),3.35(s,1H),2.23-2.17(m,3H),1.73(d,J＝6.2Hz,3H) .
实施例47：(R)-14-乙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3j]哒嗪并[6',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(47)的制备
Example 47: (R)-14-ethyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazole And[4,3j]pyridazino[6',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (47 ) preparation
步骤1：6-乙烯基咪唑并[1,2-b]哒嗪-2-羧酸乙酯(47a)的制备Step 1: Preparation of ethyl 6-vinylimidazo[1,2-b]pyridazine-2-carboxylate (47a)
将6-氯咪唑并[1,2-b]哒嗪-2-羧酸甲酯(2.00g，9.48mmol)、乙烯基硼酸(887mg，12.3mmol)、四三苯基膦钯(109mg，0.0950mmol)、碳酸铯(6.18g，18.9mmol)溶于10ml二氧六环中，于95℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得黄色固体标题化合物1.80g，收率：82.5％。6-Chloroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (2.00g, 9.48mmol), vinylboronic acid (887mg, 12.3mmol), tetrakistriphenylphosphine palladium (109mg, 0.0950 mmol), cesium carbonate (6.18g, 18.9mmol) were dissolved in 10ml of dioxane, stirred at 95°C overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA= 1:1-1:2), 1.80g of the title compound was obtained as a yellow solid, yield: 82.5%.
LC-MS：m/z＝218[M+H]+。 LC-MS: m/z=218[M+H] + .
步骤2：6-乙基咪唑并[1,2-b]哒嗪-2-羧酸乙酯(47b)的制备Step 2: Preparation of ethyl 6-ethylimidazo[1,2-b]pyridazine-2-carboxylate (47b)
将6-乙烯基咪唑并[1,2-b]哒嗪-2-羧酸乙酯(47a)(1.80g，8.26mmol)溶于甲醇(80mL)中。加入钯碳(180mg，10％wt)。将反应混合物在氢气氛围下，于室温搅拌过夜，抽滤，减压浓缩，得黄色油状标题化合物1.50g，收率：82.8％。6-Vinylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (47a) (1.80 g, 8.26 mmol) was dissolved in methanol (80 mL). Palladium on carbon (180 mg, 10% wt) was added. The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere, filtered with suction, and concentrated under reduced pressure to obtain 1.50 g of the title compound as a yellow oil, yield: 82.8%.
LC-MS：m/z＝220[M+H]+。LC-MS: m/z=220[M+H] + .
步骤3：6-乙基咪唑并[1,2-b]哒嗪-2-甲醛(47c)的制备Step 3: Preparation of 6-ethylimidazo[1,2-b]pyridazine-2-carboxaldehyde (47c)
将6-乙基咪唑并[1,2-b]哒嗪-2-羧酸乙酯(47b)(1.80g，5.96mmol)溶于二氯甲烷(20mL)中，于-78℃缓慢滴加二异丁基氢化铝(11.9ml，1M，11.9mmol)，将反应混合物于-78℃搅拌3小时，加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，减压浓缩，得黄色油状标题化合物820mg，收率：78.2％。Dissolve 6-ethylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (47b) (1.80g, 5.96mmol) in dichloromethane (20mL), and slowly add it dropwise at -78°C Diisobutylaluminum hydride (11.9ml, 1M, 11.9mmol), stir the reaction mixture at -78°C for 3 hours, add water to quench, extract with EA (50mL x 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 820 mg of the title compound was obtained as yellow oil, yield: 78.2%.
LC-MS：m/z＝176[M+H]+。LC-MS: m/z=176[M+H] + .
其他步骤与实施例14的制备方法相同，除了用6-乙基咪唑并[1,2-b]哒嗪-2-甲醛(47c)代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物47。Other steps are the same as the preparation method of Example 14, except that 6-ethylimidazo[1,2-b]pyridazine-2-carboxaldehyde (47c) is used instead of 6-(trifluoromethyl)imidazo in step 2. [1,2-a]pyridine-2-carboxaldehyde to prepare compound 47.
LC-MS：m/z＝470[M+H]+。LC-MS: m/z=470[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.07-7.92(m,2H),7.74(dd,J＝10.3,2.8Hz,1H),7.36(dd,J＝8.5,5.8Hz,1H),7.26(td,J＝8.4,2.7Hz,1H),7.14(d,J＝9.3Hz,1H),6.18(d,J＝1.9Hz,1H),6.04(s,2H),5.17(dt,J＝6.5,3.7Hz,1H),4.13(d,J＝17.1Hz,4H),3.52(d,J＝15.2Hz,1H),2.79(q,J＝7.5Hz,2H),1.73(d,J＝6.2Hz,3H),1.22(t,J＝7.5Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.07-7.92(m,2H),7.74(dd,J＝10.3,2.8Hz,1H),7.36(dd,J＝8.5,5.8Hz,1H),7.26 (td,J＝8.4,2.7Hz,1H),7.14(d,J＝9.3Hz,1H),6.18(d,J＝1.9Hz,1H),6.04(s,2H),5.17(dt,J＝ 6.5,3.7Hz,1H),4.13(d,J＝17.1Hz,4H),3.52(d,J＝15.2Hz,1H),2.79(q,J＝7.5Hz,2H),1.73(d,J＝ 6.2Hz, 3H), 1.22 (t, J = 7.5Hz, 3H).
实施例48：(R)-14-乙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]哒嗪并[6',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(48)的制备
Example 48: (R)-14-ethyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyridazine And[6',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclodeca Preparation of tetracarben-8-amine (48)
与实施例12的制备方法相同，除了用6-乙基咪唑并[1,2-b]哒嗪-2-甲醛(47c) 代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物48。The preparation method is the same as Example 12, except that 6-ethylimidazo[1,2-b]pyridazine-2-carbaldehyde (47c) is used Substituting 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde in step 1, compound 48 was obtained.
LC-MS：m/z＝471[M+H]+。LC-MS: m/z=471[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.09–8.03(m,1H),8.00(d,J＝9.2Hz,1H),7.66(dd,J＝10.3,2.7Hz,1H),7.60(s,1H),7.33-7.15(m,2H),7.13(d,J＝9.3Hz,1H),6.46(d,J＝1.7Hz,1H),6.01(s,2H),5.26-5.17(m,1H),3.94(d,J＝15.1Hz,1H),3.84(s,3H),3.22(s,1H),2.80(q,J＝7.5Hz,2H),1.73(d,J＝6.2Hz,3H),1.23(t,J＝7.5Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.09–8.03(m,1H),8.00(d,J＝9.2Hz,1H),7.66(dd,J＝10.3,2.7Hz,1H),7.60(s ,1H),7.33-7.15(m,2H),7.13(d,J＝9.3Hz,1H),6.46(d,J＝1.7Hz,1H),6.01(s,2H),5.26-5.17(m, 1H),3.94(d,J＝15.1Hz,1H),3.84(s,3H),3.22(s,1H),2.80(q,J＝7.5Hz,2H),1.73(d,J＝6.2Hz, 3H), 1.23 (t, J = 7.5Hz, 3H).
实施例49：(R)-3-氟-5,14,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]嘧啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(49)的制备
Example 49: (R)-3-fluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrimido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (49)
与实施例12的制备方法相同，除了用6-甲基咪唑并[1,2-a]嘧啶-2-甲醛代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物49。The preparation method is the same as in Example 12, except that 6-(trifluoromethyl)imidazo[1,2-a] in step 1 is replaced with 6-methylimidazo[1,2-a]pyrimidine-2-carbaldehyde. ]pyridine-2-carboxaldehyde to prepare compound 49.
LC-MS：m/z＝457[M+H]+。LC-MS: m/z=457[M+H] + .
实施例50：7-(R)-3-氟-5,14,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(50)的制备

Example 50: 7-(R)-3-fluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazino [2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecen-8-amine ( 50) Preparation

步骤1：6-甲基咪唑并[1,2-a]吡嗪-2-甲醛(50a)的制备Step 1: Preparation of 6-methylimidazo[1,2-a]pyrazine-2-carbaldehyde (50a)
于室温，将5-甲基吡嗪-2-胺(25.0g，0.229mol)、1,1,3-三氯丙酮(91.7g，0.344mmol)溶于THF(500ml)中。于室温搅拌48h，过滤，滤饼干燥，得白色固体，将白色固体加入乙醇(500ml)中，于75℃搅拌6h，减压浓缩，将残余物溶于THF/H2O(1:1)(500ml)中，加入CaCO3(45.8g，0.458mmol)，于75℃搅拌4h，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物14g，收率：37.8％。5-methylpyrazin-2-amine (25.0g, 0.229mol) and 1,1,3-trichloroacetone (91.7g, 0.344mmol) were dissolved in THF (500ml) at room temperature. Stir at room temperature for 48 hours, filter, and dry the filter cake to obtain a white solid. Add the white solid to ethanol (500 ml), stir at 75°C for 6 hours, concentrate under reduced pressure, and dissolve the residue in THF/H2O (1:1) (500 ml). ), add CaCO3 (45.8g, 0.458mmol), stir at 75°C for 4h, concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) , 14g of the title compound was obtained as a white solid, yield: 37.8%.
LC-MS：m/z＝162[M+H]+。LC-MS: m/z=162[M+H] + .
其余步骤与实施例14相同，除了用6-甲基咪唑并[1,2-a]吡嗪-2-甲醛(50a)代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物50。The remaining steps are the same as in Example 14, except that 6-methylimidazo[1,2-a]pyrazine-2-carbaldehyde (50a) is used instead of 6-(trifluoromethyl)imidazo[1, 2-a]pyridine-2-carboxaldehyde gave compound 50.
LC-MS：m/z＝456[M+H]+。LC-MS: m/z=456[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.93(d,J＝1.4Hz,1H),8.25(t,J＝1.3Hz,1H),7.76(d,J＝1.8Hz,1H),7.70(dd,J＝10.4,2.7Hz,1H),7.58(s,1H),7.30-7.11(m,2H),6.35(d,J＝1.8Hz,1H),6.18(s,2H),5.33(tt,J＝6.7,3.3Hz,1H),3.94(d,J＝15.1Hz,1H),3.82(s,3H),3.29(s,6H),3.20(d,J＝15.0Hz,1H),2.45-2.31(m,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.93 (d, J = 1.4Hz, 1H), 8.25 (t, J = 1.3Hz, 1H), 7.76 (d, J = 1.8Hz, 1H), 7.70 (dd,J＝10.4,2.7Hz,1H),7.58(s,1H),7.30-7.11(m,2H),6.35(d,J＝1.8Hz,1H),6.18(s,2H),5.33( tt,J＝6.7,3.3Hz,1H),3.94(d,J＝15.1Hz,1H),3.82(s,3H),3.29(s,6H),3.20(d,J＝15.0Hz,1H), 2.45-2.31(m,3H),1.73(d,J=6.2Hz,3H).
实施例51：(R)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]嘧啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(51)的制备

Example 51: (R)-3-Fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrimido[2',1 ':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene-8- Preparation of amine (51)

与实施例12相同，除了用咪唑并[1,2-a]嘧啶-2-甲醛代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物51。The same as Example 12, except that imidazo[1,2-a]pyrimidine-2-carboxaldehyde is used instead of 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde in step 1, Compound 51 was obtained.
LC-MS：m/z＝443[M+H]+。LC-MS: m/z=443[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.76(dd,J＝6.8,2.0Hz,1H),8.50(dd,J＝4.1,1.9Hz,1H),7.82-7.68(m,2H),7.33(dd,J＝8.5,5.8Hz,1H),7.23(dd,J＝8.4,2.7Hz,1H),7.00(dd,J＝6.9,4.1Hz,1H),6.72-6.59(m,1H),6.18-6.11(m,2H),5.27(dd,J＝6.3,2.1Hz,1H),4.14(s,3H),4.01(s,1H),3.47(d,J＝15.1Hz,1H),1.72(dd,J＝13.2,6.3Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.76 (dd, J＝6.8, 2.0Hz, 1H), 8.50 (dd, J＝4.1, 1.9Hz, 1H), 7.82-7.68 (m, 2H), 7.33 (dd,J＝8.5,5.8Hz,1H),7.23(dd,J＝8.4,2.7Hz,1H),7.00(dd,J＝6.9,4.1Hz,1H),6.72-6.59(m,1H), 6.18-6.11(m,2H),5.27(dd,J＝6.3,2.1Hz,1H),4.14(s,3H),4.01(s,1H),3.47(d,J＝15.1Hz,1H),1.72 (dd,J=13.2,6.3Hz,3H).
实施例52：(R)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(52)的制备
Example 52: (R)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazino[2', Preparation of 1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecen-8-amine (52)
与实施例14相同，除了用咪唑并[1,2-a]吡嗪-2-甲醛代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物52。Same as Example 14, except imidazo[1,2-a]pyrazine-2-carboxaldehyde is used instead of 6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde in step 2 , compound 52 was obtained.
LC-MS：m/z＝442[M+H]+。LC-MS: m/z=442[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.04(d,J＝1.4Hz,1H),8.40(dd,J＝4.7,1.5Hz,1H),7.84(d,J＝4.6Hz,1H),7.77(d,J＝1.8Hz,1H),7.70(dd,J＝10.4,2.7Hz, 1H),7.59(s,1H),7.30-7.10(m,2H),6.37(d,J＝1.9Hz,1H),6.20(s,2H),5.33(qd,J＝6.1,2.1Hz,1H),3.97(dd,J＝15.0,1.0Hz,1H),3.82(s,3H),3.23(d,J＝14.9Hz,1H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.04 (d, J = 1.4Hz, 1H), 8.40 (dd, J = 4.7, 1.5Hz, 1H), 7.84 (d, J = 4.6Hz, 1H) ,7.77(d,J＝1.8Hz,1H),7.70(dd,J＝10.4,2.7Hz, 1H),7.59(s,1H),7.30-7.10(m,2H),6.37(d,J＝1.9Hz,1H),6.20(s,2H),5.33(qd,J＝6.1,2.1Hz,1H ), 3.97 (dd, J = 15.0, 1.0 Hz, 1H), 3.82 ( s, 3H), 3.23 ( d, J = 14.9 Hz, 1H), 1.73 ( d, J = 6.2 Hz, 3H).
实施例53：(R)-3-氟-5,14,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(53)的制备
Example 53: (R)-3-fluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazino[2 ',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene Preparation of -8-amine (53)
步骤1：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-甲基咪唑并[1,2-a]吡嗪-2-基)甲醇(53a)的制备Step 1: (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-methylimidazo[1,2-a]pyrazin-2-yl)methanol Preparation of (53a)
于室温，将4,5-二溴-2-甲基-2H-1,2,3-三唑(1.83g，6.46mmol)溶于250ml THF中。于0℃，滴加异丙基溴化镁溶液(2.98ml,2M，5.96mmol)，于0℃搅拌0.5h。于0℃加入6-甲基咪唑并[1,2-a]吡嗪-2-甲醛(800mg，4.97mmol)，升至室温搅拌4h。加水淬灭，EA萃取(10mL x 3)，无水硫酸钠干燥，过滤，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄棕色固体标题化合物1.20g，收率：75％。Dissolve 4,5-dibromo-2-methyl-2H-1,2,3-triazole (1.83g, 6.46mmol) in 250ml THF at room temperature. At 0°C, add isopropylmagnesium bromide solution (2.98ml, 2M, 5.96mmol) dropwise, and stir at 0°C for 0.5h. Add 6-methylimidazo[1,2-a]pyrazine-2-carbaldehyde (800 mg, 4.97 mmol) at 0°C, raise to room temperature and stir for 4 hours. Add water to quench, extract with EA (10mL 1.20 g of the title compound as a brown solid, yield: 75%.
LC-MS：m/z＝323[M+H]+。LC-MS: m/z=323[M+H] + .
步骤2：(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-甲基咪唑并[1,2-a]吡嗪-2-基)甲酮(53b)的制备Step 2: (5-Bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-methylimidazo[1,2-a]pyrazin-2-yl)methyl Preparation of ketone (53b)
于室温，将(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-甲基咪唑并[1,2-a]吡嗪-2-基)甲醇(53a)(600mg，1.86mmol)溶于250ml二氯甲烷中。于0℃，分批加入戴斯-马丁氧化剂(945mg，2.23mmol)，于0℃搅拌16h。加水淬灭，EA萃取(10mL x 3)，无水硫酸钠干燥，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄棕色固体标题化合物500mg，收率：83.7％。At room temperature, (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-methylimidazo[1,2-a]pyrazin-2-yl) Methanol (53a) (600 mg, 1.86 mmol) was dissolved in 250 ml dichloromethane. At 0°C, Dess-Martin oxidant (945 mg, 2.23 mmol) was added in batches, and stirred at 0°C for 16 h. Add water to quench, extract with EA (10mL Title compound 500 mg, yield: 83.7%.
LC-MS：m/z＝321[M+H]+。 LC-MS: m/z=321[M+H] + .
步骤3：2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-甲基咪唑并[1,2-a]吡嗪(53c)的制备Step 3: 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-methylimidazo[1,2-a]pyrazine Preparation of (53c)
于室温，将(5-溴-2-甲基-2H-1,2,3-三唑-4-基)(6-甲基咪唑并[1,2-a]吡嗪-2-基)甲酮(53b)(500mg，1.56mmol)溶于乙醇(5ml)和水合肼(1.00ml，80％in H2O)中，于78℃搅拌15小时。减压浓缩，饱和碳酸钠溶液中和，EA萃取，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色油状标题化合物400mg，收率：83.5％。At room temperature, (5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)(6-methylimidazo[1,2-a]pyrazin-2-yl) Methyl ketone (53b) (500 mg, 1.56 mmol) was dissolved in ethanol (5 ml) and hydrazine hydrate (1.00 ml, 80% in H2O), and stirred at 78°C for 15 hours. Concentrate under reduced pressure, neutralize with saturated sodium carbonate solution, and extract with EA. The residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 400 mg of the title compound as a yellow oil, yield: 83.5% .
LC-MS：m/z＝307[M+H]+。LC-MS: m/z=307[M+H] + .
其他步骤与实施例12相同，除了用2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-甲基咪唑并[1,2-a]吡嗪(53c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物53。Other steps are the same as in Example 12, except that 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-methylimidazo[1 ,2-a]pyrazine (53c) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-( Trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 53.
LC-MS：m/z＝457[M+H]+。LC-MS: m/z=457[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.94(d,J＝1.4Hz,1H),8.22(t,J＝1.3Hz,1H),7.85-7.64(m,2H),7.33(dd,J＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.8Hz,1H),6.21(s,2H),6.13(d,J＝1.9Hz,1H),5.27(tt,J＝6.5,3.4Hz,1H),4.25–4.03(m,4H),3.48(d,J＝15.2Hz,2H),2.39(d,J＝0.9Hz,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.94 (d, J = 1.4Hz, 1H), 8.22 (t, J = 1.3Hz, 1H), 7.85-7.64 (m, 2H), 7.33 (dd, J＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.8Hz,1H),6.21(s,2H),6.13(d,J＝1.9Hz,1H),5.27(tt,J＝6.5 ,3.4Hz,1H),4.25–4.03(m,4H),3.48(d,J＝15.2Hz,2H),2.39(d,J＝0.9Hz,3H),1.73(d,J＝6.2Hz,3H ).
实施例54：(R)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(54)的制备
Example 54: (R)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazino[2', 1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene-8 - Preparation of amine (54)
步骤1：咪唑并[1,2-a]吡嗪-2-甲醛(54a)的制备Step 1: Preparation of imidazo[1,2-a]pyrazine-2-carboxaldehyde (54a)
于室温，将吡嗪-2-胺(10.0g，0.105mol)、1,1,3-三氯丙酮(44.9g，0.168mmol)溶于THF(100ml)中，于室温搅拌48h，过滤，滤饼干燥，得白色固体。将白色固体加入乙醇(500ml)中，于75℃搅拌6h。减压浓缩，将残余物溶于THF/H2O(1:1)(500ml)中，加入CaCO3(31.5g，0.315mol),于75℃搅拌4h，减压 浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物3.00g，收率：19.4％。Dissolve pyrazin-2-amine (10.0g, 0.105mol) and 1,1,3-trichloroacetone (44.9g, 0.168mmol) in THF (100ml) at room temperature, stir at room temperature for 48h, filter, and The cake is dried to obtain a white solid. The white solid was added to ethanol (500 ml) and stirred at 75°C for 6 h. Concentrate under reduced pressure, dissolve the residue in THF/H2O (1:1) (500ml), add CaCO3 (31.5g, 0.315mol), stir at 75°C for 4h, and reduce the pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 3.00g of the title compound as a white solid, yield: 19.4%.
LC-MS：m/z＝148[M+H]+。LC-MS: m/z=148[M+H] + .
其他步骤与实施例12相同，除了用咪唑并[1,2-a]吡嗪-2-甲醛(54a)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物54。Other steps are the same as Example 12, except that imidazo[1,2-a]pyrazine-2-carboxaldehyde (54a) is used instead of 6-(trifluoromethyl)imidazo[1,2-a] in step 1. Pyridine-2-carboxaldehyde gave compound 54.
LC-MS：m/z＝443[M+H]+。LC-MS: m/z=443[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.04(d,J＝1.4Hz,1H),8.37(dd,J＝4.7,1.5Hz,1H),7.83(d,J＝4.7Hz,1H),7.79(dd,J＝10.3,2.8Hz,1H),7.74(d,J＝1.8Hz,1H),7.34(dd,J＝8.6,5.9Hz,1H),7.24(td,J＝8.4,2.8Hz,1H),6.24(s,2H),6.15(d,J＝1.9Hz,1H),5.27(dt,J＝6.9,3.5Hz,1H),4.17(d,J＝15.3Hz,1H),4.14(s,3H),3.51(d,J＝15.2Hz,1H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.04 (d, J = 1.4Hz, 1H), 8.37 (dd, J = 4.7, 1.5Hz, 1H), 7.83 (d, J = 4.7Hz, 1H) ,7.79(dd,J＝10.3,2.8Hz,1H),7.74(d,J＝1.8Hz,1H),7.34(dd,J＝8.6,5.9Hz,1H),7.24(td,J＝8.4,2.8 Hz,1H),6.24(s,2H),6.15(d,J＝1.9Hz,1H),5.27(dt,J＝6.9,3.5Hz,1H),4.17(d,J＝15.3Hz,1H), 4.14(s,3H),3.51(d,J=15.2Hz,1H),1.73(d,J=6.2Hz,3H).
实施例55：(R)-3-氟-5,20-二甲基-14-(甲磺酰基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(55)的制备
Example 55: (R)-3-fluoro-5,20-dimethyl-14-(methanesulfonyl)-18,20-dihydro-5H-7,11-(methylene)benzo[l ]pyrazino[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]nitrogen Preparation of heterocyclic tetradecene-8-amine (55)
步骤1：5-(甲硫基)吡嗪-2-胺(55a)的制备Step 1: Preparation of 5-(methylthio)pyrazin-2-amine (55a)
于室温，向5-碘吡嗪-2-胺(2.40g，10.8mmol，1.00equiv)的DMF(20.0mL)溶液中，加入甲硫醇钠(912mg，13.0mmol，1.20equiv)，于100℃微波搅拌4h。将反应液倒入水中，NaOH调至碱性，反应混合物用乙酸乙酯萃取(3X50毫升)。合并有机相，硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物2.3g。收率75.5％。To a solution of 5-iodopyrazin-2-amine (2.40g, 10.8mmol, 1.00equiv) in DMF (20.0mL) at room temperature, add sodium methylmercaptide (912mg, 13.0mmol, 1.20equiv) and incubate at 100°C. Microwave and stir for 4 hours. The reaction solution was poured into water, NaOH was made alkaline, and the reaction mixture was extracted with ethyl acetate (3X50 ml). The organic phases were combined and dried over sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 2.3 g of the title compound as a white solid. The yield is 75.5%.
LC-MS：m/z 142.05[M+H]+。 LC-MS: m/z 142.05[M+H] + .
步骤2：5-(甲磺酰基)吡嗪-2-胺(55b)的制备Step 2: Preparation of 5-(methanesulfonyl)pyrazin-2-amine (55b)
于0℃，向5-(甲硫基)吡嗪-2-胺(2.50g，17.7mmol，1.00equiv)的DCM(60.0mL)溶液中加入间氯过氧苯甲酸(7.60g，44.3mmol，2.50equiv)，于室温搅拌30min。加入水淬灭，NaOH调至碱性，反应混合物用DCM萃取(3X100毫升)。合并有机相，硫酸钠干燥。所得混合物过滤后，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物2.1g。收率68.6％。To a solution of 5-(methylthio)pyrazin-2-amine (2.50g, 17.7mmol, 1.00equiv) in DCM (60.0mL) at 0°C was added m-chloroperoxybenzoic acid (7.60g, 44.3mmol, 2.50 equiv), stir at room temperature for 30 min. Water was added to quench, NaOH was made basic, and the reaction mixture was extracted with DCM (3X100 ml). The organic phases were combined and dried over sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 2.1 g of the title compound as a white solid. The yield is 68.6%.
LC-MS：m/z 174.05[M+H]+。LC-MS: m/z 174.05[M+H] + .
步骤3：2-(二氯甲基)-6-(甲基磺酰基)咪唑并[1,2-a]吡嗪(55c)的制备Step 3: Preparation of 2-(dichloromethyl)-6-(methylsulfonyl)imidazo[1,2-a]pyrazine (55c)
于室温，向5-(甲磺酰基)吡嗪-2-胺(2.10g，12.1mmol，1.00equiv)的DME(40.0mL)溶液中加入1,1,3-三氯丙-2-酮(6.40g，24.3mmol，2.00equiv)。于80℃搅拌72h。过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝10:1)，得到灰白色固体状的标题化合物1.0g。收率29.6％。To a solution of 5-(methanesulfonyl)pyrazin-2-amine (2.10 g, 12.1 mmol, 1.00 equiv) in DME (40.0 mL) at room temperature was added 1,1,3-trichloropropan-2-one ( 6.40g, 24.3mmol, 2.00equiv). Stir at 80°C for 72h. Filter, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=10:1) to obtain 1.0 g of the title compound as an off-white solid. Yield 29.6%.
LC-MS：m/z 279.05[M+H]+。LC-MS: m/z 279.05[M+H] + .
步骤4：6-(甲基磺酰基)咪唑并[1,2-a]吡嗪-2-甲醛(55d)的制备Step 4: Preparation of 6-(methylsulfonyl)imidazo[1,2-a]pyrazine-2-carbaldehyde (55d)
于室温，向2-(二氯甲基)-6-(甲基磺酰基)咪唑并[1,2-a]吡嗪(1.00g，3.58mmol，1.00equiv)的水(10.0mL)溶液中加入碳酸钙(1.43g，14.3mmol，4.00equiv)，升至80℃搅拌36h。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:3)，得到白色固体状的标题化合物700mg，收率86.9％。To a solution of 2-(dichloromethyl)-6-(methylsulfonyl)imidazo[1,2-a]pyrazine (1.00g, 3.58mmol, 1.00equiv) in water (10.0mL) at room temperature Add calcium carbonate (1.43g, 14.3mmol, 4.00equiv), raise to 80°C and stir for 36h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:3) to obtain 700 mg of the title compound as a white solid, with a yield of 86.9%.
LC-MS：m/z 226.05[M+H]+。LC-MS: m/z 226.05[M+H] + .
其他步骤与实施例12相同，除了用6-(甲基磺酰基)咪唑并[1,2-a]吡嗪-2-甲醛(55d)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物55。Other steps were the same as Example 12, except that 6-(methylsulfonyl)imidazo[1,2-a]pyrazine-2-carboxaldehyde (55d) was used instead of 6-(trifluoromethyl)imidazole in step 1. and [1,2-a]pyridine-2-carboxaldehyde to obtain compound 55.
LC-MS：m/z 521.05[M+H]+。LC-MS: m/z 521.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.21(d,J＝1.3Hz,1H),8.71(d,J＝1.3Hz,1H),7.88-7.75(m,2H),7.36(dd,J＝8.6,5.8Hz,1H),7.26(td,J＝8.4,2.7Hz,1H),6.37(s,2H),6.12(d,J＝1.9Hz,1H),5.28(dd,J＝6.7,1.9Hz,1H),4.25(d,J＝15.2Hz,1H),4.14(s,3H),3.57(d,J＝15.3Hz,1H),3.24(s,3H),1.75(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.21 (d, J = 1.3 Hz, 1H), 8.71 (d, J = 1.3 Hz, 1H), 7.88-7.75 (m, 2H), 7.36 (dd, J＝8.6,5.8Hz,1H),7.26(td,J＝8.4,2.7Hz,1H),6.37(s,2H),6.12(d,J＝1.9Hz,1H),5.28(dd,J＝6.7 ,1.9Hz,1H),4.25(d,J＝15.2Hz,1H),4.14(s,3H),3.57(d,J＝15.3Hz,1H),3.24(s,3H),1.75(d,J =6.2Hz,3H).
实施例56：(R)-3-氟-5,20-二甲基-14-(甲磺酰基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(56)的制备

Example 56: (R)-3-fluoro-5,20-dimethyl-14-(methanesulfonyl)-18,20-dihydro-5H-7,11-(methylene)benzo[l ]Pyrazino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (56)

制备方法与实施例14相同，除了用6-(甲基磺酰基)咪唑并[1,2-a]吡嗪-2-甲醛代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物56。The preparation method is the same as Example 14, except that 6-(methylsulfonyl)imidazo[1,2-a]pyrazine-2-carbaldehyde is used instead of 6-(trifluoromethyl)imidazo[1 ,2-a]pyridine-2-carboxaldehyde to obtain compound 56.
LC-MS：m/z 520.05[M+H]+。LC-MS: m/z 520.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.20(d,J＝1.2Hz,1H),8.75(d,J＝1.3Hz,1H),7.87(d,J＝1.8Hz,1H),7.71(dd,J＝10.4,2.7Hz,1H),7.59(s,1H),7.31-7.16(m,2H),6.38-6.30(m,3H),5.38-5.31(m,1H),4.04(d,J＝15.0Hz,1H),3.83(s,3H),3.27(s,1H),3.24(s,3H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.20 (d, J = 1.2 Hz, 1H), 8.75 (d, J = 1.3 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.71 (dd,J＝10.4,2.7Hz,1H),7.59(s,1H),7.31-7.16(m,2H),6.38-6.30(m,3H),5.38-5.31(m,1H),4.04(d ,J＝15.0Hz,1H),3.83(s,3H),3.27(s,1H),3.24(s,3H),1.74(d,J＝6.2Hz,3H).
实施例57：(R)-3-氟-5,14,16,20-四甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(57)的制备
Example 57: (R)-3-fluoro-5,14,16,20-tetramethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazino [2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]aza Preparation of carbene-8-amine (57)
步骤1：2-(二氯甲基)-6,8-二甲基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(57a)的制备 Step 1: Preparation of 2-(dichloromethyl)-6,8-dimethyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (57a)
于室温，将3,5-二甲基吡嗪-2-胺(3.40g，27.6mmol)、1,1,3-三氯丙酮(11.0g，41.0mmol)溶于THF(100ml)，于室温搅拌过夜，过滤，滤饼烘干，得淡黄色固体状标题化合4g，收率：58.8％。Dissolve 3,5-dimethylpyrazin-2-amine (3.40g, 27.6mmol) and 1,1,3-trichloroacetone (11.0g, 41.0mmol) in THF (100ml) at room temperature. Stir overnight, filter, and dry the filter cake to obtain 4 g of the title compound as a light yellow solid, yield: 58.8%.
LC-MS：m/z＝248[M+H]+。LC-MS: m/z=248[M+H] + .
步骤2：2-(二氯甲基)-6,8-二甲基咪唑并[1,2-a]吡嗪(57b)的制备Step 2: Preparation of 2-(dichloromethyl)-6,8-dimethylimidazo[1,2-a]pyrazine (57b)
于室温，将2-(二氯甲基)-6,8-二甲基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(57a)(4.00g，16.1mmol)溶于乙醇(50ml)中，于75℃搅拌4h，减压浓缩得白色固体标题化合物3.6g，收率：97.2％。At room temperature, 2-(dichloromethyl)-6,8-dimethyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (57a) (4.00g, 16.1 mmol) in ethanol (50 ml), stirred at 75°C for 4 h, and concentrated under reduced pressure to obtain 3.6 g of the title compound as a white solid, yield: 97.2%.
LC-MS：m/z＝230[M+H]+。LC-MS: m/z=230[M+H] + .
步骤3：6,8-二甲基咪唑并[1,2-a]吡嗪-2-甲醛(57c)的制备Step 3: Preparation of 6,8-dimethylimidazo[1,2-a]pyrazine-2-carbaldehyde (57c)
于室温，将2-(二氯甲基)-6,8-二甲基咪唑并[1,2-a]吡嗪(57b)(3.60g，15.7mmol)、碳酸钙(6.28g，62.8mmol)溶于THF/H2O(1:1)(100ml)中，于70℃搅拌4h，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物2.3g，收率：85.1％。At room temperature, mix 2-(dichloromethyl)-6,8-dimethylimidazo[1,2-a]pyrazine (57b) (3.60g, 15.7mmol) and calcium carbonate (6.28g, 62.8mmol). ) was dissolved in THF/H 2 O (1:1) (100ml), stirred at 70°C for 4 hours, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1 -1:2) to obtain 2.3g of the title compound as a white solid, yield: 85.1%.
LC-MS：m/z＝176[M+H]+。LC-MS: m/z=176[M+H] + .
其他步骤与实施例12相同，除了用6,8-二甲基咪唑并[1,2-a]吡嗪-2-甲醛(57c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物57。Other steps were the same as Example 12, except that 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxaldehyde (57c) was used instead of 6-(trifluoromethyl)imidazo in step 1. [1,2-a]pyridine-2-carboxaldehyde gave compound 57.
LC-MS：m/z＝471[M+H]+。LC-MS: m/z=471[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.78(dd,J＝10.3,2.7Hz,1H),7.68(d,J＝1.8Hz,1H),7.36-7.18(m,2H),6.19(s,1H),6.12(d,J＝1.9Hz,1H),5.33-5.23(m,1H),4.20-4.09(m,3H),3.49(s,1H),2.75(s,2H),2.34(s,2H),1.74(d,J＝6.2Hz,2H)。 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 7.78 (dd, J = 10.3, 2.7Hz, 1H), 7.68 (d, J = 1.8Hz, 1H), 7.36-7.18 (m ,2H),6.19(s,1H),6.12(d,J＝1.9Hz,1H),5.33-5.23(m,1H),4.20-4.09(m,3H),3.49(s,1H),2.75( s, 2H), 2.34 (s, 2H), 1.74 (d, J = 6.2Hz, 2H).
实施例58：(R)-3-氟-5,14,16,20-四甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(58)的制备

Example 58: (R)-3-fluoro-5,14,16,20-tetramethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazino [2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecen-8-amine ( 58) Preparation

步骤1：1-溴-3-(3-溴-1-甲基-1H吡唑-4-基)丙-2-醇(58a)的制备Step 1: Preparation of 1-bromo-3-(3-bromo-1-methyl-1Hpyrazol-4-yl)propan-2-ol (58a)
于室温，将3-溴-4-碘-1-甲基-1H吡唑(25.0g，87.4mmol)溶于250ml THF中。于0℃，滴加异丙基溴化镁溶液(19.1ml，2M，104mmol)。于0℃搅拌1h。于-50℃加入碘化亚铜(1.66g，8.74mmol)、环氧溴丙烷(15.5g，114mmol)，缓慢升温到室温后继续搅拌1h。加水淬灭，EA萃取(50mL x 3)，无水硫酸钠干燥，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：EA/PE＝1:2)，得无色油状标题化合物22.1g，收率：84.6％。Dissolve 3-bromo-4-iodo-1-methyl-1H pyrazole (25.0g, 87.4mmol) in 250ml THF at room temperature. At 0°C, isopropyl magnesium bromide solution (19.1 ml, 2 M, 104 mmol) was added dropwise. Stir at 0°C for 1 h. Add copper iodide (1.66g, 8.74mmol) and epoxypropyl bromide (15.5g, 114mmol) at -50°C, slowly raise the temperature to room temperature and continue stirring for 1 hour. Add water to quench, extract with EA (50mL 22.1 g of the title compound, yield: 84.6%.
LC-MS：m/z＝299[M+H]+。LC-MS: m/z=299[M+H] + .
步骤2：1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)的制备Step 2: Preparation of 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b)
于室温，将1-溴-3-(3-溴-1-甲基-1H吡唑-4-基)丙-2-醇(58a)(22.0g，73.6mol)溶于二氯甲烷(500ml)中。于0℃，分批加入戴斯马丁氧化剂(37.4g，88.3mmol)。于室温搅拌16h，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得淡黄色油状标题化合物18.9g，收率：86.7％。Dissolve 1-bromo-3-(3-bromo-1-methyl-1H pyrazol-4-yl)propan-2-ol (58a) (22.0g, 73.6mol) in dichloromethane (500ml) at room temperature. )middle. At 0° C., Desmartin oxidant (37.4 g, 88.3 mmol) was added in portions. Stir at room temperature for 16 hours, filter, and concentrate the filtrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2) to obtain 18.9g of the title compound as a light yellow oil, which is collected. Rate: 86.7%.
LC-MS：m/z＝297[M+H]+。LC-MS: m/z=297[M+H] + .
步骤3：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6,8-二甲基咪唑并[1,2-a]吡嗪(58c)的制备Step 3: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6,8-dimethylimidazo[1,2-a]pyrazine (58c) Preparation
于室温，将3,5-二甲基吡嗪-2-胺(1.00g，8.13mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(2.36g，8.13mmol)溶于二氧六环(20ml)，加入碳酸氢钠(1.36g，16.2mmol)，于室温搅拌过夜。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物700mg，收率：26.9％。At room temperature, 3,5-dimethylpyrazin-2-amine (1.00g, 8.13mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl) Propan-2-one (2.36g, 8.13mmol) was dissolved in dioxane (20ml), sodium bicarbonate (1.36g, 16.2mmol) was added, and the mixture was stirred at room temperature overnight. Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 700 mg of the title compound as a yellow solid, yield: 26.9%.
LC-MS：m/z＝320[M+H]+。LC-MS: m/z=320[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6,8-二甲基咪唑并[1,2-a]吡嗪(58c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物58。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6,8-dimethylimidazo[1,2- a]Pyrazine (58c) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 yl)imidazo[1,2-a]pyridine (12b) to obtain compound 58.
LC-MS：m/z＝470[M+H]+。LC-MS: m/z=470[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.70(dd,J＝10.4,2.3Hz,2H),7.56(s,1H),7.21(qd,J＝8.5,5.9Hz,3H),6.34(d,J＝1.9Hz,1H),6.16(s,2H),5.33(d,J＝7.1Hz,1H),3.93(d,J＝15.1Hz,2H),3.83(s,3H),3.18(d,J＝15.0Hz,2H),2.75(s,3H),2.41(s,1H),2.34(d,J＝1.0Hz,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.08 (s, 1H), 7.70 (dd, J＝10.4, 2.3Hz, 2H), 7.56 (s, 1H), 7.21 (qd, J＝8.5, 5.9Hz ,3H),6.34(d,J＝1.9Hz,1H),6.16(s,2H),5.33(d,J＝7.1Hz,1H),3.93(d,J＝15.1Hz,2H),3.83(s ,3H),3.18(d,J＝15.0Hz,2H),2.75(s,3H),2.41(s,1H),2.34(d,J＝1.0Hz,3H),1.73(d,J＝6.2Hz ,3H).
实施例59：(R)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(59)的制备
Example 59: (R)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazolo[4,3 Preparation of -j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (59)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6,8-二氟咪唑并[1,2-a]吡啶(59a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6,8-difluoroimidazo[1,2-a]pyridine (59a)
于室温，将3,5-二氟吡啶-2-胺(1.00g，7.69mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(2.36g，7.69mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(1.28g，15.3mmol)，于室温搅拌过夜。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物832mg，收率，33.1％。At room temperature, 3,5-difluoropyridin-2-amine (1.00g, 7.69mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan- 2-one (58b) (2.36g, 7.69mmol) was dissolved in dioxane (20ml), sodium bicarbonate (1.28g, 15.3mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 832 mg of the title compound as a yellow solid, yield 33.1%.
LC-MS：m/z＝327[M+H]+。LC-MS: m/z=327[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6,8-二氟咪唑并[1,2-a]吡啶(59a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物59。Other steps are the same as Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6,8-difluoroimidazo[1,2-a ]pyridine (59a) instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 Imidazo[1,2-a]pyridine (12b) gave compound 59.
LC-MS：m/z＝477[M+H]+。LC-MS: m/z=477[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.39(dd,J＝4.6,2.1Hz,1H),7.76-7.66(m,2H),7.61(s,1H),7.47(ddd,J＝11.0,9.0,2.0Hz,1H),7.27-7.14(m,2H),6.33(d,J＝2.0Hz,1H),6.17(s,2H),5.34(dd,J＝6.5,2.1Hz,1H),3.90(d,J＝15.2Hz,1H),3.83(s,3H),3.15(d,J＝15.0Hz,1H),1.72(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.39 (dd, J＝4.6, 2.1Hz, 1H), 7.76-7.66 (m, 2H), 7.61 (s, 1H), 7.47 (ddd, J＝11.0, 9.0,2.0Hz,1H),7.27-7.14(m,2H),6.33(d,J＝2.0Hz,1H),6.17(s,2H),5.34(dd,J＝6.5,2.1Hz,1H), 3.90(d,J＝15.2Hz,1H), 3.83(s,3H), 3.15(d,J＝15.0Hz,1H), 1.72(d,J＝6.2Hz,3H).
实施例60：(R)-3,14,16-三氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(60)的制备
Example 60: (R)-3,14,16-trifluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrido [2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]aza Preparation of carbene-8-amine (60)
步骤1：2-(二氯甲基)-6,8-二氟-2,3-二氢咪唑并[1,2-a]吡啶-2-醇(60a)的制备Step 1: Preparation of 2-(dichloromethyl)-6,8-difluoro-2,3-dihydroimidazo[1,2-a]pyridin-2-ol (60a)
于室温，将3,5-二氟吡啶-2-胺(3.40g，27.6mmol)、1,1,3-三氯丙酮(11.0g，41.0mmol)溶于THF(100ml)中，于室温搅拌过夜，过滤，滤饼烘干，得淡黄色固体状标题化合4g，收率，57.1％。Dissolve 3,5-difluoropyridin-2-amine (3.40g, 27.6mmol) and 1,1,3-trichloroacetone (11.0g, 41.0mmol) in THF (100ml) at room temperature, and stir at room temperature. Leave overnight, filter, and dry the filter cake to obtain 4 g of the title compound as a light yellow solid, yield 57.1%.
LC-MS：m/z＝255[M+H]+。LC-MS: m/z=255[M+H] + .
步骤2：2-(二氯甲基)-6,8-二氟咪唑并[1,2-a]吡啶(60b)的制备Step 2: Preparation of 2-(dichloromethyl)-6,8-difluoroimidazo[1,2-a]pyridine (60b)
于室温，将2-(二氯甲基)-6,8-二氟-2,3-二氢咪唑并[1,2-a]吡啶-2-醇(60a)(4.00g，15.6mmol)溶于乙醇(50ml)中，于75℃搅拌4h，减压浓缩得白色固体标题化合物3.0g，收率，83.3％。At room temperature, 2-(dichloromethyl)-6,8-difluoro-2,3-dihydroimidazo[1,2-a]pyridin-2-ol (60a) (4.00g, 15.6mmol) Dissolve in ethanol (50 ml), stir at 75°C for 4 hours, and concentrate under reduced pressure to obtain 3.0 g of the title compound as a white solid, yield: 83.3%.
LC-MS：m/z＝237[M+H]+。LC-MS: m/z=237[M+H] + .
步骤3：6,8-二甲基咪唑并[1,2-a]吡嗪-2-甲醛(60c)的制备Step 3: Preparation of 6,8-dimethylimidazo[1,2-a]pyrazine-2-carbaldehyde (60c)
于室温，将2-(二氯甲基)-6,8-二甲基咪唑并[1,2-a]吡嗪(60b)(3.00g，12.7mmol)、碳酸钙(2.50g，25.4mmol)溶于THF/H2O(1:1)(100ml)中，于70℃搅拌4h，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物650mg，收率，28.2％。At room temperature, mix 2-(dichloromethyl)-6,8-dimethylimidazo[1,2-a]pyrazine (60b) (3.00g, 12.7mmol) and calcium carbonate (2.50g, 25.4mmol). ) was dissolved in THF/H 2 O (1:1) (100ml), stirred at 70°C for 4 hours, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1 -1:2) to obtain 650 mg of the title compound as a white solid, yield 28.2%.
LC-MS：m/z＝183[M+H]+。LC-MS: m/z=183[M+H] + .
其他步骤与实施例12相同，除了用6,8-二甲基咪唑并[1,2-a]吡嗪-2-甲醛(60c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物60。Other steps are the same as Example 12, except that 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxaldehyde (60c) is used instead of 6-(trifluoromethyl)imidazo in step 1. [1,2-a]pyridine-2-carboxaldehyde gave compound 60.
LC-MS：m/z＝478[M+H]+。LC-MS: m/z=478[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.37(dd,J＝4.6,2.2Hz,1H),7.79(dd,J＝10.3, 2.7Hz,1H),7.71(d,J＝1.9Hz,1H),7.64-7.61(m,1H),7.48(ddd,J＝11.1,9.1,2.0Hz,1H),7.31(dd,J＝8.5,5.8Hz,1H),7.23(td,J＝8.4,2.7Hz,1H),6.21(s,2H),6.12(d,J＝1.9Hz,1H),5.28(dd,J＝6.6,2.1Hz,1H),4.12(d,J＝26.2Hz,4H),3.43(d,J＝15.2Hz,1H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.37 (dd, J＝4.6, 2.2Hz, 1H), 7.79 (dd, J＝10.3, 2.7Hz,1H),7.71(d,J＝1.9Hz,1H),7.64-7.61(m,1H),7.48(ddd,J＝11.1,9.1,2.0Hz,1H),7.31(dd,J＝8.5 ,5.8Hz,1H),7.23(td,J＝8.4,2.7Hz,1H),6.21(s,2H),6.12(d,J＝1.9Hz,1H),5.28(dd,J＝6.6,2.1Hz ,1H), 4.12(d,J＝26.2Hz,4H), 3.43(d,J＝15.2Hz,1H), 1.73(d,J＝6.2Hz,3H).
实施例61：(R)-3-氟-5,16,20-三甲基-14-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(61)的制备
Example 61: (R)-3-fluoro-5,16,20-trimethyl-14-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzene And[l]pyrazino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetrade Preparation of carbene-8-amine (61)
步骤1：3-溴-5-(三氟甲基)吡嗪-2-胺(61a)的制备Step 1: Preparation of 3-bromo-5-(trifluoromethyl)pyrazin-2-amine (61a)
于室温，将5-(三氟甲基)吡嗪-2-胺(4.00g，30.7mmol)、N-溴代丁二酰亚胺(6.55g，36.8mmol)溶于50ml乙腈中，于室温搅拌过夜。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物2.01g，收率：27.1％。Dissolve 5-(trifluoromethyl)pyrazin-2-amine (4.00g, 30.7mmol) and N-bromosuccinimide (6.55g, 36.8mmol) in 50ml acetonitrile at room temperature. Stir overnight. Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 2.01g of the title compound as a yellow solid, yield: 27.1%.
LC-MS：m/z＝242[M+H]+。LC-MS: m/z=242[M+H] + .
步骤2：3-甲基-5-(三氟甲基)吡嗪-2-胺(61b)的制备Step 2: Preparation of 3-methyl-5-(trifluoromethyl)pyrazin-2-amine (61b)
于室温，将3-溴-5-(三氟甲基)吡嗪-2-胺(61a)(4.00g，16.5mmol)、甲基硼酸(1.48g，24.8mmol)、Pd(dppf)Cl2(1.21g，1.65mmol)、碳酸铯(10.8g，33.1mmol)溶于80ml二氧六环/H2O(5:1)中，于100℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物2.81g，收率：95.2％。At room temperature, 3-bromo-5-(trifluoromethyl)pyrazin-2-amine (61a) (4.00g, 16.5mmol), methylboronic acid (1.48g, 24.8mmol), Pd(dppf)Cl 2 (1.21g, 1.65mmol) and cesium carbonate (10.8g, 33.1mmol) were dissolved in 80ml dioxane/H2O (5:1), stirred at 100°C overnight, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. After separation and purification by chromatography (mobile phase: DCM/MeOH=20:1), 2.81g of the title compound was obtained as a yellow solid, yield: 95.2%.
LC-MS：m/z＝178[M+H]+。LC-MS: m/z=178[M+H] + .
步骤3：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡嗪(61c)的制备Step 3: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (61c ) preparation
于室温，将3-甲基-5-(三氟甲基)吡嗪-2-胺(61b)(1.01g，5.67mmol)、1- 溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.68g，5.67mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(975mg，11.3mmol)，于室温搅拌过夜。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物350mg，收率：17.5％。At room temperature, 3-methyl-5-(trifluoromethyl)pyrazin-2-amine (61b) (1.01g, 5.67mmol), 1- Bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (1.68g, 5.67mmol) was dissolved in dioxane (20ml) and added Sodium bicarbonate (975 mg, 11.3 mmol), stirred at room temperature overnight. Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 350 mg of the title compound as a yellow solid, yield: 17.5%.
LC-MS：m/z＝360[M+H]+。LC-MS: m/z=360[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡嗪(61c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物61。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine (61c) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoro Methyl)imidazo[1,2-a]pyridine (12b) gave compound 61.
LC-MS：m/z＝524[M+H]+。LC-MS: m/z=524[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),7.83(d,J＝1.8Hz,1H),7.71(dd,J＝10.4,2.6Hz,1H),7.58(s,1H),7.30-7.13(m,2H),6.35(d,J＝2.0Hz,1H),6.26(s,2H),5.34(dt,J＝6.9,3.4Hz,1H),4.08-3.90(m,2H),3.83(s,4H),3.24(d,J＝15.0Hz,1H),2.86(s,3H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.58 (s, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.71 (dd, J = 10.4, 2.6 Hz, 1H), 7.58 (s, 1H),7.30-7.13(m,2H),6.35(d,J＝2.0Hz,1H),6.26(s,2H),5.34(dt,J＝6.9,3.4Hz,1H),4.08-3.90(m ,2H),3.83(s,4H),3.24(d,J＝15.0Hz,1H),2.86(s,3H),1.74(d,J＝6.2Hz,3H).
实施例62：(R)-8-氨基-3-氟-N,5,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-14-甲酰胺(62)的制备
Example 62: (R)-8-amino-3-fluoro-N,5,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyridine Azino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene-14- Preparation of formamide (62)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡嗪-6-甲酸甲酯(62a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyrazine-6-carboxylic acid methyl ester (62a)
于室温，将5-氨基吡嗪-2-羧酸甲酯(1.00g，6.53mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(2.36g，6.53mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(1.09g，13.1mmol)，于室温搅拌过夜。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物510 mg，收率，21.9％。At room temperature, add 5-aminopyrazine-2-carboxylic acid methyl ester (1.00g, 6.53mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propanol. -2-one (58b) (2.36g, 6.53mmol) was dissolved in dioxane (20ml), sodium bicarbonate (1.09g, 13.1mmol) was added, and the mixture was stirred at room temperature overnight. Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain the title compound 510 as a yellow solid. mg, yield, 21.9%.
LC-MS：m/z＝350[M+H]+。LC-MS: m/z=350[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-N-甲基咪唑并[1,2-a]吡嗪-6-甲酰胺(62b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamide ( Preparation of 62b)
于室温，将2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡嗪-6-甲酸甲酯(62a)(300mg，0.857mmol)溶于甲醇(2ml)中，加入甲醇胺水溶液(21mL，40％)，于80℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物130mg，收率，43.4％。At room temperature, 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyrazine-6-carboxylic acid methyl ester (62a) ( 300 mg, 0.857 mmol) was dissolved in methanol (2 ml), an aqueous methanolamine solution (21 mL, 40%) was added, stirred at 80°C overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM /MeOH=20:1), 130 mg of the title compound was obtained as a yellow solid, yield 43.4%.
LC-MS：m/z＝349[M+H]+。LC-MS: m/z=349[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-N-甲基咪唑并[1,2-a]吡嗪-6-甲酰胺(62b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物62。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-N-methylimidazo[1,2-a]pyra Azine-6-carboxamide (62b) replaced 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(tris Fluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 62.
LC-MS：m/z＝499[M+H]+。LC-MS: m/z=499[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.06(d,J＝1.4Hz,1H),8.78-8.68(m,2H),7.81(d,J＝1.8Hz,1H),7.70(dd,J＝10.3,2.7Hz,1H),7.59(s,1H),7.30-7.15(m,2H),6.38(d,J＝1.9Hz,1H),6.28(s,2H),5.35(dd,J＝6.5,2.1Hz,1H),4.01(d,J＝15.1Hz,1H),3.83(s,3H),3.27(d,J＝15.0Hz,1H),2.83(d,J＝4.8Hz,3H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.06 (d, J = 1.4Hz, 1H), 8.78-8.68 (m, 2H), 7.81 (d, J = 1.8Hz, 1H), 7.70 (dd, J ＝10.3,2.7Hz,1H),7.59(s,1H),7.30-7.15(m,2H),6.38(d,J＝1.9Hz,1H),6.28(s,2H),5.35(dd,J＝ 6.5,2.1Hz,1H),4.01(d,J＝15.1Hz,1H),3.83(s,3H),3.27(d,J＝15.0Hz,1H),2.83(d,J＝4.8Hz,3H) ,1.74(d,J=6.2Hz,3H).
实施例63：(R)-14-乙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(63)的制备
Example 63: (R)-14-ethyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazine And[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecen-8-amine Preparation of (63)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-乙基咪唑并[1,2-a]吡嗪(63a)的制备 Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-ethylimidazo[1,2-a]pyrazine (63a)
于室温，向5-乙基吡嗪-2-胺(200mg，1.61mmol，1.00equiv)的1,4二氧六环(10.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(978mg，3.22mmol，2.00equiv)和碳酸氢钠(270mg，3.22mmol，2.00equiv)，于80℃搅拌过夜。反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷:甲醇＝10:1)，得到淡黄色油状的标题化合物100mg。收率19.5％。To a solution of 5-ethylpyrazin-2-amine (200 mg, 1.61 mmol, 1.00 equiv) in 1,4 dioxane (10.0 mL) was added 1-bromo-3-(3-bromo-1) at room temperature. -Methyl-1H-pyrazol-4-yl)propan-2-one (58b) (978 mg, 3.22 mmol, 2.00 equiv) and sodium bicarbonate (270 mg, 3.22 mmol, 2.00 equiv) were stirred at 80°C overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride:methanol=10:1) to obtain 100 mg of the title compound as a light yellow oil. Yield 19.5%.
LC-MS：m/z 320.10[M+H]+。LC-MS: m/z 320.10[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-乙基咪唑并[1,2-a]吡嗪(63a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物63。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-ethylimidazo[1,2-a]pyra 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazole in step 3 and [1,2-a]pyridine (12b) to obtain compound 63.
LC-MS：m/z 470.05[M+H]+。LC-MS: m/z 470.05[M+H] + .
1H NMR(400MHz,CHCl3-d)δ9.02(d,J＝1.4Hz,1H),8.01-7.96(m,1H),7.78(d,J＝1.7Hz,1H),7.41(s,1H),7.33(dd,J＝9.8,2.7Hz,1H),7.21(dd,J＝8.5,5.7Hz,1H),7.06(td,J＝8.2,2.7Hz,1H),6.62(d,J＝1.9Hz,1H),5.43(td,J＝6.8,4.8Hz,1H),5.13-5.01(m,2H),4.06(dd,J＝15.1,1.0Hz,1H),3.88(s,3H),3.45(d,J＝15.1Hz,1H),2.81-2.71(m,2H),1.29(t,J＝7.5Hz,3H)。 1 H NMR (400MHz, CHCl 3 -d) δ9.02 (d, J = 1.4Hz, 1H), 8.01-7.96 (m, 1H), 7.78 (d, J = 1.7Hz, 1H), 7.41 (s, 1H),7.33(dd,J＝9.8,2.7Hz,1H),7.21(dd,J＝8.5,5.7Hz,1H),7.06(td,J＝8.2,2.7Hz,1H),6.62(d,J ＝1.9Hz,1H),5.43(td,J＝6.8,4.8Hz,1H),5.13-5.01(m,2H),4.06(dd,J＝15.1,1.0Hz,1H),3.88(s,3H) ,3.45(d,J＝15.1Hz,1H),2.81-2.71(m,2H),1.29(t,J＝7.5Hz,3H).
实施例64：(R)-14-乙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g]三唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(64)的制备
Example 64: (R)-14-ethyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazine And[2',1':2,3]imidazo[4,5-g]triazolo[4,3-j][1]oxa[4]azacyclotetradecen-8-amine Preparation of (64)
步骤1：2-(二氯甲基)-6-乙基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(64a)的制备Step 1: Preparation of 2-(dichloromethyl)-6-ethyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (64a)
于0℃，向5-乙基吡嗪-2-胺(3.30g，26.8mmol，1.00equiv)的THF(40.0mL)溶液中加入1,1,3-三氯丙-2-酮(14.3g，53.6mmol，2.00equiv)，于室温搅拌过夜。直接过滤，收集滤饼干燥，得到白色固体状的标题化合物1.5g，收率22.6％。 To a solution of 5-ethylpyrazin-2-amine (3.30g, 26.8mmol, 1.00equiv) in THF (40.0mL) at 0°C, 1,1,3-trichloropropan-2-one (14.3g , 53.6mmol, 2.00equiv), stirred at room temperature overnight. Filter directly, collect the filter cake and dry it to obtain 1.5 g of the title compound as a white solid, with a yield of 22.6%.
LC-MS：m/z 248.05[M+H]+。LC-MS: m/z 248.05[M+H] + .
步骤2：2-(二氯甲基)-6-乙基咪唑并[1,2-a]吡嗪(64b)的制备Step 2: Preparation of 2-(dichloromethyl)-6-ethylimidazo[1,2-a]pyrazine (64b)
于室温，将2-(二氯甲基)-6-乙基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(64a)(1.50g，6.07mmol，1.00equiv)溶于乙醇(40.0mL)中，于85℃搅拌1小时，将反应液减压浓缩，得到白色固体状的标题化合物1.2g。收率86.3％。At room temperature, 2-(dichloromethyl)-6-ethyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (64a) (1.50g, 6.07mmol, 1.00 equiv) was dissolved in ethanol (40.0 mL), stirred at 85°C for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain 1.2 g of the title compound as a white solid. The yield is 86.3%.
LC-MS：m/z 230.05[M+H]+。LC-MS: m/z 230.05[M+H] + .
步骤3：6-乙基咪唑并[1,2-a]吡嗪-2-甲醛(64c)的制备Step 3: Preparation of 6-ethylimidazo[1,2-a]pyrazine-2-carbaldehyde (64c)
于室温，向2-(二氯甲基)-6-乙基咪唑并[1,2-a]吡嗪(64b)(1.30g，5.67mmol，1.00equiv)的四氢呋喃(20.0mL)和水(10mL)溶液中加入碳酸钙(2.27g，22.7mmol，4.00equiv)。于80℃搅拌4小时，直接减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:10)，得到白色固体状的标题化合物700mg。收率70.5％。To 2-(dichloromethyl)-6-ethylimidazo[1,2-a]pyrazine (64b) (1.30 g, 5.67 mmol, 1.00 equiv) in tetrahydrofuran (20.0 mL) and water ( Calcium carbonate (2.27g, 22.7mmol, 4.00equiv) was added to the solution. Stir at 80°C for 4 hours, and then concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:10) to obtain 700 mg of the title compound as a white solid. The yield is 70.5%.
LC-MS：m/z 176.05[M+H]+。LC-MS: m/z 176.05[M+H] + .
其他步骤与实施例12相同，除了用6-乙基咪唑并[1,2-a]吡嗪-2-甲醛(64c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物64。Other steps are the same as in Example 12, except that 6-ethylimidazo[1,2-a]pyrazine-2-carboxaldehyde (64c) is used instead of 6-(trifluoromethyl)imidazo[1, 2-a]pyridine-2-carboxaldehyde gave compound 64.
LC-MS：m/z 471.10[M+H]+。LC-MS: m/z 471.10[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.98(d,J＝1.4Hz,1H),8.16(d,J＝1.4Hz,1H),7.83-7.71(m,2H),7.33(dd,J＝8.5,5.9Hz,1H),7.24(td,J＝8.4,2.8Hz,1H),6.21(s,2H),6.12(d,J＝1.9Hz,1H),5.27(dt,J＝6.7,3.4Hz,1H),4.15(d,J＝9.4Hz,4H),3.49(d,J＝15.2Hz,1H),2.69(q,J＝7.4Hz,2H),1.74(d,J＝6.2Hz,3H),1.20(t,J＝7.5Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.98 (d, J = 1.4Hz, 1H), 8.16 (d, J = 1.4Hz, 1H), 7.83-7.71 (m, 2H), 7.33 (dd, J＝8.5,5.9Hz,1H),7.24(td,J＝8.4,2.8Hz,1H),6.21(s,2H),6.12(d,J＝1.9Hz,1H),5.27(dt,J＝6.7 ,3.4Hz,1H),4.15(d,J＝9.4Hz,4H),3.49(d,J＝15.2Hz,1H),2.69(q,J＝7.4Hz,2H),1.74(d,J＝6.2 Hz, 3H), 1.20 (t, J = 7.5Hz, 3H).
实施例65：(R)-3-氟-14-异丙基-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(65)的制备

Example 65: (R)-3-fluoro-14-isopropyl-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyridine Azino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene-8- Preparation of amine (65)

步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-异丙基咪唑并[1,2-a]吡嗪(65a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-isopropylimidazo[1,2-a]pyrazine (65a)
于室温，向5-异丙基吡嗪-2-胺(200mg，1.45mmol，1.00equiv)的1,4二氧六环(10.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(858mg，2.91mmol，2.00equiv)和碳酸氢钠(367mg，4.37mmol，3.00equiv)，于80℃搅拌过夜。反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物180mg。收率37.3％。To a solution of 5-isopropylpyrazin-2-amine (200 mg, 1.45 mmol, 1.00 equiv) in 1,4 dioxane (10.0 mL) was added 1-bromo-3-(3-bromo- 1-Methyl-1H-pyrazol-4-yl)propan-2-one (58b) (858mg, 2.91mmol, 2.00equiv) and sodium bicarbonate (367mg, 4.37mmol, 3.00equiv), stirred at 80°C overnight . The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=10:1) to obtain 180 mg of the title compound as a light yellow oil. The yield is 37.3%.
LC-MS：m/z 334.10[M+H]+。LC-MS: m/z 334.10[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-异丙基咪唑并[1,2-a]吡嗪(65a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物65。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-isopropylimidazo[1,2-a] Pyrazine (65a) replaced 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 Imidazo[1,2-a]pyridine (12b) gave compound 65.
LC-MS：m/z 484.05[M+H]+。LC-MS: m/z 484.05[M+H] + .
1H NMR(400MHz,CHCl3-d)δ9.04(d,J＝1.3Hz,1H),7.96(d,J＝1.4Hz,1H),7.76(s,1H),7.42(s,1H),7.33(dd,J＝9.8,2.7Hz,1H),7.22(dd,J＝8.5,5.7Hz,1H),7.07(td,J＝8.2,2.7Hz,1H),6.65(d,J＝1.7Hz,1H),5.43(td,J＝6.9,4.9Hz,1H),5.27(s,2H),4.11-4.02(m,1H),3.88(s,3H),3.45(d,J＝15.1Hz,1H),2.98(h,J＝6.8Hz,1H),1.84(d,J＝6.3Hz,3H),1.30(dd,J＝6.8,5.1Hz,6H)。 1 H NMR (400MHz, CHCl 3 -d) δ9.04 (d, J = 1.3Hz, 1H), 7.96 (d, J = 1.4Hz, 1H), 7.76 (s, 1H), 7.42 (s, 1H) ,7.33(dd,J＝9.8,2.7Hz,1H),7.22(dd,J＝8.5,5.7Hz,1H),7.07(td,J＝8.2,2.7Hz,1H),6.65(d,J＝1.7 Hz,1H),5.43(td,J＝6.9,4.9Hz,1H),5.27(s,2H),4.11-4.02(m,1H),3.88(s,3H),3.45(d,J＝15.1Hz ,1H),2.98(h,J＝6.8Hz,1H),1.84(d,J＝6.3Hz,3H),1.30(dd,J＝6.8,5.1Hz,6H).
实施例66：(R)-3-氟-14-异丙基-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(66)的制备

Example 66: (R)-3-fluoro-14-isopropyl-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyridine Azino[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azeterocycle Preparation of tetradecene-8-amine (66)

步骤1：5-(丙-1-烯-2-基)吡嗪-2-胺(66a)的制备Step 1: Preparation of 5-(prop-1-en-2-yl)pyrazin-2-amine (66a)
于室温，向5-溴吡嗪-2-胺(10.0g，57.8mmol，1.00equiv)的1,4-二氧六环(100mL)和水(40mL)溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(4.20g，5.78mmol，0.100equiv)、碳酸铯(56.0g，173mmol，3.00equiv)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼烷(12.6g，75.1mmol，1.30equiv)。于氮气氛围下85℃搅拌过夜，反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色固体状的标题化合物6.2g，收率79.4％。To a solution of 5-bromopyrazin-2-amine (10.0 g, 57.8 mmol, 1.00 equiv) in 1,4-dioxane (100 mL) and water (40 mL) at room temperature was added [1,1'-bis (Diphenylphosphine)ferrocene]palladium dichloride (4.20g, 5.78mmol, 0.100equiv), cesium carbonate (56.0g, 173mmol, 3.00equiv) and 4,4,5,5-tetramethyl-2 -(Prop-1-en-2-yl)-1,3,2-dioxaborane (12.6 g, 75.1 mmol, 1.30 equiv). The mixture was stirred at 85°C overnight under nitrogen atmosphere, and the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 6.2 g of the title compound as a light yellow solid, with a yield of 79.4%.
LC-MS：m/z 136.05[M+H]+。LC-MS: m/z 136.05[M+H] + .
步骤2：5-异丙基吡嗪-2-胺(66b)的制备Step 2: Preparation of 5-isopropylpyrazin-2-amine (66b)
于室温，向5-(丙-1-烯-2-基)吡嗪-2-胺(66a)(8.50g，62.5mmol，1.00equiv)的乙酸乙酯(100mL)溶液中加入钯碳(800mg，10％)。于氢气氛围下室温搅拌过夜，过滤，滤液减压浓缩。得到淡黄色固体状的标题化合物8.0g，收率93.4％。To a solution of 5-(prop-1-en-2-yl)pyrazin-2-amine (66a) (8.50 g, 62.5 mmol, 1.00 equiv) in ethyl acetate (100 mL) was added palladium on carbon (800 mg) at room temperature. , 10%). Stir at room temperature overnight under hydrogen atmosphere, filter, and concentrate the filtrate under reduced pressure. 8.0 g of the title compound was obtained as a light yellow solid, with a yield of 93.4%.
LC-MS：m/z 138.05[M+H]+。LC-MS: m/z 138.05[M+H] + .
步骤3：2-(二氯甲基)-6-异丙基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(66c)的制备Step 3: Preparation of 2-(dichloromethyl)-6-isopropyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (66c)
于0℃向5-异丙基吡嗪-2-胺(3.00g，21.7mmol，1.00equiv)的THF(20.0mL)溶液中加入1,1,3-三氯丙-2-酮(11.5g，43.4mmol，2.00equiv)，于室温搅拌过夜。直接过滤，收集滤饼干燥，得到白色固体状的标题化合物4.00g，收率73.0％。To a solution of 5-isopropylpyrazin-2-amine (3.00g, 21.7mmol, 1.00equiv) in THF (20.0mL) at 0°C was added 1,1,3-trichloropropan-2-one (11.5g , 43.4mmol, 2.00equiv), stirred at room temperature overnight. Filter directly, collect the filter cake and dry it to obtain 4.00g of the title compound as a white solid, with a yield of 73.0%.
LC-MS：m/z 262.05[M+H]+。LC-MS: m/z 262.05[M+H] + .
步骤4：2-(二氯甲基)-6-异丙基咪唑并[1,2-a]吡嗪(66d)的制备Step 4: Preparation of 2-(dichloromethyl)-6-isopropylimidazo[1,2-a]pyrazine (66d)
于室温，将2-(二氯甲基)-6-异丙基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(4.00g，15.3mmol，1.00equiv)溶于乙醇(40.0mL)中。于85℃搅拌1小时，将反应液浓缩，得到白色固体状的标题化合物3.8g粗品，直接用于下一步。At room temperature, 2-(dichloromethyl)-6-isopropyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (4.00g, 15.3mmol, 1.00equiv) Dissolve in ethanol (40.0 mL). Stir at 85°C for 1 hour, and concentrate the reaction solution to obtain 3.8 g of crude product of the title compound as a white solid, which is used directly in the next step.
LC-MS：m/z 244.05[M+H]+。LC-MS: m/z 244.05[M+H] + .
步骤5：6-异丙基咪唑并[1,2-a]吡嗪-2-甲醛(66e)的制备Step 5: Preparation of 6-isopropylimidazo[1,2-a]pyrazine-2-carbaldehyde (66e)
于室温，向2-(二氯甲基)-6-异丙基咪唑并[1,2-a]吡嗪(3.80g，15.6mmol，1.00equiv)的四氢呋喃(60.0mL)和水(20mL)溶液中加入碳酸钙(6.20g，62.5mmol，4.00equiv)。于80℃搅拌4小时，将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:10)，得到白色固体状的标题化合物1.5g。收率，50.9％。 To 2-(dichloromethyl)-6-isopropylimidazo[1,2-a]pyrazine (3.80 g, 15.6 mmol, 1.00 equiv) in tetrahydrofuran (60.0 mL) and water (20 mL) at room temperature Calcium carbonate (6.20g, 62.5mmol, 4.00equiv) was added to the solution. After stirring at 80° C. for 4 hours, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:10) to obtain 1.5 g of the title compound as a white solid. Yield, 50.9%.
LC-MS：m/z 190.05[M+H]+。LC-MS: m/z 190.05[M+H] + .
其他步骤与实施例12相同，除了用6-异丙基咪唑并[1,2-a]吡嗪-2-甲醛(66e)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物66。Other steps are the same as Example 12, except that 6-isopropylimidazo[1,2-a]pyrazine-2-carboxaldehyde (66e) is used instead of 6-(trifluoromethyl)imidazo[1] in step 1. ,2-a]pyridine-2-carboxaldehyde to obtain compound 66.
LC-M：m/z 485.10[M+H]+。LC-M: m/z 485.10[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.00(d,J＝1.4Hz,1H),8.09(d,J＝1.6Hz,1H),7.83-7.73(m,2H),7.33(dd,J＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.21(s,2H),6.11(d,J＝2.0Hz,1H),5.27(tt,J＝6.7,3.3Hz,1H),4.19-4.10(m,4H),3.49(d,J＝15.2Hz,1H),3.01(h,J＝6.8Hz,1H),1.74(d,J＝6.2Hz,3H),1.22(dd,J＝13.5,6.8Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.00 (d, J = 1.4Hz, 1H), 8.09 (d, J = 1.6Hz, 1H), 7.83-7.73 (m, 2H), 7.33 (dd, J＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.21(s,2H),6.11(d,J＝2.0Hz,1H),5.27(tt,J＝6.7 ,3.3Hz,1H),4.19-4.10(m,4H),3.49(d,J＝15.2Hz,1H),3.01(h,J＝6.8Hz,1H),1.74(d,J＝6.2Hz,3H ), 1.22 (dd, J = 13.5, 6.8Hz, 6H).
实施例67：(R)-14-(二氟甲基)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪[2',1':2,3]咪唑并[4,5-g]吡唑[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(67)的制备
Example 67: (R)-14-(difluoromethyl)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[ l]pyrazine[2',1':2,3]imidazo[4,5-g]pyrazole[4,3-j][1]oxa[4]azacyclotetradecene-8 - Preparation of amine (67)
步骤1：2-氯-5-(二氟甲基)吡嗪(67a)的制备Step 1: Preparation of 2-chloro-5-(difluoromethyl)pyrazine (67a)
于室温，将5-氯吡嗪-2-甲醛(2.00g，14.0mmol)、二乙胺基三氟化硫(DAST)(8.00g，35.2mmol)、三乙胺三氢氟酸盐(2.28ml，14.0mmol)溶于DCM(20ml)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝3:1)，得黄色液体标题化合物1.60g，收率：69.5％。At room temperature, add 5-chloropyrazine-2-carbaldehyde (2.00g, 14.0mmol), diethylamine sulfur trifluoride (DAST) (8.00g, 35.2mmol), and triethylamine trihydrofuride (2.28 ml, 14.0 mmol) was dissolved in DCM (20 ml), stirred at room temperature overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=3:1) to obtain the title compound as a yellow liquid. 1.60g, yield: 69.5%.
LC-MS：m/z＝165[M+H]+。LC-MS: m/z=165[M+H] + .
步骤2：5-(二氟甲基)-N-(4-甲氧基苄基)吡嗪-2-胺(67b)的制备Step 2: Preparation of 5-(difluoromethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (67b)
于室温，将2-氯-5-(二氟甲基)吡嗪(1.60g，9.69mmol)、对甲氧基苄胺(3.32g，24.2mmol)溶于THF(20ml)，于70℃搅拌过夜。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得白色液体标题化合物1.60g， 收率：62.2％。Dissolve 2-chloro-5-(difluoromethyl)pyrazine (1.60g, 9.69mmol) and p-methoxybenzylamine (3.32g, 24.2mmol) in THF (20ml) at room temperature, and stir at 70°C. overnight. Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=2:1) to obtain 1.60g of the title compound as a white liquid. Yield: 62.2%.
LC-MS：m/z＝266[M+H]+。LC-MS: m/z=266[M+H] + .
步骤3：5-(二氟甲基)吡嗪-2-胺(67c)的制备Step 3: Preparation of 5-(difluoromethyl)pyrazin-2-amine (67c)
于室温，将5-(二氟甲基)-N-(4-甲氧基苄基)吡嗪-2-胺(1.60g，6.01mmol)溶于TFA(10ml)，于60℃搅拌过夜。减压浓缩，饱和碳酸氢钠溶液调PH至中性，EA萃取，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得淡黄色固体标题化合物810mg，收率：92.9％。Dissolve 5-(difluoromethyl)-N-(4-methoxybenzyl)pyrazin-2-amine (1.60g, 6.01mmol) in TFA (10ml) at room temperature, and stir at 60°C overnight. Concentrate under reduced pressure, adjust the pH to neutral with saturated sodium bicarbonate solution, extract with EA, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=2:1) to obtain a light yellow solid. Title compound 810 mg, yield: 92.9%.
LC-MS：m/z＝146[M+H]+。LC-MS: m/z=146[M+H] + .
步骤4：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(二氟甲基)咪唑并[1,2-a]吡嗪(67d)的制备。Step 4: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine (67d ) preparation.
于室温，将5-(二氟甲基)吡嗪-2-胺(600mg，4.10mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.20g，4.10mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(688mg，8.20mmol)，于80℃搅拌过夜。减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物370mg，收率：26.4％。At room temperature, 5-(difluoromethyl)pyrazin-2-amine (600 mg, 4.10 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl) Propan-2-one (58b) (1.20g, 4.10mmol) was dissolved in dioxane (20ml), sodium bicarbonate (688mg, 8.20mmol) was added, and the mixture was stirred at 80°C overnight. Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 370 mg of the title compound as a yellow solid, yield: 26.4%.
LC-MS：m/z＝342[M+H]+。LC-MS: m/z=342[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(二氟甲基)咪唑并[1,2-a]吡嗪(67d)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物67。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(difluoromethyl)imidazo[1,2 -a]pyrazine (67d) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoro Methyl)imidazo[1,2-a]pyridine (12b) gave compound 67.
LC-MS：m/z＝499[M+H]+。LC-MS: m/z=499[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.06(d,J＝1.4Hz,1H),8.78-8.68(m,2H),7.81(d,J＝1.8Hz,1H),7.70(dd,J＝10.3,2.7Hz,1H),7.59(s,1H),7.30-7.15(m,2H),6.38(d,J＝1.9Hz,1H),6.28(s,2H),5.35(dd,J＝6.5,2.1Hz,1H),4.01(d,J＝15.1Hz,1H),3.83(s,3H),3.27(d,J＝15.0Hz,1H),2.83(d,J＝4.8Hz,3H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.06 (d, J = 1.4Hz, 1H), 8.78-8.68 (m, 2H), 7.81 (d, J = 1.8Hz, 1H), 7.70 (dd, J ＝10.3,2.7Hz,1H),7.59(s,1H),7.30-7.15(m,2H),6.38(d,J＝1.9Hz,1H),6.28(s,2H),5.35(dd,J＝ 6.5,2.1Hz,1H),4.01(d,J＝15.1Hz,1H),3.83(s,3H),3.27(d,J＝15.0Hz,1H),2.83(d,J＝4.8Hz,3H) ,1.74(d,J=6.2Hz,3H).
实施例68：(R)-3-氟-5,20-二甲基-14-(吡咯烷-1-基)-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(68)的制备

Example 68: (R)-3-fluoro-5,20-dimethyl-14-(pyrrolidin-1-yl)-18,20-dihydro-5H-7,11-(methylene)benzene And[1]pyrazino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetrade Preparation of carbene-8-amine (68)

步骤1：5-(吡咯烷-1-基)吡嗪-2-胺(68a)的制备Step 1: Preparation of 5-(pyrrolidin-1-yl)pyrazin-2-amine (68a)
于室温，将5-溴-4-氟吡啶-2-胺(5.00g，28.9mmol)溶于10ml四氢吡咯中，于180℃微波搅拌3h，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物3.21g，收率：67.2％。Dissolve 5-bromo-4-fluoropyridin-2-amine (5.00g, 28.9mmol) in 10ml tetrahydropyrrole at room temperature, stir in microwave at 180°C for 3h, concentrate under reduced pressure, and use silica gel column chromatography to chromatograph the residue. Separate and purify using the method (mobile phase: DCM/MeOH=20:1) to obtain 3.21g of the title compound as a yellow solid, yield: 67.2%.
LC-MS：m/z＝165[M+H]+。LC-MS: m/z=165[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(吡咯烷-1-基)咪唑并[1,2-a]吡嗪(68b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyrazine Preparation of (68b)
于室温，将5-(吡咯烷-1-基)吡嗪-2-胺(68a)(2.00g，12.1mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(3.58g，12.1mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(2.12g，24.2mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物220mg，收率：5.03％。At room temperature, 5-(pyrrolidin-1-yl)pyrazin-2-amine (68a) (2.00g, 12.1mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyra Azol-4-yl)propan-2-one (58b) (3.58g, 12.1mmol) was dissolved in dioxane (20ml), sodium bicarbonate (2.12g, 24.2mmol) was added, stirred at room temperature overnight, and reduced Concentrate under pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 220 mg of the title compound as a yellow solid, yield: 5.03%.
LC-MS：m/z＝361[M+H]+。LC-MS: m/z=361[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(吡咯烷-1-基)咪唑并[1,2-a]吡嗪(68b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物68。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(pyrrolidin-1-yl)imidazo[1 ,2-a]pyrazine (68b) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-( Trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 68.
LC-MS：m/z＝511[M+H]+。LC-MS: m/z=511[M+H] + .
实施例69：(R)-3,15-二氟-5,14,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(69)的制备

Example 69: (R)-3,15-difluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazole And[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine ( 69) Preparation

步骤1：4-氟-5-甲基吡啶-2-胺(69a)的制备Step 1: Preparation of 4-fluoro-5-methylpyridin-2-amine (69a)
于室温，将5-溴-4-氟吡啶-2-胺(500mg，2.64mmol)、甲基硼酸(238mg，3.96mmol)、Pd(dppf)Cl2(193mg，0.264mmol)、碳酸铯(1.72g，5.28mmol)溶于20ml二氧六环/H2O(5:1)中，升至100℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物210mg，收率：63.4％。At room temperature, 5-bromo-4-fluoropyridin-2-amine (500mg, 2.64mmol), methylboronic acid (238mg, 3.96mmol), Pd(dppf)Cl 2 (193mg, 0.264mmol), cesium carbonate (1.72 g, 5.28 mmol) was dissolved in 20 ml dioxane/H 2 O (5:1), raised to 100°C and stirred overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM /MeOH=20:1), 210 mg of the title compound was obtained as a yellow solid, yield: 63.4%.
LC-MS：m/z＝127[M+H]+。LC-MS: m/z=127[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-氟-6-甲基咪唑并[1,2-a]吡啶(69b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-fluoro-6-methylimidazo[1,2-a]pyridine (69b) Preparation
于室温，将4-氟-5-甲基吡啶-2-胺(69a)(210mg，1.65mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(489mg，1.65mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(284mg，3.31mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物230mg，收率：42.9％。At room temperature, 4-fluoro-5-methylpyridin-2-amine (69a) (210 mg, 1.65 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazole-4- Propan-2-one (58b) (489 mg, 1.65 mmol) was dissolved in dioxane (20 ml), sodium bicarbonate (284 mg, 3.31 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was Separate and purify by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 230 mg of the title compound as a yellow solid, yield: 42.9%.
LC-MS：m/z＝323[M+H]+。LC-MS: m/z=323[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-氟-6-甲基咪唑并[1,2-a]吡啶(69b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物69。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-fluoro-6-methylimidazo[1,2 -a]pyridine (69b) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 yl)imidazo[1,2-a]pyridine (12b) to obtain compound 69.
LC-MS：m/z＝473[M+H]+。LC-MS: m/z=473[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.29(dd,J＝7.5,1.3Hz,1H),7.70(dd,J＝10.4,2.2Hz,2H),7.57(s,1H),7.38(d,J＝10.4Hz,1H),7.27-7.13(m,2H),6.32(d,J＝1.9Hz,1H),6.07(s,2H),5.33(dt,J＝6.8,3.5Hz,1H),3.82(s,3H),3.86-3.77(m,1H),3.10(d,J＝14.9Hz,1H),2.57-2.51(m,1H),2.20(d,J＝1.5Hz,3H),1.72(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.29 (dd, J＝7.5, 1.3Hz, 1H), 7.70 (dd, J＝10.4, 2.2Hz, 2H), 7.57 (s, 1H), 7.38 (d ,J＝10.4Hz,1H),7.27-7.13(m,2H),6.32(d,J＝1.9Hz,1H),6.07(s,2H),5.33(dt,J＝6.8,3.5Hz,1H) ,3.82(s,3H),3.86-3.77(m,1H),3.10(d,J＝14.9Hz,1H),2.57-2.51(m,1H),2.20(d,J＝1.5Hz,3H), 1.72(d,J=6.2Hz,3H).
实施例70：(R)-3,14,15-三氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(70)的制备
Example 70: (R)-3,14,15-trifluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazole And[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine ( 70) Preparation
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6,7-二氟咪唑并[1,2-a]吡嗪(70a)的制备Step 1: 2-((3-Bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6,7-difluoroimidazo[1,2-a]pyrazine (70a) preparation
于室温，将4,5-二氟吡嗪-2-胺(100mg，0.769mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(227mg，0.769mmol)溶于二氧六环(5ml)中，加入碳酸氢钠(163mg，1.54mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物60mg，收率：24.1％。At room temperature, 4,5-difluoropyrazin-2-amine (100 mg, 0.769 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan- 2-Keto (58b) (227 mg, 0.769 mmol) was dissolved in dioxane (5 ml), sodium bicarbonate (163 mg, 1.54 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Separate and purify by chromatography (mobile phase: DCM/MeOH=20:1) to obtain 60 mg of the title compound as a yellow solid, yield: 24.1%.
LC-MS：m/z＝327[M+H]+。LC-MS: m/z=327[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6,7-二氟咪唑并[1,2-a]吡嗪(70a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物70。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6,7-difluoroimidazo[1,2-a ]pyrazine (70a) instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 ) imidazo[1,2-a]pyridine (12b) to obtain compound 70.
LC-MS：m/z＝477[M+H]+。LC-MS: m/z=477[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.70(dd,J＝7.4,5.9Hz,1H),7.88–7.65(m,3H),7.56(s,1H),7.20(qd,J＝8.5,6.0Hz,2H),6.32(d,J＝1.8Hz,1H),6.12(s,2H),5.33(td,J＝6.6,4.6Hz,1H),3.83(s,4H),3.12(d,J＝15.0Hz,1H),1.82–1.63(m,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.70 (dd, J＝7.4, 5.9Hz, 1H), 7.88–7.65 (m, 3H), 7.56 (s, 1H), 7.20 (qd, J＝8.5 ,6.0Hz,2H),6.32(d,J＝1.8Hz,1H),6.12(s,2H),5.33(td,J＝6.6,4.6Hz,1H),3.83(s,4H),3.12(d ,J＝15.0Hz,1H),1.82–1.63(m,3H).
实施例71：3,15-二氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并吡唑并[4,3-j]吡啶并[2,1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(71)的制备
Example 71: 3,15-difluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzopyrazolo[4,3-j]pyridine Preparation of [2,1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (71)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-氟咪唑并[1,2-a]吡啶(71a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-fluoroimidazo[1,2-a]pyridine (71a)
于室温，向4-氟吡啶-2-胺(500mg，4.46mmol，1.00equiv)的1,4二氧六环(20.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.30g，4.46mmol，1.00equiv)和碳酸氢钠(1.12g，13.3mmol，2.00equiv)，于80℃搅拌过夜。反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物600mg，收率43.7％。To a solution of 4-fluoropyridin-2-amine (500 mg, 4.46 mmol, 1.00 equiv) in 1,4dioxane (20.0 mL) was added 1-bromo-3-(3-bromo-1-methyl) at room temperature. 1H-pyrazol-4-yl)propan-2-one (58b) (1.30g, 4.46mmol, 1.00equiv) and sodium bicarbonate (1.12g, 13.3mmol, 2.00equiv) were stirred at 80°C overnight. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 600 mg of the title compound as a light yellow oil, with a yield of 43.7%.
LC-MS：m/z 309.10[M+H]+。LC-MS: m/z 309.10[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-氟咪唑并[1,2-a]吡啶(71a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物71。Other steps are the same as Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-fluoroimidazo[1,2-a]pyridine ( 71a) Replace 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine (12b) gave compound 71.
LC-MS：m/z 459.05[M+H]+。LC-MS: m/z 459.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.39(dd,J＝7.6,5.8Hz,1H),7.74-7.66(m,2H),7.58(s,1H),7.42(dd,J＝10.0,2.7Hz,1H),7.20(qd,J＝8.5,5.9Hz,2H),6.89(td,J＝7.5,2.7Hz,1H),6.34(d,J＝1.9Hz,1H),6.09(s,2H),5.33(dd,J＝6.5,2.1Hz,1H),3.83(s,3H),3.13(d,J＝15.0Hz,1H),2.54(s,1H),1.72(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.39 (dd, J = 7.6, 5.8 Hz, 1H), 7.74-7.66 (m, 2H), 7.58 (s, 1H), 7.42 (dd, J = 10.0 ,2.7Hz,1H),7.20(qd,J＝8.5,5.9Hz,2H),6.89(td,J＝7.5,2.7Hz,1H),6.34(d,J＝1.9Hz,1H),6.09(s ,2H),5.33(dd,J＝6.5,2.1Hz,1H),3.83(s,3H),3.13(d,J＝15.0Hz,1H),2.54(s,1H),1.72(d,J＝ 6.2Hz,3H).
实施例72：(R)-3,15-二氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(72)的制备
Example 72: (R)-3,15-difluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrido[2 ',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecene Preparation of -8-amine (72)
步骤1：2-(二氯甲基)-7-氟-2,3-二氢咪唑并[1,2-a]吡啶-2-醇(72a)的制备Step 1: Preparation of 2-(dichloromethyl)-7-fluoro-2,3-dihydroimidazo[1,2-a]pyridin-2-ol (72a)
于0℃，向4-氟吡啶-2-胺(5.00g，44.6mmol，1.00equiv)的THF(50.0mL)溶液中加入1,1,3-三氯丙-2-酮(23.8g，89.2mmol，2.00equiv)，于室温搅拌过夜。将反应液直接过滤，收集滤饼，干燥，得到白色固体状的标题化合物10.0g，直接用于下一步，收率94.8％。To a solution of 4-fluoropyridin-2-amine (5.00g, 44.6mmol, 1.00equiv) in THF (50.0mL) at 0°C was added 1,1,3-trichloropropan-2-one (23.8g, 89.2 mmol, 2.00 equiv), stir at room temperature overnight. The reaction solution was directly filtered, and the filter cake was collected and dried to obtain 10.0 g of the title compound as a white solid, which was used directly in the next step with a yield of 94.8%.
LC-MS：m/z 237.05[M+H]+。LC-MS: m/z 237.05[M+H] + .
步骤2：2-(二氯甲基)-7-氟咪唑并[1,2-a]吡啶(72b)的制备Step 2: Preparation of 2-(dichloromethyl)-7-fluoroimidazo[1,2-a]pyridine (72b)
于室温，将2-(二氯甲基)-7-氟-2,3-二氢咪唑并[1,2-a]吡啶-2-醇(10.0g，42.3mmol，1.00equiv)溶于乙醇(150.0mL)中，于85℃搅拌1小时，将反应液直接浓缩，得到白色固体状的标题化合物8.0g粗品，直接用于下一步。Dissolve 2-(dichloromethyl)-7-fluoro-2,3-dihydroimidazo[1,2-a]pyridin-2-ol (10.0g, 42.3mmol, 1.00equiv) in ethanol at room temperature (150.0 mL), stirred at 85° C. for 1 hour, and concentrated the reaction solution directly to obtain 8.0 g of crude product of the title compound as a white solid, which was used directly in the next step.
LC-MS：m/z 219.05[M+H]+。LC-MS: m/z 219.05[M+H] + .
步骤3：7-氟咪唑并[1,2-a]吡啶-2-甲醛(72c)的制备Step 3: Preparation of 7-fluoroimidazo[1,2-a]pyridine-2-carboxaldehyde (72c)
于室温，向2-(二氯甲基)-7-氟咪唑并[1,2-a]吡啶(72b)(10.0g，45.8mmol，1.00equiv)的四氢呋喃(60.0mL)和水(60.0mL)溶液中加入碳酸钙(18.3g，183mmol，4.0 0equiv)。于80℃搅拌4小时，将反应液直接浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:10)，得到白色固体状的标题化合物5.2g。收率69.2％To 2-(dichloromethyl)-7-fluoroimidazo[1,2-a]pyridine (72b) (10.0 g, 45.8 mmol, 1.00 equiv) in tetrahydrofuran (60.0 mL) and water (60.0 mL) at room temperature ) solution was added calcium carbonate (18.3g, 183mmol, 4.00equiv). After stirring at 80° C. for 4 hours, the reaction solution was directly concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:10) to obtain 5.2 g of the title compound as a white solid. Yield 69.2%
LC-MS：m/z 165.05[M+H]+。LC-MS: m/z 165.05[M+H] + .
其他步骤与实施例12相同，除了用7-氟咪唑并[1,2-a]吡啶-2-甲醛(72c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物72，50mg。收率35.13％。Other steps are the same as in Example 12, except that 7-fluoroimidazo[1,2-a]pyridine-2-carboxaldehyde (72c) is used instead of 6-(trifluoromethyl)imidazo[1,2- a] Pyridine-2-carboxaldehyde to obtain compound 72, 50 mg. The yield is 35.13%.
LC-MS：m/z 460.10[M+H]+。LC-MS: m/z 460.10[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.36(dd,J＝7.6,5.8Hz,1H),7.78(dd,J＝10.4, 2.8Hz,1H),7.68(d,J＝1.8Hz,1H),7.42(dd,J＝10.0,2.6Hz,1H),7.31(dd,J＝8.5,5.8Hz,1H),7.22(td,J＝8.5,2.8Hz,1H),6.89(td,J＝7.6,2.7Hz,1H),6.12(d,J＝2.1Hz,3H),5.28(dt,J＝6.5,3.3Hz,1H),4.14(s,3H),4.04(d,J＝15.2Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.36 (dd, J = 7.6, 5.8 Hz, 1H), 7.78 (dd, J = 10.4, 2.8Hz,1H),7.68(d,J＝1.8Hz,1H),7.42(dd,J＝10.0,2.6Hz,1H),7.31(dd,J＝8.5,5.8Hz,1H),7.22(td, J＝8.5,2.8Hz,1H),6.89(td,J＝7.6,2.7Hz,1H),6.12(d,J＝2.1Hz,3H),5.28(dt,J＝6.5,3.3Hz,1H), 4.14 (s, 3H), 4.04 (d, J = 15.2Hz, 1H).
实施例73：(R)-8-氨基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-15-腈(73)的制备
Example 73: (R)-8-amino-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazolo [4,3j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene-15-nitrile (73) preparation
步骤1：2-(3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-7-腈(73a)的制备Step 1: Preparation of 2-(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile (73a)
于室温，将2-氨基-4-氰基吡啶(500mg，4.20mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.24g，4.20mmol)溶于二氧六环(5ml)中，加入碳酸氢钠(722mg，8.41mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物900mg，收率：68.2％。At room temperature, 2-amino-4-cyanopyridine (500 mg, 4.20 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (1.24g, 4.20mmol) was dissolved in dioxane (5ml), sodium bicarbonate (722mg, 8.41mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. After separation and purification (mobile phase: DCM/MeOH=20:1), 900 mg of the title compound was obtained as a yellow solid, yield: 68.2%.
LC-MS：m/z＝316[M+H]+。LC-MS: m/z=316[M+H] + .
其他步骤与实施例12相同，除了用2-(3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-7-腈(73a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物73。Other steps are the same as Example 12, except that 2-(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-7-carbonitrile (73a ) in step 3 instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyridine (12b) to obtain compound 73.
LC-MS：m/z＝466[M+H]+。LC-MS: m/z=466[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.50(dd,J＝7.2,1.0Hz,1H),8.33(dd,J＝1.7,0.9Hz,1H),7.76(d,J＝1.8Hz,1H),7.71(dd,J＝10.4,2.7Hz,1H),7.57(s,1H),7.28-7.15(m,2H),7.13(dd,J＝7.2,1.7Hz,1H),6.36(d,J＝1.9Hz,1H),6.21(s,2H),5.34(td,J＝6.7,4.6Hz,1H),3.95(d,J＝15.1Hz,1H),3.82(s,3H),3.20(d,J＝14.9Hz,1H),1.78-1.63(m,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.50 (dd, J＝7.2, 1.0Hz, 1H), 8.33 (dd, J＝1.7, 0.9Hz, 1H), 7.76 (d, J＝1.8Hz, 1H),7.71(dd,J＝10.4,2.7Hz,1H),7.57(s,1H),7.28-7.15(m,2H),7.13(dd,J＝7.2,1.7Hz,1H),6.36(d ,J＝1.9Hz,1H),6.21(s,2H),5.34(td,J＝6.7,4.6Hz,1H),3.95(d,J＝15.1Hz,1H),3.82(s,3H),3.20 (d,J＝14.9Hz,1H),1.78-1.63(m,3H).
实施例74：(R)-3-氟-5,20-二甲基-15-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(74)的制备
Example 74: (R)-3-fluoro-5,20-dimethyl-15-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo[ 1]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (74)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-(三氟甲基)咪唑并[1,2-a]吡啶(74a)的制备Step 1: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine (74a) Preparation
于室温，将2-氨基-6-(三氟甲基)吡啶(500mg，3.08mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(907mg，3.08mmol)溶于二氧六环(10ml)中，加入碳酸氢钠(504mg，6.16mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色油状标题化合物300mg，收率：27.2％。At room temperature, 2-amino-6-(trifluoromethyl)pyridine (500 mg, 3.08 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propane -2-one (58b) (907 mg, 3.08 mmol) was dissolved in dioxane (10 ml), sodium bicarbonate (504 mg, 6.16 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was subjected to silica gel column layer Separate and purify by chromatography (mobile phase: DCM/MeOH=20:1) to obtain 300 mg of the title compound as yellow oil, yield: 27.2%.
LC-MS：m/z＝359[M+H]+。LC-MS: m/z=359[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-(三氟甲基)咪唑并[1,2-a]吡啶(74a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物74。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-(trifluoromethyl)imidazo[1,2 -a]pyridine (74a) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 yl)imidazo[1,2-a]pyridine (12b) to obtain compound 74.
LC-MS：m/z＝509[M+H]+。LC-MS: m/z=509[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.55(d,J＝7.3Hz,1H),8.05(dd,J＝2.1,1.1Hz,1H),7.80-7.67(m,2H),7.56(s,1H),7.29-7.14(m,2H),7.09(dd,J＝7.3,2.0Hz,1H),6.36(d,J＝2.0Hz,1H),6.18(s,2H),5.34(d,J＝5.2Hz,1H),3.95(d,J＝15.0Hz,1H),3.82(s,3H),3.20(d,J＝15.0Hz,1H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.55 (d, J＝7.3Hz, 1H), 8.05 (dd, J＝2.1, 1.1Hz, 1H), 7.80-7.67 (m, 2H), 7.56 (s ,1H),7.29-7.14(m,2H),7.09(dd,J＝7.3,2.0Hz,1H),6.36(d,J＝2.0Hz,1H),6.18(s,2H),5.34(d, J＝5.2Hz,1H),3.95(d,J＝15.0Hz,1H),3.82(s,3H),3.20(d,J＝15.0Hz,1H),1.73(d,J＝6.2Hz,3H) .
实施例75：(R)-3-氟-5,20-二甲基-15-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳 烯-8-胺(75)的制备
Example 75: (R)-3-fluoro-5,20-dimethyl-15-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo[ 1]pyrido[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]nitrogen Heterocyclic 14-carbon Preparation of en-8-amine (75)
步骤1：2-(二氯甲基)-7-(三氟甲基)-2,3-二氢咪唑并[1,2-a]吡啶-2-醇(75a)的制备Step 1: Preparation of 2-(dichloromethyl)-7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyridin-2-ol (75a)
于室温，将2-氨基-6-(三氟甲基)吡啶(4.00g，24.6mmol)、1,1,3-三氯丙酮(9.90g，36.9mmol)溶于THF(100ml)，于室温搅拌过夜，过滤，滤饼烘干，得白色固体状标题化合物6.20g，收率，16.6％。Dissolve 2-amino-6-(trifluoromethyl)pyridine (4.00g, 24.6mmol) and 1,1,3-trichloroacetone (9.90g, 36.9mmol) in THF (100ml) at room temperature. Stir overnight, filter, and dry the filter cake to obtain 6.20 g of the title compound as a white solid, yield 16.6%.
LC-MS：m/z＝287[M+H]+。LC-MS: m/z=287[M+H] + .
步骤2：2-(二氯甲基)-7-(三氟甲基)咪唑并[1,2-a]吡啶(75b)的制备Step 2: Preparation of 2-(dichloromethyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine (75b)
于室温，将2-(二氯甲基)-7-(三氟甲基)-2,3-二氢咪唑并[1,2-a]吡啶-2-醇(6.20g，21.6mmol)溶于乙醇(100ml)中，于75℃搅拌4h，减压浓缩得白色固体标题化合物6.00g，收率：91.3％。Dissolve 2-(dichloromethyl)-7-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyridin-2-ol (6.20g, 21.6mmol) at room temperature. in ethanol (100 ml), stirred at 75°C for 4 h, and concentrated under reduced pressure to obtain 6.00 g of the title compound as a white solid, yield: 91.3%.
LC-MS：m/z＝269[M+H]+。LC-MS: m/z=269[M+H] + .
步骤3：7-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(75c)的制备Step 3: Preparation of 7-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (75c)
于室温，将2-(二氯甲基)-7-(三氟甲基)咪唑并[1,2-a]吡啶(6.00g，22.3mmol)、碳酸钙(6.70g，67.1mmol)溶于THF/H2O(1:1)(100ml)中，于70℃搅拌4h，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物3.5g，收率：49.6％。At room temperature, dissolve 2-(dichloromethyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine (6.00g, 22.3mmol) and calcium carbonate (6.70g, 67.1mmol) in THF/H 2 O (1:1) (100ml), stirred at 70°C for 4h, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1: 2), 3.5g of the title compound was obtained as a white solid, yield: 49.6%.
LC-MS：m/z＝215[M+H]+。LC-MS: m/z=215[M+H] + .
其他步骤与实施例12相同，除了用7-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛(75c)代替代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物75。 Other steps are the same as Example 12, except that 7-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxaldehyde (75c) is used instead of 6-(trifluoromethyl)imidazole in step 1. and [1,2-a]pyridine-2-carboxaldehyde to obtain compound 75.
LC-MS：m/z＝510[M+H]+。LC-MS: m/z=510[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝7.2Hz,1H),8.07(s,1H),7.83-7.71(m,2H),7.33(dd,J＝8.5,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),7.09(dd,J＝7.3,1.9Hz,1H),6.21(s,2H),6.15(d,J＝1.8Hz,1H),5.29(dd,J＝6.3,2.1Hz,1H),4.15(d,J＝11.7Hz,4H),3.48(d,J＝15.2Hz,2H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.52 (d, J＝7.2Hz, 1H), 8.07 (s, 1H), 7.83-7.71 (m, 2H), 7.33 (dd, J＝8.5, 5.8Hz ,1H),7.24(td,J＝8.4,2.7Hz,1H),7.09(dd,J＝7.3,1.9Hz,1H),6.21(s,2H),6.15(d,J＝1.8Hz,1H) ,5.29(dd,J＝6.3,2.1Hz,1H),4.15(d,J＝11.7Hz,4H),3.48(d,J＝15.2Hz,2H),1.74(d,J＝6.2Hz,3H) .
实施例76：(R)-3-氟-14-异丁基-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(76)的制备
Example 76: (R)-3-fluoro-14-isobutyl-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyridine Azino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene-8- Preparation of amine (76)
步骤1：5-异丁基吡嗪-2-胺(76a)的制备Step 1: Preparation of 5-isobutylpyrazin-2-amine (76a)
于0℃，将氯化锌溶液(45ml，1M)缓慢滴入异丁基溴化镁溶液(75ml，1M)中，于室温搅拌75分钟，加入到2-氨基-5-溴吡嗪(5.00g，28.9mmol)、1,3-双(二苯基膦丙烷)二氯化镍(1.56g，2.89mmol)的二氧六环(10ml)溶液中，加入碳酸氢钠(514mg，6.12mmol)，于48℃搅拌15min，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1)，得棕色油状体标题化合物2.3g，收率：52.3％。At 0°C, slowly drop zinc chloride solution (45ml, 1M) into isobutylmagnesium bromide solution (75ml, 1M), stir at room temperature for 75 minutes, and add 2-amino-5-bromopyrazine (5.00 g, 28.9mmol), 1,3-bis(diphenylphosphinepropane)nickel dichloride (1.56g, 2.89mmol) in dioxane (10ml), add sodium bicarbonate (514mg, 6.12mmol) , stirred at 48°C for 15 min, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1) to obtain 2.3 g of the title compound as a brown oil, yield: 52.3%.
LC-MS：m/z＝152[M+H]+。LC-MS: m/z=152[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-异丁基咪唑并[1,2-a]吡嗪(76b)的制备Step 2: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-isobutylimidazo[1,2-a]pyrazine (76b)
于室温，将5-异丁基吡嗪-2-胺(500mg，3.28mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(967mg，3.28mmol)溶于二氧六环(10ml)中，加入碳酸氢钠(551mg，6.56mmol)，于80℃搅拌过夜，减压浓缩，残余物用硅胶柱 层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物230mg，收率：20.1％。At room temperature, 5-isobutylpyrazin-2-amine (500 mg, 3.28 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2 - Ketone (58b) (967 mg, 3.28 mmol) was dissolved in dioxane (10 ml), sodium bicarbonate (551 mg, 6.56 mmol) was added, stirred at 80°C overnight, concentrated under reduced pressure, and the residue was purified with a silica gel column Separate and purify by chromatography (mobile phase: DCM/MeOH=20:1) to obtain 230 mg of the title compound as a brown solid, yield: 20.1%.
LC-MS：m/z＝348[M+H]+。LC-MS: m/z=348[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-异丁基咪唑并[1,2-a]吡嗪(76b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物76。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-isobutylimidazo[1,2-a] Pyrazine (76b) replaced 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 Imidazo[1,2-a]pyridine (12b) gave compound 76.
LC-MS：m/z＝498[M+H]+。LC-MS: m/z=498[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.97(d,J＝1.4Hz,1H),8.22–8.14(m,1H),7.77–7.66(m,2H),7.59(s,1H),7.29–7.14(m,2H),6.36(d,J＝1.9Hz,1H),6.18(s,2H),5.33(dd,J＝6.6,2.1Hz,1H),3.94(d,J＝15.1Hz,1H),3.82(s,3H),3.21(d,J＝15.0Hz,2H),2.62–2.51(m,7H),2.04(hept,J＝6.7Hz,1H),1.73(d,J＝6.3Hz,3H),0.86(dd,J＝27.6,6.6Hz,6H)。 1 H NMR (400MHz, DMSO-d6) δ8.97 (d, J＝1.4Hz, 1H), 8.22–8.14 (m, 1H), 7.77–7.66 (m, 2H), 7.59 (s, 1H), 7.29 –7.14(m,2H),6.36(d,J＝1.9Hz,1H),6.18(s,2H),5.33(dd,J＝6.6,2.1Hz,1H),3.94(d,J＝15.1Hz, 1H),3.82(s,3H),3.21(d,J＝15.0Hz,2H),2.62–2.51(m,7H),2.04(hept,J＝6.7Hz,1H),1.73(d,J＝6.3 Hz, 3H), 0.86 (dd, J = 27.6, 6.6Hz, 6H).
实施例77：(R)-3-氟-14-异丁基-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡嗪并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-8-胺(77)的制备
Example 77: (R)-3-fluoro-14-isobutyl-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyridine Azino[2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azeterocycle Preparation of tetradecene-8-amine (77)
步骤1：2-(二氯甲基)-6-异丁基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(77a)的制备Step 1: Preparation of 2-(dichloromethyl)-6-isobutyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (77a)
于室温，将5-异丁基吡嗪-2-胺(2.00g，13.1mmol)、1,1,3-三氯丙酮(5.28g，19.7mmol)溶于THF(50ml)，于室温搅拌过夜，过滤，滤饼烘干，得白色固体状标题化合物600mg，收率，16.6％。Dissolve 5-isobutylpyrazin-2-amine (2.00g, 13.1mmol) and 1,1,3-trichloroacetone (5.28g, 19.7mmol) in THF (50ml) at room temperature, and stir at room temperature overnight. , filtered, and the filter cake was dried to obtain 600 mg of the title compound as a white solid, yield 16.6%.
LC-MS：m/z＝276[M+H]+。LC-MS: m/z=276[M+H] + .
步骤2：2-(二氯甲基)-6-异丁基咪唑并[1,2-a]吡嗪(77b)的制备Step 2: Preparation of 2-(dichloromethyl)-6-isobutylimidazo[1,2-a]pyrazine (77b)
于室温，将2-(二氯甲基)-6-异丁基-2,3-二氢咪唑并[1,2-a]吡嗪-2-醇(600mg，2.18mmol)溶于乙醇(10ml)中，于75℃搅拌4h，减压浓缩得白色固体标题化合物510mg，收率，91.3％。 Dissolve 2-(dichloromethyl)-6-isobutyl-2,3-dihydroimidazo[1,2-a]pyrazin-2-ol (600 mg, 2.18 mmol) in ethanol ( 10 ml), stirred at 75°C for 4 h, and concentrated under reduced pressure to obtain 510 mg of the title compound as a white solid, yield 91.3%.
LC-MS：m/z＝257[M+H]+。LC-MS: m/z=257[M+H] + .
步骤3：6-异丁基咪唑并[1,2-a]吡嗪-2-甲醛(77c)的制备Step 3: Preparation of 6-isobutylimidazo[1,2-a]pyrazine-2-carbaldehyde (77c)
于室温，将2-(二氯甲基)-6-异丁基咪唑并[1,2-a]吡嗪(510mg，1.99mmol)、碳酸钙(597mg，5.97mmol)溶于THF/H2O(1:1)(100ml)中，于70℃搅拌4h，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝1:1-1:2)，得白色固体标题化合物200mg，收率，49.6％。Dissolve 2-(dichloromethyl)-6-isobutylimidazo[1,2-a]pyrazine (510 mg, 1.99 mmol) and calcium carbonate (597 mg, 5.97 mmol) in THF/H 2 at room temperature. O(1:1) (100ml), stirred at 70°C for 4h, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=1:1-1:2), to obtain The title compound was a white solid, 200 mg, yield, 49.6%.
LC-MS：m/z＝204[M+H]+。LC-MS: m/z=204[M+H] + .
其他步骤与实施例12相同，除了用6-异丁基咪唑并[1,2-a]吡嗪-2-甲醛(77c)代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物77。Other steps are the same as Example 12, except that 6-isobutylimidazo[1,2-a]pyrazine-2-carboxaldehyde (77c) is used instead of 6-(trifluoromethyl)imidazo[1] in step 1. ,2-a]pyridine-2-carboxaldehyde to obtain compound 77.
LC-MS：m/z＝499[M+H]+。LC-MS: m/z=499[M+H] + .
实施例78：(R)-3-氟-14-(甲氧基甲基)-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(78)的制备
Example 78: (R)-3-fluoro-14-(methoxymethyl)-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo [l]Pyrazino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azonacyclic fourteen carbon Preparation of en-8-amine (78)
步骤1：(5-(溴甲基)吡嗪-2-基)氨基甲酸叔丁酯(78a)的制备Step 1 Preparation of: (5-(bromomethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (78a)
于室温，向(5-甲基吡嗪-2-基)氨基甲酸叔丁酯(23.0g，110mmol，1.00equiv)的四氯化碳(350.0mL)溶液中加入NBS(19.6g，110mmol，1.00equiv)和AIBN(5.4g，33.0mmol，0.300equiv)，于80℃搅拌过夜。反应混合物用水稀释。用二氯甲烷萃取(3X150毫升)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5:1)，得到黄色固体状的标题化合物25g，收率79.2％To a solution of tert-butyl (5-methylpyrazin-2-yl)carbamate (23.0g, 110mmol, 1.00equiv) in carbon tetrachloride (350.0mL) at room temperature was added NBS (19.6g, 110mmol, 1.00 equiv) and AIBN (5.4g, 33.0mmol, 0.300equiv), stirred at 80°C overnight. The reaction mixture was diluted with water. Extract with dichloromethane (3X150 ml). The organic phases were combined and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 5:1) to obtain 25 g of the title compound as a yellow solid, with a yield of 79.2%.
LC-MS：m/z 288.10[M+H]+。LC-MS: m/z 288.10[M+H] + .
步骤2：(5-(甲氧基甲基)吡嗪-2-基)氨基甲酸叔丁酯(78b)的制备Step 2 Preparation of: (5-(methoxymethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (78b)
于室温，向(5-(溴甲基)吡嗪-2-基)氨基甲酸叔丁酯(2.00g，6.96mmol，1.00 equiv)的无水甲醇(20.0mL)溶液中加入碳酸钾(1.44g，10.4mmol，1.50equiv)，于室温搅拌2小时。反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5:1)，得到淡黄色油状的标题化合物500mg，收率30.15％。To (5-(bromomethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (2.00g, 6.96mmol, 1.00 equiv) in anhydrous methanol (20.0 mL), add potassium carbonate (1.44g, 10.4 mmol, 1.50 equiv), and stir at room temperature for 2 hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 5:1) to obtain 500 mg of the title compound as a light yellow oil, with a yield of 30.15%.
LC-MS：m/z 340.10[M+H]+。LC-MS: m/z 340.10[M+H] + .
步骤3：5-(甲氧基甲基)吡嗪-2-胺(78c)的制备Step 3: Preparation of 5-(methoxymethyl)pyrazin-2-amine (78c)
于室温，向(5-(甲氧基甲基)吡嗪-2-基)氨基甲酸叔丁酯(500mg，2.09mmol，1.00equiv)的二氯甲烷(5.0mL)溶液中加入三氟乙酸(1.0mL)，于室温搅拌3小时。反应液浓缩，加入碳酸氢钠调节至碱性，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物250mg，收率86.1％。To a solution of (5-(methoxymethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (500 mg, 2.09 mmol, 1.00 equiv) in dichloromethane (5.0 mL) at room temperature was added trifluoroacetic acid ( 1.0 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated, and sodium bicarbonate was added to adjust to alkalinity. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 250 mg of the title compound as a light yellow oil, yield 86.1%.
LC-MS：m/z 140.10[M+H]+。LC-MS: m/z 140.10[M+H] + .
步骤4：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(甲氧基甲基)咪唑并[1,2-a]吡啶(78d)的制备Step 4: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(methoxymethyl)imidazo[1,2-a]pyridine (78d ) preparation
于室温，向5-(甲氧基甲基)吡嗪-2-胺(78c)(300mg，2.15mmol，1.00equiv)的1,4二氧六环(20.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(634mg，2.15mmol，1.00equiv)和碳酸氢钠(543mg，6.47mmol，3.00equiv)，于80℃搅拌过夜。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物400mg，收率55.5％。To a solution of 5-(methoxymethyl)pyrazin-2-amine (78c) (300 mg, 2.15 mmol, 1.00 equiv) in 1,4 dioxane (20.0 mL) at room temperature was added 1-bromo- 3-(3-Bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (634 mg, 2.15 mmol, 1.00 equiv) and sodium bicarbonate (543 mg, 6.47 mmol, 3.00 equiv ), stir at 80°C overnight. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 400 mg of the title compound as a light yellow oil, with a yield of 55.5%.
LC-MS：m/z 336.10[M+H]+。LC-MS: m/z 336.10[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(甲氧基甲基)咪唑并[1,2-a]吡啶(78d)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物78。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(methoxymethyl)imidazo[1, 2-a]pyridine (78d) replaced 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoro Methyl)imidazo[1,2-a]pyridine (12b) gave compound 78.
LC-MS：m/z 486.05[M+H]+。LC-MS: m/z 486.05[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.01(d,J＝1.4Hz,1H),8.31(d,J＝1.4Hz,1H),7.79–7.66(m,2H),7.59(s,1H),7.29–7.15(m,2H),6.36(d,J＝1.9Hz,1H),6.21(s,2H),5.34(dt,J＝6.4,3.2Hz,1H),4.48(d,J＝2.8Hz,2H),3.97(d,J＝15.1Hz,1H),3.82(s,3H),3.32(s,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.01(d,J＝1.4Hz,1H),8.31(d,J＝1.4Hz,1H),7.79–7.66(m,2H),7.59(s,1H ),7.29–7.15(m,2H),6.36(d,J＝1.9Hz,1H),6.21(s,2H),5.34(dt,J＝6.4,3.2Hz,1H),4.48(d,J＝ 2.8Hz, 2H), 3.97 (d, J = 15.1Hz, 1H), 3.82 (s, 3H), 3.32 (s, 3H), 1.73 (d, J = 6.2Hz, 3H).
实施例79：(R)-3-氟-5,20-二甲基-14-((甲氨基)甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(79)的制备

Example 79: (R)-3-fluoro-5,20-dimethyl-14-((methylamino)methyl)-18,20-dihydro-5H-7,11-(methylene)benzene And[l]pyrazino[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetrade Preparation of carbene-8-amine (79)

步骤1：(5-((苄基(甲基)氨基)甲基)吡嗪-2-基)氨基甲酸叔丁酯(79a)的制备Step 1 Preparation of: (5-((benzyl(methyl)amino)methyl)pyrazin-2-yl)carbamic acid tert-butyl ester (79a)
于室温，向(5-(溴甲基)吡嗪-2-基)氨基甲酸叔丁酯(5.00g，17.4mmol，1.00equiv)的无水四氢呋喃(50.0mL)溶液中加入N-甲基-1-苯基甲胺(4.21g，34.8mmol，2.00equiv)，于室温搅拌2小时。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5:1)，得到淡黄色油状的标题化合物3.80g，收率66.6％。To a solution of (5-(bromomethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (5.00 g, 17.4 mmol, 1.00 equiv) in anhydrous tetrahydrofuran (50.0 mL) at room temperature was added N-methyl- 1-Phenylmethylamine (4.21g, 34.8mmol, 2.00equiv), stirred at room temperature for 2 hours. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 5:1) to obtain 3.80 g of the title compound as a light yellow oil, with a yield of 66.6%.
LC-MS：m/z 329.10[M+H]+。LC-MS: m/z 329.10[M+H] + .
步骤2：5-((苄基(甲基)氨基)甲基)吡嗪-2-胺(79b)的制备Step 2: Preparation of 5-((benzyl(methyl)amino)methyl)pyrazin-2-amine (79b)
于室温，向(5-((苄基(甲基)氨基)甲基)吡嗪-2-基)氨基甲酸叔丁酯(3.50g，10.7mmol，1.00equiv)的二氯甲烷(35.0mL)溶液中加入三氟乙酸(7.0mL)，于室温搅拌3小时。反应液浓缩，加入碳酸氢钠调节至碱性，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物2.1g，收率86.3％。To (tert-butyl 5-((benzyl(methyl)amino)methyl)pyrazin-2-yl)carbamate (3.50 g, 10.7 mmol, 1.00 equiv) was dissolved in dichloromethane (35.0 mL) at room temperature. Trifluoroacetic acid (7.0 mL) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and sodium bicarbonate was added to adjust to alkalinity. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 2.1 g of the title compound as a light yellow oil, which was collected. The rate is 86.3%.
LC-MS：m/z 229.10[M+H]+。LC-MS: m/z 229.10[M+H] + .
步骤3：N-苄基-1-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡嗪-6-基)-N-甲基甲胺(79c)的制备Step 3: N-benzyl-1-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyrazine-6- Preparation of (79c)-N-methylmethylamine (79c)
于室温，向5-((苄基(甲基)氨基)甲基)吡嗪-2-胺(500mg，2.19mmol，1.00equiv)的1,4二氧六环(20.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(644mg，2.19mmol，1.00equiv)和碳酸氢钠(552mg，6.57mmol，3.00equiv)，于80℃搅拌过夜。反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物270mg，收率29.1％。To a solution of 5-((benzyl(methyl)amino)methyl)pyrazin-2-amine (500 mg, 2.19 mmol, 1.00 equiv) in 1,4 dioxane (20.0 mL) at room temperature was added 1 -Bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (644 mg, 2.19 mmol, 1.00 equiv) and sodium bicarbonate (552 mg, 6.57 mmol , 3.00 equiv), stir at 80°C overnight. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 270 mg of the title compound as a light yellow oil, with a yield of 29.1%.
LC-MS：m/z 425.10[M+H]+。LC-MS: m/z 425.10[M+H] + .
其他步骤与实施例12相同，除了用N-苄基-1-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡嗪-6-基)-N-甲基甲胺(79c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物79g。Other steps are the same as in Example 12, except that N-benzyl-1-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2- a]pyrazin-6-yl)-N-methylmethylamine (79c) instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazole-4-) in step 3 (methyl)methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (12b) to obtain 79 g of compound.
LC-MS:m/z 575.05[M+H]+。LC-MS: m/z 575.05[M+H] + .
步骤4：(R)-3-氟-5,20-二甲基-14-((甲氨基)甲基)-18,20-二氢-5H-7,11-(甲酰基) 苯并[l]吡嗪并[2',1':2,3]咪唑并[4,5-g]吡唑[4,3-j][1]氧杂[4]氮杂环十四烷-8-胺(79)的制备Step 4: (R)-3-fluoro-5,20-dimethyl-14-((methylamino)methyl)-18,20-dihydro-5H-7,11-(formyl) Benzo[l]pyrazino[2',1':2,3]imidazo[4,5-g]pyrazole[4,3-j][1]oxa[4]azacyclotetradine Preparation of alkane-8-amine (79)
于室温，向化合物79g(900mg，0.15mmol，1.00equiv)的甲醇(5.0mL)溶液中加入钯碳(30mg，10％)。于氢气氛围下，室温搅拌过夜，过滤，收集滤液，浓缩滤液。得到粗品。粗品通过高效液相色谱法纯化(色谱柱型号：XBridge Prep OBD C18 Column，30*150mm，5μm；流动相A：水(10mmol/L碳酸氢铵+0.1％氨水)，流动相B：乙腈；流速：60mL/min；梯度：47％B to 74％B in 8min)得到白色固体状的标题化合物3.3mg，收率4.37％。To a solution of compound 79g (900 mg, 0.15 mmol, 1.00 equiv) in methanol (5.0 mL) was added palladium on carbon (30 mg, 10%) at room temperature. Stir at room temperature overnight under a hydrogen atmosphere, filter, collect the filtrate, and concentrate the filtrate. Get crude product. The crude product was purified by high performance liquid chromatography (column model: : 60mL/min; gradient: 47%B to 74%B in 8min) to obtain 3.3mg of the title compound as a white solid, with a yield of 4.37%.
LC-MS：m/z 485.05[M+H]+。LC-MS: m/z 485.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.00(d,J＝1.4Hz,1H),8.09(d,J＝1.6Hz,1H),7.83–7.73(m,2H),7.33(dd,J＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.21(s,2H),6.11(d,J＝2.0Hz,1H),5.27(tt,J＝6.7,3.3Hz,1H),4.19–4.10(m,4H),3.49(d,J＝15.2Hz,1H),3.01(h,J＝6.8Hz,1H),1.74(d,J＝6.2Hz,3H),1.22(dd,J＝13.5,6.8Hz,6H)。 1 H NMR (400MHz, DMSO-d6) δ9.00(d,J＝1.4Hz,1H),8.09(d,J＝1.6Hz,1H),7.83–7.73(m,2H),7.33(dd,J ＝8.6,5.8Hz,1H),7.24(td,J＝8.4,2.7Hz,1H),6.21(s,2H),6.11(d,J＝2.0Hz,1H),5.27(tt,J＝6.7, 3.3Hz,1H),4.19–4.10(m,4H),3.49(d,J＝15.2Hz,1H),3.01(h,J＝6.8Hz,1H),1.74(d,J＝6.2Hz,3H) ,1.22(dd,J=13.5,6.8Hz,6H).
实施例80：(R)-14-(环丙基甲基)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(80)的制备
Example 80: (R)-14-(cyclopropylmethyl)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo [l]pyrazine[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene -Preparation of 8-amine (80)
步骤1：(5-氨基吡嗪-2-基)(环丙基)甲醇(80a)的制备Step 1 Preparation of: (5-aminopyrazin-2-yl)(cyclopropyl)methanol (80a)
于室温，将5-溴吡嗪-2-胺(500mg，2.89mmol)溶于四氢呋喃(10mL)中，将反应体系温度降低至-78℃，缓慢滴加正丁基锂(3.46mL，2.50M，8.67mol)， 于-78℃搅拌30min，缓慢滴加环丙基甲醛(708mg，10.1mol)，缓慢升至室温继续反应1h，冰水淬灭，EA萃取，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝10:1)，得黄色油状标题化合物210mg，收率：43.8％。Dissolve 5-bromopyrazin-2-amine (500mg, 2.89mmol) in tetrahydrofuran (10mL) at room temperature, reduce the temperature of the reaction system to -78°C, and slowly add n-butyllithium (3.46mL, 2.50M ,8.67mol), Stir at -78°C for 30 minutes, slowly add cyclopropylcarbaldehyde (708 mg, 10.1 mol) dropwise, slowly rise to room temperature and continue the reaction for 1 hour, quench with ice water, extract with EA, and concentrate under reduced pressure. The residue is subjected to silica gel column chromatography. After separation and purification (mobile phase: DCM/MeOH=10:1), 210 mg of the title compound was obtained as yellow oil, yield: 43.8%.
LC-MS：m/z＝166[M+H]+。LC-MS: m/z=166[M+H] + .
步骤2：5-(环丙基甲基)吡嗪-2-胺(80b)的制备Step 2: Preparation of 5-(cyclopropylmethyl)pyrazin-2-amine (80b)
于室温，向(5-氨基吡嗪-2-基)(环丙基)甲醇(80a)(210mg，1.27mmol)的二氯甲烷(2.0mL)溶液中加入三氟乙酸(1.00mL)和三乙基硅烷(1.00mL)，于室温搅拌16小时。反应液浓缩。加入碳酸氢钠调至碱性，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物150mg，收率79.3％。To a solution of (5-aminopyrazin-2-yl)(cyclopropyl)methanol (80a) (210 mg, 1.27 mmol) in dichloromethane (2.0 mL) at room temperature was added trifluoroacetic acid (1.00 mL) and trifluoroacetic acid (1.00 mL). Ethylsilane (1.00 mL), stirred at room temperature for 16 hours. The reaction solution was concentrated. Sodium bicarbonate was added to make it alkaline, and the residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 150 mg of the title compound as a light yellow oil, with a yield of 79.3%.
LC-MS：m/z＝150.10[M+H]+。LC-MS: m/z=150.10[M+H] + .
步骤3：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(环丙基甲基)咪唑并[1,2-a]吡嗪(80c)的制备Step 3: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(cyclopropylmethyl)imidazo[1,2-a]pyrazine ( Preparation of 80c)
于室温，将5-(环丙基甲基)吡嗪-2-胺(150mg，1.00mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(297mg，1.00mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(168mg，2.00mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物260mg，收率：75.3％。At room temperature, 5-(cyclopropylmethyl)pyrazin-2-amine (150 mg, 1.00 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl) ) Propan-2-one (58b) (297 mg, 1.00 mmol) was dissolved in dioxane (20 ml), sodium bicarbonate (168 mg, 2.00 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was washed with silica gel Separate and purify by column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 260 mg of the title compound as a yellow solid, yield: 75.3%.
LC-MS：m/z＝346[M+H]+。LC-MS: m/z=346[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(环丙基甲基)咪唑并[1,2-a]吡嗪(80c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物80。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(cyclopropylmethyl)imidazo[1, 2-a]pyrazine (80c) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(tris Fluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 80.
LC-MS:m/z＝496[M+H]+。LC-MS: m/z=496[M+H] + .
实施例81：(R)-8-氨基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡啶并[2',1':2,3]咪唑并[4,5-g][1,2,3]三唑并[4,5-j][1]氧杂[4]氮杂环十四碳烯-14-腈(81)的制备

Example 81: (R)-8-amino-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrido[ 2',1':2,3]imidazo[4,5-g][1,2,3]triazolo[4,5-j][1]oxa[4]azonacyclic fourteen carbon Preparation of ene-14-nitrile (81)

步骤1:2-(3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-腈(81a)的制备Step 1: Preparation of 2-(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carbonitrile (81a)
于室温，将6-氨基烟腈(500mg，4.20mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.24g，4.20mmol)溶于二氧六环(5ml)中，加入碳酸氢钠(722mg，8.41mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物300mg，收率：22.7％。At room temperature, 6-aminonicotinonitrile (500 mg, 4.20 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) ( 1.24g, 4.20mmol) was dissolved in dioxane (5ml), sodium bicarbonate (722mg, 8.41mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile Phase: DCM/MeOH=20:1), 300 mg of the title compound was obtained as a yellow solid, yield: 22.7%.
LC-MS:m/z＝316[M+H]+。LC-MS: m/z=316[M+H] + .
其他步骤与实施例12相同，除了用2-(3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-腈(81a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物81。Other steps are the same as Example 12, except that 2-(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carbonitrile (81a ) in step 3 instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyridine (12b) to obtain compound 81.
LC-MS：m/z＝466[M+H]+。LC-MS: m/z=466[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.82(s,1H),7.76–7.67(m,2H),7.58(s,1H),7.46(dd,J＝9.3,1.5Hz,1H),7.21(qd,J＝8.5,6.0Hz,2H),6.34(d,J＝1.7Hz,2H),6.14(d,J＝27.6Hz,2H),5.39–5.31(m,1H),3.91(d,J＝15.0Hz,1H),3.82(s,3H),3.18(d,J＝14.9Hz,1H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.04 (s, 1H), 7.82 (s, 1H), 7.76–7.67 (m, 2H), 7.58 (s, 1H), 7.46 (dd, J = 9.3 ,1.5Hz,1H),7.21(qd,J＝8.5,6.0Hz,2H),6.34(d,J＝1.7Hz,2H),6.14(d,J＝27.6Hz,2H),5.39–5.31(m ,1H),3.91(d,J＝15.0Hz,1H),3.82(s,3H),3.18(d,J＝14.9Hz,1H),1.73(d,J＝6.2Hz,3H).
实施例82：(R)-3-氟-14-甲氧基-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]哒嗪并[6',1'：2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(82)的制备

Example 82: (R)-3-fluoro-14-methoxy-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyridine Azolo[4,3-j]pyridazino[6',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene-8- Preparation of amine (82)

步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-甲氧基咪唑并[1,2-b]哒嗪(82a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-methoxyimidazo[1,2-b]pyridazine (82a)
于室温，将3-氨基-6-甲氧基哒嗪(500mg，4.00mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(1.17g，4.00mmol)溶于二氧六环(10ml)中，加入碳酸氢钠(672mg，8.00mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物700mg，收率：54.6％。At room temperature, 3-amino-6-methoxypyridazine (500 mg, 4.00 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2 - Dissolve ketone (1.17g, 4.00mmol) in dioxane (10ml), add sodium bicarbonate (672mg, 8.00mmol), stir at room temperature overnight, concentrate under reduced pressure, and use silica gel column chromatography to separate the residue. After purification (mobile phase: DCM/MeOH=20:1), 700 mg of the title compound was obtained as a brown solid, yield: 54.6%.
LC-MS：m/z＝322[M+H]+。LC-MS: m/z=322[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-甲氧基咪唑并[1,2-b]哒嗪(82a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物82。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-methoxyimidazo[1,2-b] Pyridazine (82a) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 Imidazo[1,2-a]pyridine (12b) gave compound 82.
LC-MS：m/z＝472[M+H]+。LC-MS: m/z=472[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.11(d,J＝1.7Hz,1H),7.98(d,J＝9.6Hz,1H),7.65(dd,J＝10.3,2.7Hz,1H),7.60(s,1H),7.31–7.16(m,2H),6.83(d,J＝9.6Hz,1H),6.46(d,J＝1.9Hz,1H),5.98(s,2H),5.22(s,1H),3.95–3.77(m,7H),3.20(d,J＝15.1Hz,1H),1.72(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J＝1.7Hz,1H),7.98(d,J＝9.6Hz,1H),7.65(dd,J＝10.3,2.7Hz,1H), 7.60(s,1H),7.31–7.16(m,2H),6.83(d,J＝9.6Hz,1H),6.46(d,J＝1.9Hz,1H),5.98(s,2H),5.22(s ,1H),3.95–3.77(m,7H),3.20(d,J＝15.1Hz,1H),1.72(d,J＝6.2Hz,3H).
实施例83：(R)-3-氟-5,20-二甲基-14-(甲磺酰基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]哒嗪并[6',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(83)的制备

Example 83: (R)-3-fluoro-5,20-dimethyl-14-(methanesulfonyl)-18,20-dihydro-5H-7,11-(methylene)benzo[l ]pyrazolo[4,3-j]pyridazino[6',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (83)

步骤1：6-(甲磺酰基)咪唑并[1,2-b]哒嗪-2-羧酸甲酯(83a)的制备Step 1: Preparation of 6-(methanesulfonyl)imidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (83a)
于室温，向6-氯咪唑并[1,2-b]哒嗪-2-羧酸甲酯(1.50g，7.10mmol，1.00equiv)的DMSO(10.00mL)溶液中加入甲烷亚磺酸钠(805mg，7.81mmol，1.10equiv)和碘化亚铜(278mg，1.42mmol，0.200equiv)。于氮气氛围下，140℃搅拌2h。加水淬灭，EA萃取，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物800mg，收率44.18％。To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (1.50 g, 7.10 mmol, 1.00 equiv) in DMSO (10.00 mL) at room temperature was added sodium methane sulfinate ( 805 mg, 7.81 mmol, 1.10 equiv) and copper iodide (278 mg, 1.42 mmol, 0.200 equiv). Stir at 140°C for 2 hours under nitrogen atmosphere. Add water to quench, extract with EA, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 800 mg of the title compound as a white solid, with a yield of 44.18%.
LC-MS：m/z 256.05[M+H]+。LC-MS: m/z 256.05[M+H] + .
步骤2：6-(甲磺酰基)咪唑并[1,2-b]哒嗪-2-甲醛(83b)的制备Step 2: Preparation of 6-(methanesulfonyl)imidazo[1,2-b]pyridazine-2-carboxaldehyde (83b)
氮气氛围下，于-78℃向6-(甲磺酰基)咪唑并[1,2-b]哒嗪-2-羧酸甲酯(800mg，3.13mmol，1.00equiv)的二氯甲烷(20.0mL)溶液中加入二异丁基氢化铝(6.27mL，6.27mmol，2.00equiv)，继续搅拌1.5小时。缓慢加入甲醇淬灭，加入1M盐酸调节PH～7，反应混合物用二氯甲烷萃取(3X50毫升)。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物380mg。收率53.9％Under nitrogen atmosphere, add 6-(methanesulfonyl)imidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (800 mg, 3.13 mmol, 1.00 equiv) in dichloromethane (20.0 mL) at -78°C. ) solution, add diisobutylaluminum hydride (6.27mL, 6.27mmol, 2.00equiv), and continue stirring for 1.5 hours. Methanol was slowly added to quench, 1M hydrochloric acid was added to adjust the pH to ~7, and the reaction mixture was extracted with dichloromethane (3X50 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 380 mg of the title compound as a white solid. Yield 53.9%
LC-MS：m/z 226.05[M+H]+。LC-MS: m/z 226.05[M+H] + .
其他步骤与实施例14的制备方法相同，除了用6-(甲磺酰基)咪唑并[1,2-b]哒嗪-2-甲醛(83b)代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物83。Other steps are the same as the preparation method of Example 14, except that 6-(methanesulfonyl)imidazo[1,2-b]pyridazine-2-carboxaldehyde (83b) is used instead of 6-(trifluoromethyl) in step 2. )imidazo[1,2-a]pyridine-2-carboxaldehyde to prepare compound 83.
LC-MS：m/z 520[M+H]+。LC-MS: m/z 520[M+H] + .
实施例84：(R)-3-氟-5,20-二甲基-14-(三氟甲基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡嗪[2',1':2,3]咪唑并[4,5-g]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(84)的制备
Example 84: (R)-3-fluoro-5,20-dimethyl-14-(trifluoromethyl)-18,20-dihydro-5H-7,11-(methylene)benzo[ l]pyrazine[2',1':2,3]imidazo[4,5-g]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (84)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡嗪(84a)的制备Step 1: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (84a ) preparation
于室温，将2-氨基-5-三氟甲基吡嗪(500mg，3.06mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(901mg，3.06mmol)溶于二氧六环(10ml)中，加入碳酸氢钠(514mg，6.12mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物280mg，收率：21.9％。At room temperature, 2-amino-5-trifluoromethylpyrazine (500 mg, 3.06 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan- 2-one (58b) (901 mg, 3.06 mmol) was dissolved in dioxane (10 ml), sodium bicarbonate (514 mg, 6.12 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. After separation and purification by chromatography (mobile phase: DCM/MeOH=20:1), 280 mg of the title compound was obtained as a brown solid, yield: 21.9%.
LC-MS：m/z＝360[M+H]+。LC-MS: m/z=360[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡嗪(84a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物84。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine (84a) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoro Methyl)imidazo[1,2-a]pyridine (12b) gave compound 84.
LC-MS：m/z＝510[M+H]+。LC-MS: m/z=510[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.18(d,J＝1.2Hz,1H),8.73(d,J＝1.2Hz,1H),7.88(d,J＝1.8Hz,1H),7.71(dd,J＝10.3,2.7Hz,1H),7.59(s,1H),7.30–7.15(m,2H),6.35(d,J＝1.9Hz,1H),6.28(s,2H),5.39–5.29(m,1H),4.02(d,J＝15.2Hz,1H),3.82(s,3H),2.57–2.50(m,3H),1.74(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.18(d,J＝1.2Hz,1H),8.73(d,J＝1.2Hz,1H),7.88(d,J＝1.8Hz,1H),7.71( dd,J＝10.3,2.7Hz,1H),7.59(s,1H),7.30–7.15(m,2H),6.35(d,J＝1.9Hz,1H),6.28(s,2H),5.39–5.29 (m,1H),4.02(d,J＝15.2Hz,1H),3.82(s,3H),2.57–2.50(m,3H),1.74(d,J＝6.2Hz,3H).
实施例85：(R)-14-环丙基-3,15-二氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(85)的制备
Example 85: (R)-14-cyclopropyl-3,15-difluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[ l]pyrazolo[4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene-8- Preparation of amine (85)
步骤1：5-环丙基-4-氟吡啶-2-胺(85a)的制备Step 1: Preparation of 5-cyclopropyl-4-fluoropyridin-2-amine (85a)
于室温，将5-溴-2-氨基-4-氟吡啶(1.00g，5.20mmol)、环丙基硼酸(675mg，7.90mmol)、醋酸钯(116mg，0.520mmol)、磷酸钾(3.30g，15.6mmol)、三环己基膦(280mg，1.00mmol)溶于甲苯/H2O(10:1)(20ml)中，于100℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得白色固体标题化合物400mg，收率：50.6％。At room temperature, 5-bromo-2-amino-4-fluoropyridine (1.00g, 5.20mmol), cyclopropylboronic acid (675mg, 7.90mmol), palladium acetate (116mg, 0.520mmol), potassium phosphate (3.30g, 15.6mmol), tricyclohexylphosphine (280mg, 1.00mmol) were dissolved in toluene/H 2 O (10:1) (20ml), stirred at 100°C overnight, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. After separation and purification (mobile phase: DCM/MeOH=20:1), 400 mg of the title compound was obtained as a white solid, yield: 50.6%.
LC-MS：m/z＝153[M+H]+。LC-MS: m/z=153[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-环丙基-7-氟咪唑并[1,2-a]吡啶(85b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-cyclopropyl-7-fluoroimidazo[1,2-a]pyridine (85b ) preparation
于室温，将5-环丙基-4-氟吡啶-2-胺(85a)(400mg，1.30mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(384mg，1.30mmol)溶于二氧六环(10ml)中，加入碳酸氢钠(218mg，2.60mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物238mg，收率：52.5％。At room temperature, 5-cyclopropyl-4-fluoropyridin-2-amine (85a) (400 mg, 1.30 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazole-4 -Propan-2-one (58b) (384 mg, 1.30 mmol) was dissolved in dioxane (10 ml), sodium bicarbonate (218 mg, 2.60 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue Separate and purify by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 238 mg of the title compound as a brown solid, yield: 52.5%.
LC-MS：m/z＝349[M+H]+。LC-MS: m/z=349[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-环丙基-7-氟咪唑并[1,2-a]吡啶(85b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物85。Other steps are the same as Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-cyclopropyl-7-fluoroimidazo[1, 2-a]pyridine (85b) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoro Methyl)imidazo[1,2-a]pyridine (12b) gave compound 85.
LC-MS：m/z＝499[M+H]+。LC-MS: m/z=499[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.91(d,J＝7.2Hz,1H),7.71(dq,J＝10.4,3.9,2.6Hz,2H),7.57(d,J＝13.4Hz,1H),7.39(d,J＝10.8Hz,1H),7.26–7.15(m,2H),6.30(d,J＝1.9Hz,1H),6.07(s,2H),5.36–5.27(m,1H),3.80(d,J＝17.3Hz,4H),3.09(d,J＝14.9Hz,1H),1.91(td,J＝8.3,4.3Hz,1H),1.72(d,J＝6.2Hz,2H),1.24(s, 1H),0.92–0.83(m,2H),0.75–0.58(m,2H)。 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J＝7.2Hz,1H),7.71(dq,J＝10.4,3.9,2.6Hz,2H),7.57(d,J＝13.4Hz,1H ),7.39(d,J＝10.8Hz,1H),7.26–7.15(m,2H),6.30(d,J＝1.9Hz,1H),6.07(s,2H),5.36–5.27(m,1H) ,3.80(d,J＝17.3Hz,4H),3.09(d,J＝14.9Hz,1H),1.91(td,J＝8.3,4.3Hz,1H),1.72(d,J＝6.2Hz,2H) ,1.24(s, 1H),0.92–0.83(m,2H),0.75–0.58(m,2H).
实施例86：(R)-3-氟-14-甲氧基-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(86)的制备
Example 86: (R)-3-fluoro-14-methoxy-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyridine Azolo[4,3j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (86 ) preparation
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-甲氧基咪唑并[1,2-a]吡啶(86a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-methoxyimidazo[1,2-a]pyridine (86a)
于室温，向5-甲氧基吡啶-2-胺(500mg，3.59mmol，1.00equiv)的1,4二氧六环(20.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.05g，3.59mmol，1.00equiv)和碳酸氢钠(906mg，10.7mmol，3.00equiv)，于80℃搅拌过夜。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物600mg，收率52.2％。To a solution of 5-methoxypyridin-2-amine (500 mg, 3.59 mmol, 1.00 equiv) in 1,4 dioxane (20.0 mL) was added 1-bromo-3-(3-bromo-1) at room temperature. -Methyl-1H-pyrazol-4-yl)propan-2-one (58b) (1.05g, 3.59mmol, 1.00equiv) and sodium bicarbonate (906mg, 10.7mmol, 3.00equiv), stirred at 80°C overnight . The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 600 mg of the title compound as a light yellow oil, with a yield of 52.2%.
LC-MS：m/z 321.10[M+H]+。LC-MS: m/z 321.10[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-甲氧基咪唑并[1,2-a]吡啶(86a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物86。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-methoxyimidazo[1,2-a] Pyridine (86a) replaced 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazole in step 3 and [1,2-a]pyridine (12b) to obtain compound 86.
LC-MS：m/z 471.05[M+H]+。LC-MS: m/z 471.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.82–7.76(m,2H),7.70(dd,J＝10.4,2.6Hz,1H),7.56(s,1H),7.50(d,J＝9.7Hz,1H),7.29–7.13(m,2H),7.00(dd,J＝9.7,2.3Hz,1H),6.34(d,J＝1.9Hz,1H),6.06(s,2H),5.34(tt,J＝6.7,3.4Hz,1H),3.82(s,4H),3.74(s,3H),3.12(d,J＝14.9Hz,1H),1.72(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.82–7.76 (m, 2H), 7.70 (dd, J = 10.4, 2.6 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 9.7 Hz,1H),7.29–7.13(m,2H),7.00(dd,J＝9.7,2.3Hz,1H),6.34(d,J＝1.9Hz,1H),6.06(s,2H),5.34(tt ,J＝6.7,3.4Hz,1H),3.82(s,4H),3.74(s,3H),3.12(d,J＝14.9Hz,1H),1.72(d,J＝6.2Hz,3H).
实施例87：(R)-3-氟-14-(2-甲氧基乙氧基)-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(87)的制备
Example 87: (R)-3-fluoro-14-(2-methoxyethoxy)-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene )benzo[l]pyrazole[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecane Preparation of carbene-8-amine (87)
步骤1：5-(2-甲氧基乙氧基)吡啶-2-胺(87a)的制备Step 1: Preparation of 5-(2-methoxyethoxy)pyridin-2-amine (87a)
于室温，向5-溴吡啶-2-胺(3.00g，17.4mmol，1.00equiv)的2-甲氧基乙烷-1-醇(30.0mL)溶液中加入铜粉(4.40g，69.7mmol，4.00equiv)和叔丁醇钾(10.4g，8.70mmol，2.00equiv)，于180℃微波搅拌16小时。过滤去除铜粉，反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物2.2g，收率75.3％。To a solution of 5-bromopyridin-2-amine (3.00g, 17.4mmol, 1.00equiv) in 2-methoxyethane-1-ol (30.0mL) at room temperature was added copper powder (4.40g, 69.7mmol, 4.00 equiv) and potassium tert-butoxide (10.4 g, 8.70 mmol, 2.00 equiv), stir in microwave at 180°C for 16 hours. The copper powder was removed by filtration, and the reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 2.2 g of the title compound as a light yellow oil, with a yield of 75.3%.
LC-MS：m/z 169.10[M+H]+。LC-MS: m/z 169.10[M+H] + .
步骤2：2-(3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(2-甲氧基乙氧基)咪唑并[1，2-a]吡啶(87b)的制备Step 2: 2-(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(2-methoxyethoxy)imidazo[1,2-a]pyridine Preparation of (87b)
于室温，向5-(2-甲氧基乙氧基)吡啶-2-胺(700mg，4.14mmol，1.00equiv)的1,4-二氧六环(20.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.2g，4.4mmol，1.00equiv)和碳酸氢钠(1.04g，12.4mmol，3.00equiv)，于80℃搅拌过夜。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物600mg，收率39.8％。To a solution of 5-(2-methoxyethoxy)pyridin-2-amine (700 mg, 4.14 mmol, 1.00 equiv) in 1,4-dioxane (20.0 mL) at room temperature was added 1-bromo- 3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (1.2g, 4.4mmol, 1.00equiv) and sodium bicarbonate (1.04g, 12.4mmol, 3.00 equiv), stir at 80°C overnight. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 600 mg of the title compound as a light yellow oil, with a yield of 39.8%.
LC-MS：m/z 364.10[M+H]+。LC-MS: m/z 364.10[M+H] + .
其他步骤与实施例12相同，除了用2-(3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(2-甲氧基乙氧基)咪唑并[1，2-a]吡啶(87b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物87。Other steps are the same as Example 12, except that 2-(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(2-methoxyethoxy)imidazo[ 1,2-a]pyridine (87b) replaced 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-( Trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 87.
LC-MS：m/z 515.05[M+H]+。LC-MS: m/z 515.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.84(d,J＝2.3Hz,1H),7.77(d,J＝1.8Hz,1H),7.70(dd,J＝10.4,2.6Hz,1H),7.56(s,1H),7.49(d,J＝9.7Hz,1H),7.20(qd,J＝8.4,5.9Hz,2H),7.02(dd,J＝9.7,2.3Hz,1H),6.34(d,J＝1.9Hz,1H),6.05(s,2H),5.34(td,J＝6.9,4.8Hz,1H),4.11(dt,J＝10.9,4.4Hz,1H),4.01(dt,J＝10.8,4.4Hz,1H),3.82(s,4H),3.62(t,J＝4.5Hz,2H),3.28(s,3H),3.12(d,J＝14.9Hz,1H),1.72 (d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.84 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.70 (dd, J = 10.4, 2.6 Hz, 1H) ,7.56(s,1H),7.49(d,J＝9.7Hz,1H),7.20(qd,J＝8.4,5.9Hz,2H),7.02(dd,J＝9.7,2.3Hz,1H),6.34( d,J＝1.9Hz,1H),6.05(s,2H),5.34(td,J＝6.9,4.8Hz,1H),4.11(dt,J＝10.9,4.4Hz,1H),4.01(dt,J ＝10.8,4.4Hz,1H),3.82(s,4H),3.62(t,J＝4.5Hz,2H),3.28(s,3H),3.12(d,J＝14.9Hz,1H),1.72 (d,J=6.2Hz,3H).
实施例88：(R)-14-乙基-3,15-二氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(88)的制备
Example 88: (R)-14-ethyl-3,15-difluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l ]Pyrazolo[4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine Preparation of (88)
步骤1：4-氟-5-乙烯基吡啶-2-胺(88a)的制备Step 1: Preparation of 4-fluoro-5-vinylpyridin-2-amine (88a)
于室温，将5-溴-4-氟吡啶-2-胺(500mg，2.64mmol)、乙烯三氟硼酸钾(530mg，3.96mmol)、Pd(dppf)Cl2(193mg，0.264mmol)、碳酸铯(1.72g，5.28mmol)溶于20ml二氧六环/H2O(5:1)中，于100℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物220mg，收率：65.1％。At room temperature, 5-bromo-4-fluoropyridin-2-amine (500mg, 2.64mmol), potassium ethylene trifluoroborate (530mg, 3.96mmol), Pd(dppf)Cl 2 (193mg, 0.264mmol), cesium carbonate (1.72g, 5.28mmol) was dissolved in 20ml dioxane/H 2 O (5:1), stirred at 100°C overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1), 220 mg of the title compound was obtained as a yellow solid, yield: 65.1%.
LC-MS：m/z＝139[M+H]+。LC-MS: m/z=139[M+H] + .
步骤2：4-氟-5-乙基吡啶-2-胺(88b)的制备Step 2: Preparation of 4-fluoro-5-ethylpyridin-2-amine (88b)
于室温，将4-氟-5-乙烯基吡啶-2-胺(88a)(220mg，1.65mmol)溶于甲醇(20ml)中，于氢气氛下，室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物210mg，收率：95.2％。4-Fluoro-5-vinylpyridin-2-amine (88a) (220 mg, 1.65 mmol) was dissolved in methanol (20 ml) at room temperature, stirred at room temperature overnight under a hydrogen atmosphere, concentrated under reduced pressure, and the residue was Separate and purify by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 210 mg of the title compound as a yellow solid, yield: 95.2%.
LC-MS：m/z＝141[M+H]+。LC-MS: m/z=141[M+H] + .
步骤3：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-氟-6-乙基咪唑并[1,2-a]吡啶(88c)的制备Step 3: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-fluoro-6-ethylimidazo[1,2-a]pyridine (88c) Preparation
于室温，将4-氟-5-乙基吡啶-2-胺(88b)(210mg，1.65mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(489mg，1.65mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(284mg，3.31mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物251mg，收率：42.9％。 At room temperature, 4-fluoro-5-ethylpyridin-2-amine (88b) (210 mg, 1.65 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazole-4- Propan-2-one (58b) (489 mg, 1.65 mmol) was dissolved in dioxane (20 ml), sodium bicarbonate (284 mg, 3.31 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was Separate and purify by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 251 mg of the title compound as a yellow solid, yield: 42.9%.
LC-MS：m/z＝337[M+H]+。LC-MS: m/z=337[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-氟-6-乙基咪唑并[1,2-a]吡啶(88c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物88。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-fluoro-6-ethylimidazo[1,2 -a]pyridine (88c) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 yl)imidazo[1,2-a]pyridine (12b) to obtain compound 88.
LC-MS：m/z＝487[M+H]+。LC-MS: m/z=487[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.23(d,J＝7.2Hz,1H),7.80–7.63(m,2H),7.56(s,1H),7.39(d,J＝10.9Hz,1H),7.20(qd,J＝8.5,5.9Hz,2H),6.32(d,J＝1.9Hz,1H),6.07(s,2H),5.43–5.25(m,1H),3.82(s,4H),3.11(d,J＝15.0Hz,1H),2.62(q,J＝7.4Hz,2H),1.72(d,J＝6.2Hz,3H),1.14(t,J＝7.4Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.23 (d, J = 7.2Hz, 1H), 7.80–7.63 (m, 2H), 7.56 (s, 1H), 7.39 (d, J = 10.9Hz, 1H),7.20(qd,J＝8.5,5.9Hz,2H),6.32(d,J＝1.9Hz,1H),6.07(s,2H),5.43–5.25(m,1H),3.82(s,4H ), 3.11 (d, J = 15.0Hz, 1H), 2.62 (q, J = 7.4Hz, 2H), 1.72 (d, J = 6.2Hz, 3H), 1.14 (t, J = 7.4Hz, 3H).
实施例89：(R)-3-氟-5,20-二甲基-14-(哌啶-4-基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(89)的制备
Example 89: (R)-3-fluoro-5,20-dimethyl-14-(piperidin-4-yl)-18,20-dihydro-5H-7,11-(methylene)benzene And[l]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecane Preparation of en-8-amine (89)
步骤1：4-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)哌啶-1-羧酸叔丁酯(89a)的制备Step 1: 4-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)piperidine-1 - Preparation of tert-butyl carboxylate (89a)
于室温，将4-(6-氨基吡啶-3-基)哌啶-1-羧酸叔丁酯(600mg，2.16mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(640mg，2.16mmol)溶于二氧六环(5ml)中，加入碳酸氢钠(362mg，4.32mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物800mg，收率：80.1％。At room temperature, 4-(6-aminopyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (600 mg, 2.16 mmol), 1-bromo-3-(3-bromo-1-methyl-1H -Pyrazol-4-yl)propan-2-one (58b) (640 mg, 2.16 mmol) was dissolved in dioxane (5 ml), sodium bicarbonate (362 mg, 4.32 mmol) was added, stirred at room temperature overnight, and reduced Concentrate under pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 800 mg of the title compound as a yellow solid, yield: 80.1%.
LC-MS：m/z＝474[M+H]+。LC-MS: m/z=474[M+H] + .
其他步骤与实施例12相同，除了用4-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)哌啶-1-羧酸叔丁酯(89a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物89e。Other steps are the same as Example 12, except using 4-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6 -yl)piperidine-1-carboxylic acid tert-butyl ester (89a) instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl in step 3 methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (12b) to obtain compound 89e.
LC-MS：m/z＝624[M+H]+。 LC-MS: m/z=624[M+H] + .
步骤2:(R)-3-氟-5,20-二甲基-14-(哌啶-4-基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(89)的制备Step 2: (R)-3-fluoro-5,20-dimethyl-14-(piperidin-4-yl)-18,20-dihydro-5H-7,11-(methylene)benzo [l]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene -Preparation of 8-amine (89)
于室温，将(R)-4-(8-氨基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-14-基)哌啶-1-羧酸叔丁酯(89e)(16.1mg，0.0260mmol)溶于二氯甲烷中，于0℃加入三氟乙酸(1mL)，继续搅拌0.5h，加10mL水淬灭，乙酸乙酯萃取(10mL x 3)，饱和食盐水洗涤(10mL x 1)，无水硫酸钠干燥，过滤，减压浓缩，残余物通过高压制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um 100A，流动相：乙腈/水(0.05％甲酸)，梯度：30％-70％)，得白色固体状标题化合物7mg，收率：59.5％。At room temperature, (R)-4-(8-amino-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1] Pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene-14- tert-butyl piperidine-1-carboxylate (89e) (16.1 mg, 0.0260 mmol) was dissolved in dichloromethane, added trifluoroacetic acid (1 mL) at 0°C, continued stirring for 0.5 h, and added 10 mL of water to quench , extracted with ethyl acetate (10mL *250mm, C18, 10um 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 30%-70%), 7 mg of the title compound was obtained as a white solid, yield: 59.5%.
LC-MS：m/z＝524[M+H]+。LC-MS: m/z=524[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.76–7.66(m,2H),7.54(q,J＝8.9Hz,2H),7.27–7.10(m,3H),6.33(d,J＝1.9Hz,1H),6.06(s,2H),5.43–5.24(m,1H),3.95–3.80(m,4H),3.14(d,J＝14.9Hz,1H),3.02(d,J＝11.5Hz,2H),1.57–1.39(m,3H),2.72–2.53(m,4H),1.70(dd,J＝20.0,10.3Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.08 (s, 1H), 7.76–7.66 (m, 2H), 7.54 (q, J = 8.9Hz, 2H), 7.27–7.10 (m, 3H), 6.33(d,J＝1.9Hz,1H),6.06(s,2H),5.43–5.24(m,1H),3.95–3.80(m,4H),3.14(d,J＝14.9Hz,1H),3.02 (d,J＝11.5Hz,2H),1.57–1.39(m,3H),2.72–2.53(m,4H),1.70(dd,J＝20.0,10.3Hz,6H).
实施例90：(R)-14-氯-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(90)的制备
Example 90: (R)-14-chloro-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazolo [4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (90) preparation
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-氯咪唑并[1,2-a]吡啶(90a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-chloroimidazo[1,2-a]pyridine (90a)
于室温，将5-氯吡啶-2-胺(200mg，1.56mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(462mg，1.56mmol)溶于二氧六环(10ml)中，加入 碳酸氢钠(262mg，3.12mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物350mg，收率：69.0％。At room temperature, 5-chloropyridin-2-amine (200 mg, 1.56 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one ( 58b) (462mg, 1.56mmol) was dissolved in dioxane (10ml) and added Sodium bicarbonate (262 mg, 3.12 mmol) was stirred at room temperature overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 350 mg of the title compound as a brown solid. Yield: 69.0%.
LC-MS：m/z＝325[M+H]+。LC-MS: m/z=325[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-氯咪唑并[1,2-a]吡啶(90a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物90。Other steps are the same as Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-chloroimidazo[1,2-a]pyridine ( 90a) Replace 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine (12b) gave compound 90.
LC-MS：m/z＝475[M+H]+。LC-MS: m/z=475[M+H] + .
实施例91：(R)-3,14-二氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]哒嗪并[6',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(91)的制备
Example 91: (R)-3,14-difluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l]pyrazolo[ 4,3-j]pyridazino[6',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (91 ) preparation
步骤1：6-氟咪唑并[1,2-b]哒嗪-2-羧酸甲酯(91a)的制备Step 1: Preparation of 6-fluoroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (91a)
于室温，向6-氯咪唑并[1,2-b]哒嗪-2-羧酸甲酯(2.00g，9.47mmol，1.00equiv)的DMSO(50.0mL)溶液中加入四丁基氟化铵三水化合物(3.25g，14.2mmol，1.50equiv)，于氮气氛围下80℃搅拌16h。加水淬灭，EA萃取。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物1.20g，收率65.0％。To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (2.00 g, 9.47 mmol, 1.00 equiv) in DMSO (50.0 mL) at room temperature was added tetrabutylammonium fluoride Trihydrate (3.25g, 14.2mmol, 1.50equiv) was stirred at 80°C for 16h under nitrogen atmosphere. Add water to quench and extract with EA. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 1.20 g of the title compound as a white solid, with a yield of 65.0%.
LC-MS：m/z 196.05[M+H]+。LC-MS: m/z 196.05[M+H] + .
步骤2：6-氟咪唑并[1,2-b]哒嗪-2-甲醛(91b)的制备Step 2: Preparation of 6-fluoroimidazo[1,2-b]pyridazine-2-carboxaldehyde (91b)
氮气氛围下，于-78℃向6-氟咪唑并[1,2-b]哒嗪-2-羧酸甲酯(1.20g，6.15mmol，1.00equiv)的二氯甲烷(15.0mL)溶液中加入二异丁基氢化铝(12.3mL，12.3mmol， 2.00equiv)，继续搅拌1.5小时。缓慢加入甲醇淬灭，加入1M盐酸调节PH至约7，反应混合物用二氯甲烷萃取(3X50毫升)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物800mg。收率78.8％。To a solution of 6-fluoroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (1.20g, 6.15mmol, 1.00equiv) in dichloromethane (15.0mL) at -78°C under nitrogen atmosphere Add diisobutylaluminum hydride (12.3mL, 12.3mmol, 2.00 equiv) and continue stirring for 1.5 hours. Methanol was slowly added to quench, 1M hydrochloric acid was added to adjust the pH to about 7, and the reaction mixture was extracted with dichloromethane (3X50 ml). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 800 mg of the title compound as a white solid. The yield is 78.8%.
LC-MS：m/z 166.05[M+H]+。LC-MS: m/z 166.05[M+H] + .
其他步骤与实施例12相同，除了用6-氟咪唑并[1,2-b]哒嗪-2-甲醛(91b)代替代替步骤1中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，得到化合物91。Other steps are the same as in Example 12, except that 6-fluoroimidazo[1,2-b]pyridazine-2-carboxaldehyde (91b) is used instead of 6-(trifluoromethyl)imidazo[1, 2-a]pyridine-2-carboxaldehyde gave compound 91.
LC-MS：m/z 460.05[M+H]+。LC-MS: m/z 460.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.31(dd,J＝9.6,7.5Hz,1H),7.95(d,J＝1.7Hz,1H),7.67(dd,J＝10.3,2.7Hz,1H),7.61(s,1H),7.32-7.17(m,3H),6.44(d,J＝1.9Hz,1H),6.13(s,2H),5.30-5.20(m,1H),3.97(d,J＝15.2Hz,1H),3.84(s,3H),3.26(d,J＝15.1Hz,1H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.31(dd,J＝9.6,7.5Hz,1H),7.95(d,J＝1.7Hz,1H),7.67(dd,J＝10.3,2.7Hz,1H ),7.61(s,1H),7.32-7.17(m,3H),6.44(d,J＝1.9Hz,1H),6.13(s,2H),5.30-5.20(m,1H),3.97(d, J＝15.2Hz,1H),3.84(s,3H),3.26(d,J＝15.1Hz,1H),1.73(d,J＝6.2Hz,3H).
实施例92：(R)-8-氨基-3-氟-N,5,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-14-甲酰胺(92)的制备
Example 92: (R)-8-amino-3-fluoro-N,5,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyridine Azolo[4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene-14-carboxamide ( 92) Preparation
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-羧酸甲酯(92a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (92a)
于室温，将6-氨基烟酸甲酯(500mg，3.28mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(967mg，3.28mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(551mg，6.56mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物620mg，收率：54.1％。 At room temperature, 6-aminonicotinic acid methyl ester (500 mg, 3.28 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b ) (967 mg, 3.28 mmol) was dissolved in dioxane (20 ml), sodium bicarbonate (551 mg, 6.56 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography ( Mobile phase: DCM/MeOH=20:1), 620 mg of the title compound was obtained as a yellow solid, yield: 54.1%.
LC-MS：m/z＝349[M+H]+。LC-MS: m/z=349[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-N-甲基咪唑并[1,2-a]吡啶-6-甲酰胺(92b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-N-methylimidazo[1,2-a]pyridine-6-carboxamide (92b ) preparation
于室温，将2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-羧酸甲酯(92a)(300mg，0.862mmol)溶于甲醇(5ml)中，加入甲醇胺水溶液40％(2ml)，于80℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物240mg，收率：43.4％。At room temperature, 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (92a) ( 300 mg, 0.862 mmol) was dissolved in methanol (5 ml), 40% methanolamine aqueous solution (2 ml) was added, stirred at 80°C overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/ MeOH=20:1), 240 mg of the title compound was obtained as a yellow solid, yield: 43.4%.
LC-MS：m/z＝348[M+H]+。LC-MS: m/z=348[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-N-甲基咪唑并[1,2-a]吡啶-6-甲酰胺(92b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物92。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-N-methylimidazo[1,2-a]pyridine -6-carboxamide (92b) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoro Methyl)imidazo[1,2-a]pyridine (12b) gave compound 92.
LC-MS：m/z＝498[M+H]+。LC-MS: m/z=498[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.79(t,J＝1.4Hz,1H),8.59(d,J＝4.7Hz,1H),7.79(d,J＝1.8Hz,1H),7.71(dd,J＝10.4,2.7Hz,1H),7.67–7.56(m,3H),7.27–7.14(m,2H),6.35(d,J＝1.9Hz,1H),6.14(s,2H),5.35(dd,J＝6.5,2.1Hz,1H),3.88(d,J＝15.0Hz,1H),3.82(s,3H),3.17(d,J＝14.9Hz,1H),2.76(d,J＝4.5Hz,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.79(t,J＝1.4Hz,1H),8.59(d,J＝4.7Hz,1H),7.79(d,J＝1.8Hz,1H),7.71( dd,J＝10.4,2.7Hz,1H),7.67–7.56(m,3H),7.27–7.14(m,2H),6.35(d,J＝1.9Hz,1H),6.14(s,2H),5.35 (dd,J＝6.5,2.1Hz,1H),3.88(d,J＝15.0Hz,1H),3.82(s,3H),3.17(d,J＝14.9Hz,1H),2.76(d,J＝ 4.5Hz, 3H), 1.73 (d, J = 6.2Hz, 3H).
实施例93：(R)-3-氟-5,14,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)[1,2,4]三嗪[3',2':2,3]咪唑并[4,5-g]苯并[l]吡唑并[4,3-j][1]氧杂[4]氮杂环十四碳烯-8-胺(93)的制备
Example 93: (R)-3-fluoro-5,14,20-trimethyl-18,20-dihydro-5H-7,11-(methylene)[1,2,4]triazine[ 3',2':2,3]imidazo[4,5-g]benzo[l]pyrazolo[4,3-j][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (93)
步骤1：6-甲基-1,2,4-三嗪-3-胺(93a)的制备Step 1: Preparation of 6-methyl-1,2,4-triazin-3-amine (93a)
于室温，将3-氨基-6-溴-1,2,4-三嗪(420mg，2.39mmol)、三甲基环三硼氧烷 (420mg，3.35mmol)、碳酸铯(2.80g，8.59mmol)、Pd(dppf)Cl2(196mg，0.239mmol)溶于二氧六环(10ml)中，于135℃，微波反应4h。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得白色固体标题化合物160mg，收率：43.8％。At room temperature, 3-amino-6-bromo-1,2,4-triazine (420 mg, 2.39 mmol), trimethylcyclotriboroxane (420 mg, 3.35 mmol), cesium carbonate (2.80 g, 8.59 mmol), and Pd(dppf)Cl 2 (196 mg, 0.239 mmol) were dissolved in dioxane (10 ml), and reacted under microwave at 135°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 160 mg of the title compound as a white solid, yield: 43.8%.
LC-MS：m/z＝153[M+H]+。LC-MS: m/z=153[M+H]+.
步骤2：6-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-2-甲基咪唑并[1,2-b][1,2,4]三嗪(93b)的制备Step 2: 6-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-2-methylimidazo[1,2-b][1,2,4]tri Preparation of oxazine (93b)
于室温，将6-甲基-1,2,4-三嗪-3-胺(93a)(160mg，1.45mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(427mg，1.45mmol)溶于二氧六环(10ml)中，加入碳酸氢钠(243mg，2.60mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物130mg，收率：29.3％。At room temperature, 6-methyl-1,2,4-triazin-3-amine (93a) (160 mg, 1.45 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyridine) Azol-4-yl)propan-2-one (58b) (427 mg, 1.45 mmol) was dissolved in dioxane (10 ml), sodium bicarbonate (243 mg, 2.60 mmol) was added, stirred at room temperature overnight, and concentrated under reduced pressure. , the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 130 mg of the title compound as a brown solid, yield: 29.3%.
LC-MS：m/z＝307[M+H]+。LC-MS: m/z=307[M+H] + .
其他步骤与实施例12相同，除了用6-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-2-甲基咪唑并[1,2-b][1,2,4]三嗪(93b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物93。Other steps are the same as Example 12, except using 6-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-2-methylimidazo[1,2-b][ 1,2,4]triazine (93b) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6- in step 3 (Trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 93.
LC-MS：m/z＝457[M+H]+。LC-MS: m/z=457[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.99(d,J＝1.8Hz,1H),7.67(d,J＝2.7Hz,1H),7.65(d,J＝4.8Hz,1H),7.33–7.17(m,2H),6.46(d,J＝1.9Hz,1H),6.11(s,2H),5.24(dd,J＝6.4,2.1Hz,1H),4.00(d,J＝15.1Hz,1H),3.84(s,3H),3.26(s,1H),2.53(s,3H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.99(d,J＝1.8Hz,1H),7.67(d,J＝2.7Hz,1H),7.65(d,J＝4.8 Hz,1H),7.33–7.17(m,2H),6.46(d,J＝1.9Hz,1H),6.11(s,2H),5.24(dd,J＝6.4,2.1Hz,1H),4.00(d ,J＝15.1Hz,1H),3.84(s,3H),3.26(s,1H),2.53(s,3H),1.73(d,J＝6.2Hz,3H).
实施例94：(R)-3-氟-5,20-二甲基-14-吗啉基-18,20-二氢-5H-7,11-(甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(94)的制备
Example 94: (R)-3-fluoro-5,20-dimethyl-14-morpholinyl-18,20-dihydro-5H-7,11-(methyl)benzo[l]pyrazole And[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine ( 94) Preparation
步骤1：4-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)吗啉(94a)的制备Step 1: 4-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)morpholine (94a ) preparation
于室温，将5-吗啉吡啶-2-胺(500mg，2.79mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(822mg，2.79mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(468mg，5.58mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物800mg，收率：54.1％。Dissolve 5-morpholinopyridin-2-amine (500 mg, 2.79 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one at room temperature. (58b) (822 mg, 2.79 mmol) was dissolved in dioxane (20 ml), sodium bicarbonate (468 mg, 5.58 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. After purification (mobile phase: DCM/MeOH=20:1), 800 mg of the title compound was obtained as a yellow solid, yield: 54.1%.
LC-MS：m/z＝376[M+H]+。LC-MS: m/z=376[M+H] + .
其他步骤与实施例12相同，除了用4-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)吗啉(94a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物94。Other steps are the same as Example 12, except using 4-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6 -yl)morpholine (94a) instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoro Methyl)imidazo[1,2-a]pyridine (12b) gave compound 94.
LC-MS：m/z＝526[M+H]+。LC-MS: m/z=526[M+H] + .
实施例95：(R)-14-环丙基-3-氟-5,19-二甲基-17,19-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3]噻唑并[2',3':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(95)的制备
Example 95: (R)-14-cyclopropyl-3-fluoro-5,19-dimethyl-17,19-dihydro-5H-7,11-(methylene)benzo[1]pyridine Azolo[4,3]thiazolo[2',3':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (95 ) preparation
步骤1：6-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-2-环丙基咪唑并[2,1-b]噻唑(95a)的制备Step 1: Preparation of 6-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-2-cyclopropylimidazo[2,1-b]thiazole (95a)
于室温，将5-环丙基噻唑-2-胺(500mg，3.57mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.06g，3.57mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(600mg，7.14mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物870mg，收率：72.5％。 At room temperature, 5-cyclopropylthiazol-2-amine (500 mg, 3.57 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2- Ketone (58b) (1.06g, 3.57mmol) was dissolved in dioxane (20ml), sodium bicarbonate (600mg, 7.14mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Separate and purify using the method (mobile phase: DCM/MeOH=20:1) to obtain 870 mg of the title compound as a yellow solid, yield: 72.5%.
LC-MS：m/z＝337[M+H]+。LC-MS: m/z=337[M+H] + .
其他步骤与实施例12相同，除了用6-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-2-环丙基咪唑并[2,1-b]噻唑(95a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物95。Other steps are the same as Example 12, except using 6-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-2-cyclopropylimidazo[2,1-b] Thiazole (95a) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl)imidazole in step 3 and [1,2-a]pyridine (12b) to obtain compound 95.
LC-MS：m/z＝487[M+H]+。LC-MS: m/z=487[M+H] + .
实施例96：(R)-3-氟-5,20-二甲基-14-(1-甲基哌啶-4-基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(96)的制备
Example 96: (R)-3-fluoro-5,20-dimethyl-14-(1-methylpiperidin-4-yl)-18,20-dihydro-5H-7,11-(methane Methyl)benzo[l]pyrazole[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azeterocycle Preparation of tetradecene-8-amine (96)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(哌啶-4-基)咪唑并[1,2-a]吡啶(96a)的制备Step 1: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyridine ( Preparation of 96a)
于室温，向4-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)哌啶-1-羧酸叔丁酯(89a)(1.00g，2.11mmol)的二氯甲烷(5.0mL)溶液中加入三氟乙酸(2.0mL)，于室温搅拌3小时。反应液浓缩，加入碳酸氢钠调至碱性，乙酸乙酯萃取(20mLx2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物700mg，收率88.8％。To 4-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)piperidine- Trifluoroacetic acid (2.0 mL) was added to a solution of tert-butyl 1-carboxylate (89a) (1.00 g, 2.11 mmol) in dichloromethane (5.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, sodium bicarbonate was added to make it alkaline, extracted with ethyl acetate (20 mL Methyl chloride/methanol = 10:1) to obtain 700 mg of the title compound as a light yellow oil, with a yield of 88.8%.
LC-MS：m/z＝374[M+H]+。LC-MS: m/z=374[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(1-甲基哌啶-4-基)咪唑并[1,2-a]吡啶(96b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(1-methylpiperidin-4-yl)imidazo[1,2- a] Preparation of pyridine (96b)
于室温，向2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(哌啶-4-基)咪唑并[1,2-a]吡啶(700mg，2.11mmol)的甲醇(7.0mL)溶液中加入水合甲醛(2.0mL，37％)和氰基硼氢化钠(56.0mg，4.22mmol)，于室温搅拌3小时。反应液浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油 状的标题化合物700mg，收率86.1％。To 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(piperidin-4-yl)imidazo[1,2-a]pyridine at room temperature To a solution of (700 mg, 2.11 mmol) in methanol (7.0 mL) were added hydrated formaldehyde (2.0 mL, 37%) and sodium cyanoborohydride (56.0 mg, 4.22 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane/methanol=10:1) to obtain light yellow oil. 700 mg of the title compound, yield 86.1%.
LC-MS:m/z＝374[M+H]+。LC-MS: m/z=374[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(1-甲基哌啶-4-基)咪唑并[1,2-a]吡啶(96b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物96。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(1-methylpiperidin-4-yl) Imidazo[1,2-a]pyridine (96b) replaced 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)- in step 3 6-(Trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 96.
LC-MS：m/z＝538[M+H]+。LC-MS: m/z=538[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.10(d,J＝1.5Hz,1H),7.75–7.63(m,2H),7.59–7.44(m,2H),7.30–7.11(m,3H),6.33(d,J＝1.9Hz,1H),6.06(s,2H),5.33(dt,J＝6.6,3.3Hz,1H),3.82(s,4H),3.14(d,J＝14.9Hz,1H),2.93–2.78(m,2H),2.20(s,3H),2.09–1.92(m,2H),1.81–1.52(m,7H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.10 (d, J＝1.5Hz, 1H), 7.75–7.63 (m, 2H), 7.59–7.44 (m, 2H), 7.30–7.11 (m, 3H ),6.33(d,J＝1.9Hz,1H),6.06(s,2H),5.33(dt,J＝6.6,3.3Hz,1H),3.82(s,4H),3.14(d,J＝14.9Hz ,1H),2.93–2.78(m,2H),2.20(s,3H),2.09–1.92(m,2H),1.81–1.52(m,7H).
实施例97：(R)-3-氟-5,14,19-三甲基-17,19-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]噻唑并[2',3':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8胺(97)的制备
Example 97: (R)-3-Fluoro-5,14,19-trimethyl-17,19-dihydro-5H-7,11-(methylene)benzo[l]pyrazolo[4 Preparation of ,3-j]thiazolo[2',3':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene-8amine (97)
步骤1：6-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-2-甲基咪唑并[2,1-b]噻唑(97a)的制备Step 1: Preparation of 6-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-2-methylimidazo[2,1-b]thiazole (97a)
于室温，将5-甲基噻唑-2-胺(500mg，4.39mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.30g，4.39mmol)溶于二氧六环(20ml)中，加入碳酸氢钠(737mg，8.78mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物900mg，收率，66.1％。Dissolve 5-methylthiazol-2-amine (500 mg, 4.39 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one at room temperature. (58b) (1.30g, 4.39mmol) was dissolved in dioxane (20ml), sodium bicarbonate (737mg, 8.78mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. After separation and purification (mobile phase: DCM/MeOH=20:1), 900 mg of the title compound was obtained as a yellow solid, with a yield of 66.1%.
LC-MS：m/z＝311[M+H]+。LC-MS: m/z=311[M+H] + .
其他步骤与实施例12相同，除了用6-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-2-甲基咪唑并[2,1-b]噻唑(97a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基) 甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物97。Other steps are the same as Example 12, except that 6-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-2-methylimidazo[2,1-b]thiazole is used (97a) Replace 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl) in step 3 Methyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 97.
LC-MS：m/z＝461[M+H]+。LC-MS: m/z=461[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.78–7.63(m,2H),7.56(dd,J＝8.6,5.8Hz,1H),7.40(dd,J＝10.4,2.9Hz,1H),7.09(td,J＝8.4,2.8Hz,1H),6.63(d,J＝2.0Hz,1H),6.42(d,J＝17.8Hz,3H),5.41–5.26(m,1H),4.09(d,J＝16.9Hz,1H),3.82(s,4H),2.32(s,3H),1.93(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ7.78–7.63(m,2H),7.56(dd,J＝8.6,5.8Hz,1H),7.40(dd,J＝10.4,2.9Hz,1H),7.09 (td,J＝8.4,2.8Hz,1H),6.63(d,J＝2.0Hz,1H),6.42(d,J＝17.8Hz,3H),5.41–5.26(m,1H),4.09(d, J＝16.9Hz,1H),3.82(s,4H),2.32(s,3H),1.93(d,J＝6.2Hz,3H).
实施例98：(R)-8-氨基-N-环丙基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-14-甲酰胺(98)的制备
Example 98: (R)-8-amino-N-cyclopropyl-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo [l]pyrazolo[4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene-14 -Preparation of formamide (98)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-N-环丙基咪唑并[1,2-a]吡啶-6-甲酰胺(98a)的制备Step 1: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-N-cyclopropylimidazo[1,2-a]pyridine-6-carboxamide ( Preparation of 98a)
于室温，将2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-羧酸甲酯(92a)(350mg，1.00mmol)溶于甲醇(5ml)中，加入环丙胺(1ml)，于80℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物130mg，收率，34.7％。At room temperature, 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (92a) ( 350 mg, 1.00 mmol) was dissolved in methanol (5 ml), cyclopropylamine (1 ml) was added, stirred at 80°C overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20 :1), 130 mg of the title compound was obtained as a yellow solid, yield: 34.7%.
LC-MS：m/z＝374[M+H]+。LC-MS: m/z=374[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-N-环丙基咪唑并[1，2-a]吡啶-6-甲酰胺(98a)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物98。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-N-cyclopropylimidazo[1,2-a] Pyridine-6-carboxamide (98a) replaced 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(tris Fluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 98.
LC-MS：m/z＝524[M+H]+。LC-MS: m/z=524[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.76(t,J＝1.3Hz,1H),8.61(d,J＝4.0Hz,1H),7.80(d,J＝1.8Hz,1H),7.71(dd,J＝10.3,2.6Hz,1H),7.66–7.56(m,3H),7.27–7.16(m,2H),6.35(d,J＝1.8Hz,1H),6.14(s,2H),5.35(d,J＝5.4Hz,1H),3.87(d,J ＝15.0Hz,2H),3.82(s,3H),3.16(d,J＝14.9Hz,1H),1.73(d,J＝6.2Hz,3H),0.69(dd,J＝7.4,2.4Hz,2H),0.54(tt,J＝4.2,2.6Hz,2H)。 1 H NMR (400MHz, DMSO-d6) δ8.76(t,J＝1.3Hz,1H),8.61(d,J＝4.0Hz,1H),7.80(d,J＝1.8Hz,1H),7.71( dd,J＝10.3,2.6Hz,1H),7.66–7.56(m,3H),7.27–7.16(m,2H),6.35(d,J＝1.8Hz,1H),6.14(s,2H),5.35 (d,J＝5.4Hz,1H),3.87(d,J ＝15.0Hz,2H),3.82(s,3H),3.16(d,J＝14.9Hz,1H),1.73(d,J＝6.2Hz,3H),0.69(dd,J＝7.4,2.4Hz,2H ),0.54(tt,J＝4.2,2.6Hz,2H).
实施例99：(R)-8-氨基-N-环丙基-3-氟-N,5,20-三甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-14-甲酰胺(99)的制备
Example 99: (R)-8-amino-N-cyclopropyl-3-fluoro-N,5,20-trimethyl-18,20-dihydro-5H-7,11-(methylene) Benzo[l]pyrazolo[4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene -Preparation of 14-carboxamide (99)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-羧酸(99a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid (99a)
于室温，将2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-羧酸甲酯(92a)(1.00g，2.87mmol)溶于甲醇/H2O(10ml)中，加入氢氧化钠(230mg，5.87mmol)，于室温搅拌过夜，将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物920mg，收率：96.0％。At room temperature, 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (92a) ( 1.00g, 2.87mmol) was dissolved in methanol/H 2 O (10ml), sodium hydroxide (230mg, 5.87mmol) was added, stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. After separation and purification (mobile phase: DCM/MeOH=20:1), 920 mg of the title compound was obtained as a yellow solid, yield: 96.0%.
LC-MS：m/z＝335[M+H]+。LC-MS: m/z=335[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-N-环丙基-N-甲基咪唑并[1,2-a]吡啶-6-甲酰胺(99b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-N-cyclopropyl-N-methylimidazo[1,2-a]pyridine- Preparation of 6-carboxamide (99b)
于室温，将2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-羧酸(99a)(900mg，2.69mmol)、HBTU(1.29g，4.04mmol)、N-甲基环丙胺盐酸盐(575mg，5.38mmol)、DIEA(1.38g，10.7mmol)溶于DMF(20ml)中，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得黄色固体标题化合物300mg，收率：28.7％。2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid (99a) (900 mg, 2.69mmol), HBTU (1.29g, 4.04mmol), N-methylcyclopropylamine hydrochloride (575mg, 5.38mmol), DIEA (1.38g, 10.7mmol) were dissolved in DMF (20ml) and stirred at room temperature overnight. Concentrate under reduced pressure, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 300 mg of the title compound as a yellow solid, yield: 28.7%.
LC-MS：m/z＝388[M+H]+。LC-MS: m/z=388[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-N-环丙基咪唑并[1，2-a]吡啶-6-甲酰胺(99b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物99。 Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-N-cyclopropylimidazo[1,2-a] Pyridine-6-carboxamide (99b) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(tris Fluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 99.
LC-MS：m/z＝538[M+H]+。LC-MS: m/z=538[M+H] + .
实施例100：(R)-3,15-二氟-14-异丙基-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(100)的制备
Example 100: (R)-3,15-difluoro-14-isopropyl-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[ l]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene- Preparation of 8-amine (100)
步骤1：4-氟-5-(丙-1-烯-2-基)吡啶-2-胺(100a)的制备Step 1: Preparation of 4-fluoro-5-(prop-1-en-2-yl)pyridin-2-amine (100a)
于室温，向5-溴-4-氟吡啶-2-胺(1.50g，7.89mmol，1.00equiv)的1,4-二氧六环(20.0mL)和水(4.0mL)溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(644mg，0.780mmol，0.100equiv)、碳酸铯(3.20g，23.6mmol，3.00equiv)和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧杂硼烷(1.32g，8.68mmol，1.10equiv)。于氮气氛围下，90℃搅拌过夜，将反应液直接浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色固体状的标题化合物1.10g，收率91.7％。To a solution of 5-bromo-4-fluoropyridin-2-amine (1.50 g, 7.89 mmol, 1.00 equiv) in 1,4-dioxane (20.0 mL) and water (4.0 mL) at room temperature was added [1 ,1'-Bis(diphenylphosphine)ferrocene]palladium dichloride (644mg, 0.780mmol, 0.100equiv), cesium carbonate (3.20g, 23.6mmol, 3.00equiv) and 4,4,5,5- Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane (1.32 g, 8.68 mmol, 1.10 equiv). Stir overnight at 90°C under nitrogen atmosphere, and then concentrate the reaction solution directly. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 1.10 g of the title compound as a light yellow solid, with a yield of 91.7%.
LC-MS：m/z 153.05[M+H]+。LC-MS: m/z 153.05[M+H] + .
步骤2：4-氟-5-异丙基吡啶-2-胺(100b)的制备Step 2: Preparation of 4-fluoro-5-isopropylpyridin-2-amine (100b)
于室温，向4-氟-5-(丙-1-烯-2-基)吡啶-2-胺(1.20g，7.89mmol，1.00equiv)的乙酸乙酯(20.0mL)溶液中加入钯碳(200mg，10％)。于氢气氛围下，室温搅拌过夜。过滤，滤液浓缩。得到淡黄色固体状的标题化合物1.0g，收率82.3％。To a solution of 4-fluoro-5-(prop-1-en-2-yl)pyridin-2-amine (1.20 g, 7.89 mmol, 1.00 equiv) in ethyl acetate (20.0 mL) at room temperature was added palladium on carbon ( 200mg, 10%). Stir overnight at room temperature under hydrogen atmosphere. Filter and concentrate the filtrate. 1.0 g of the title compound was obtained as a light yellow solid, with a yield of 82.3%.
LC-MS：m/z 155.05[M+H]+ LC-MS: m/z 155.05[M+H] +
步骤3：2-(3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-氟-6-异丙基咪唑并[1,2-a]吡啶(100c)的制备Step 3: 2-(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-fluoro-6-isopropylimidazo[1,2-a]pyridine (100c) Preparation
于室温，向4-氟-5-异丙基吡啶-2-胺(200mg，1.29mmol，1.00equiv)的1,4二氧六环(10.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(381mg，1.29mmol，1.00equiv)和碳酸氢钠(327mg，3.89mmol，3.00equiv)， 于80℃搅拌过夜。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物400mg。收率88.6％。To a solution of 4-fluoro-5-isopropylpyridin-2-amine (200 mg, 1.29 mmol, 1.00 equiv) in 1,4 dioxane (10.0 mL) at room temperature was added 1-bromo-3-(3 -Bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (381 mg, 1.29 mmol, 1.00 equiv) and sodium bicarbonate (327 mg, 3.89 mmol, 3.00 equiv), Stir at 80°C overnight. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 400 mg of the title compound as a light yellow oil. The yield is 88.6%.
LC-MS：m/z 351.10[M+H]+。LC-MS: m/z 351.10[M+H] + .
其他步骤与实施例12相同，除了用2-(3-溴-1-甲基-1H-吡唑-4-基)甲基)-7-氟-6-异丙基咪唑并[1,2-a]吡啶(100c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物100。Other steps are the same as in Example 12, except that 2-(3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-7-fluoro-6-isopropylimidazo[1,2 -a]pyridine (100c) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 yl)imidazo[1,2-a]pyridine (12b) to obtain compound 100.
LC-MS：m/z 501.05[M+H]+。LC-MS: m/z 501.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.09(d,J＝7.2Hz,1H),7.78–7.66(m,2H),7.56(s,1H),7.40(d,J＝11.4Hz,1H),7.26–7.15(m,2H),6.32(d,J＝1.9Hz,1H),6.08(s,2H),5.33(tt,J＝6.5,3.5Hz,1H),3.83(s,4H),3.16–3.03(m,2H),2.54(s,1H),1.73(d,J＝6.3Hz,3H),1.23(dd,J＝18.5,6.9Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.09 (d, J = 7.2Hz, 1H), 7.78–7.66 (m, 2H), 7.56 (s, 1H), 7.40 (d, J = 11.4Hz, 1H),7.26–7.15(m,2H),6.32(d,J＝1.9Hz,1H),6.08(s,2H),5.33(tt,J＝6.5,3.5Hz,1H),3.83(s,4H ), 3.16–3.03(m,2H),2.54(s,1H),1.73(d,J＝6.3Hz,3H),1.23(dd,J＝18.5,6.9Hz,6H).
实施例101：(R)-(8-氨基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四烷-14基)(吡咯烷-1-基)甲酮(101)的制备
Example 101: (R)-(8-amino-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyrazole And[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecan-14yl) (pyrrole Preparation of alk-1-yl)methanone (101)
步骤1：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(101a)的制备Step 1: Preparation of 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (101a)
于室温，向6-氨基烟酸甲酯(1.50g，9.86mmol，1.00equiv)的1,4二氧六环(30.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(3.19g，10.8mmol，1.10equiv)和碳酸氢钠(2.48g，29.6mmol，3.00equiv)，于80℃搅拌过夜。反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物2.1g。收率61.2％。To a solution of 6-aminonicotinic acid methyl ester (1.50 g, 9.86 mmol, 1.00 equiv) in 1,4 dioxane (30.0 mL) was added 1-bromo-3-(3-bromo-1-methyl 1H-pyrazol-4-yl)propan-2-one (58b) (3.19g, 10.8mmol, 1.10equiv) and sodium bicarbonate (2.48g, 29.6mmol, 3.00equiv) were stirred at 80°C overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 2.1 g of the title compound as a light yellow oil. Yield 61.2%.
LC-MS：m/z 349.10[M+H]+。LC-MS: m/z 349.10[M+H] + .
步骤2：(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)(吡咯烷-1-基)甲酮(101b)的制备 Step 2: (2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)(pyrrolidin-1- Preparation of methyl ketone (101b)
于室温，向2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(500mg，1.43mmol，1.00equiv)的甲醇(4.0mL)溶液中加入吡咯烷(4.0mL)，于80℃搅拌过夜。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物500mg。收率90.3％。To 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (500 mg, 1.43 mmol) at room temperature , 1.00 equiv) in methanol (4.0 mL), add pyrrolidine (4.0 mL), and stir at 80°C overnight. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 500 mg of the title compound as a light yellow oil. The yield is 90.3%.
LC-MS：m/z 387.10[M+H]+。LC-MS: m/z 387.10[M+H] + .
其他步骤与实施例12相同，除了用(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)(吡咯烷-1-基)甲酮(101b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物101。Other steps are the same as Example 12, except using (2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl )(pyrrolidin-1-yl)methanone (101b) instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl) in step 3 -6-(trifluoromethyl)imidazo[1,2-a]pyridine (12b) to obtain compound 101.
LC-MS：m/z 538.05[M+H]+。LC-MS: m/z 538.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝1.4Hz,1H),7.76–7.66(m,2H),7.60(d,J＝9.6Hz,2H),7.37(dd,J＝9.2,1.6Hz,1H),7.28–7.14(m,2H),6.35(d,J＝1.8Hz,1H),6.11(s,2H),5.34(tt,J＝6.5,3.8Hz,1H),3.89(d,J＝15.0Hz,1H),3.83(s,3H),3.44(t,J＝6.6Hz,4H),3.18(d,J＝14.9Hz,1H),1.82(dd,J＝14.0,7.1Hz,4H),1.73(d,J＝6.2Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.47 (d, J = 1.4 Hz, 1H), 7.76–7.66 (m, 2H), 7.60 (d, J = 9.6 Hz, 2H), 7.37 (dd, J＝9.2,1.6Hz,1H),7.28–7.14(m,2H),6.35(d,J＝1.8Hz,1H),6.11(s,2H),5.34(tt,J＝6.5,3.8Hz,1H ),3.89(d,J＝15.0Hz,1H),3.83(s,3H),3.44(t,J＝6.6Hz,4H),3.18(d,J＝14.9Hz,1H),1.82(dd,J =14.0,7.1Hz,4H),1.73(d,J=6.2Hz,3H).
实施例102：(R)-N-(8-氨基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-14基)环丙烷甲酰胺(102)的制备
Example 102: (R)-N-(8-amino-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1] Pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-14yl ) Preparation of cyclopropanecarboxamide (102)
步骤1：N-(6-氟吡啶-3-基)环丙烷甲酰胺(102a)的制备Step 1: Preparation of N-(6-fluoropyridin-3-yl)cyclopropanecarboxamide (102a)
于0℃，向6-氟吡啶-3-胺(500mg，4.46mmol，1.00equiv)的二氯甲烷(20.0mL)溶液中加入环丙烷酰氯(559mg，5.35mmol，1.20equiv)和三乙胺(1.24ml，89.2mmol，2.00equiv)，于室温搅拌2小时。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物800mg。收率99.6％。To a solution of 6-fluoropyridin-3-amine (500 mg, 4.46 mmol, 1.00 equiv) in dichloromethane (20.0 mL) was added cyclopropane acid chloride (559 mg, 5.35 mmol, 1.20 equiv) and triethylamine ( 1.24ml, 89.2mmol, 2.00equiv), stir at room temperature for 2 hours. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 800 mg of the title compound as a light yellow oil. The yield is 99.6%.
LC-MS：m/z 181.10[M+H]+。 LC-MS: m/z 181.10[M+H] + .
步骤2：N-(6-氨基吡啶-3-基)环丙烷酰胺(102b)的制备Step 2: Preparation of N-(6-aminopyridin-3-yl)cyclopropanamide (102b)
于室温，将N-(6-氟吡啶-3-基)环丙烷甲酰胺(1.4g，7.77mmol，1.00equiv)溶于氨水(30.0mL)中，升温至120℃搅拌过夜。将反应液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物590mg。收率42.9％。Dissolve N-(6-fluoropyridin-3-yl)cyclopropanecarboxamide (1.4g, 7.77mmol, 1.00equiv) in ammonia water (30.0mL) at room temperature, raise the temperature to 120°C and stir overnight. The reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 590 mg of the title compound as a light yellow oil. Yield 42.9%.
LC-MS：m/z 178.10[M+H]+。LC-MS: m/z 178.10[M+H] + .
步骤3：N-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)环丙烷甲酰胺(102c)的制备Step 3: N-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)cyclopropanecarboxamide Preparation of (102c)
于室温，向N-(6-氨基吡啶-3-基)环丙烷酰胺(300mg，1.69mmol，1.00equiv)的1,4-二氧六环(20.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(548mg，1.86mmol，1.10equiv)和碳酸氢钠(427mg，5.08mmol，3.00equiv)，于80℃搅拌过夜。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物240mg。收率38.1％。To a solution of N-(6-aminopyridin-3-yl)cyclopropanamide (300 mg, 1.69 mmol, 1.00 equiv) in 1,4-dioxane (20.0 mL) was added 1-bromo-3- (3-Bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (548 mg, 1.86 mmol, 1.10 equiv) and sodium bicarbonate (427 mg, 5.08 mmol, 3.00 equiv), Stir at 80°C overnight. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 240 mg of the title compound as a light yellow oil. The yield is 38.1%.
LC-MS：m/z 374.10[M+H]+。LC-MS: m/z 374.10[M+H] + .
其他步骤与实施例12相同，除了用N-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)环丙烷甲酰胺(102c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物102。Other steps are the same as Example 12, except using N-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6 -yl)cyclopropanecarboxamide (102c) instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-( Trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 102.
LC-MS：m/z 524.05[M+H]+。LC-MS: m/z 524.05[M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),9.18–9.12(m,1H),7.75–7.61(m,2H),7.61–7.51(m,2H),7.28–7.13(m,3H),6.33(d,J＝1.8Hz,1H),6.06(s,2H),5.34(dt,J＝6.6,3.7Hz,1H),3.82(s,3H),3.14(d,J＝14.9Hz,1H),2.54(s,2H),1.78–1.74(m,1H),1.72(d,J＝6.2Hz,3H),0.78(q,J＝4.7,3.9Hz,4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.28(s,1H),9.18–9.12(m,1H),7.75–7.61(m,2H),7.61–7.51(m,2H),7.28–7.13 (m,3H),6.33(d,J＝1.8Hz,1H),6.06(s,2H),5.34(dt,J＝6.6,3.7Hz,1H),3.82(s,3H),3.14(d, J＝14.9Hz,1H),2.54(s,2H),1.78–1.74(m,1H),1.72(d,J＝6.2Hz,3H),0.78(q,J＝4.7,3.9Hz,4H).
实施例103：(R)-14-(环丙基磺酰基)-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]哒嗪并[6',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(103)的制备

Example 103: (R)-14-(cyclopropylsulfonyl)-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo [l]pyrazolo[4,3-j]pyridazino[6',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecane Preparation of en-8-amine (103)

步骤1：6-(环丙基磺酰基)咪唑并[1,2-b]哒嗪-2-羧酸甲酯(103a)的制备Step 1: Preparation of 6-(cyclopropylsulfonyl)imidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (103a)
于室温，向6-氯咪唑并[1,2-b]哒嗪-2-羧酸甲酯(1.50g，7.10mmol，1.00equiv)的DMSO(20.00mL)溶液中加入环丙基亚磺酸钠(1.00g，7.81mmol，1.10equiv)和碘化亚铜(270mg，1.42mmol，0.200equiv)。于氮气氛围下，140℃搅拌6h。加水淬灭，EA萃取，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝3:1)，得到白色固体状的标题化合物1.5g，收率75.2％。To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (1.50 g, 7.10 mmol, 1.00 equiv) in DMSO (20.00 mL) at room temperature was added cyclopropylsulfinic acid Sodium (1.00g, 7.81mmol, 1.10equiv) and copper iodide (270mg, 1.42mmol, 0.200equiv). Stir at 140°C for 6 hours under nitrogen atmosphere. Add water to quench, extract with EA, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to obtain 1.5 g of the title compound as a white solid, with a yield of 75.2%.
LC-MS：m/z 282.05[M+H]+。LC-MS: m/z 282.05[M+H] + .
步骤2：6-(环丙基磺酰基)咪唑并[1,2-b]哒嗪-2-甲醛(103b)的制备Step 2: Preparation of 6-(cyclopropylsulfonyl)imidazo[1,2-b]pyridazine-2-carbaldehyde (103b)
氮气氛围下，于-78℃向6-(环丙基磺酰基)咪唑并[1,2-b]哒嗪-2-羧酸甲酯(1.30g，4.62mmol，1.00equiv)的二氯甲烷(20.0mL)溶液中加入二异丁基氢化铝(9.25mL，9.25mmol，2.00equiv)，继续搅拌1.5小时。缓慢加入甲醇淬灭，加入1M盐酸调节PH至约7，反应混合物用二氯甲烷萃取(3X50毫升)。合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝1:1)，得到白色固体状的标题化合物900mg。收率77.6％Under nitrogen atmosphere, add 6-(cyclopropylsulfonyl)imidazo[1,2-b]pyridazine-2-carboxylic acid methyl ester (1.30g, 4.62mmol, 1.00equiv) in dichloromethane at -78°C. (20.0 mL) diisobutylaluminum hydride (9.25 mL, 9.25 mmol, 2.00 equiv) was added to the solution, and stirring was continued for 1.5 hours. Methanol was slowly added to quench, 1M hydrochloric acid was added to adjust the pH to about 7, and the reaction mixture was extracted with dichloromethane (3X50 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 1:1) to obtain 900 mg of the title compound as a white solid. Yield 77.6%
LC-MS：m/z 252.05[M+H]+。LC-MS: m/z 252.05[M+H] + .
其他步骤与实施例14的制备方法相同，除了用6-(环丙基磺酰基)咪唑并[1,2-b]哒嗪-2-甲醛(103b)代替步骤2中的6-(三氟甲基)咪唑并[1,2-a]吡啶-2-甲醛，制得化合物103。Other steps are the same as the preparation method of Example 14, except that 6-(cyclopropylsulfonyl)imidazo[1,2-b]pyridazine-2-carbaldehyde (103b) is used instead of 6-(trifluorofluoride) in step 2. Methyl)imidazo[1,2-a]pyridine-2-carboxaldehyde gave compound 103.
LC-MS：m/z 546[M+H]+。LC-MS: m/z 546[M+H] + .
实施例104：(R)-3-氟-5,20-二甲基-14-(噻唑-2-基)-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(104)的制备
Example 104: (R)-3-fluoro-5,20-dimethyl-14-(thiazol-2-yl)-18,20-dihydro-5H-7,11-(methylene)benzo [l]pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecene -Preparation of 8-amine (104)
步骤1：2-(6-氯吡啶-3-基)噻唑(104a)的制备Step 1: Preparation of 2-(6-chloropyridin-3-yl)thiazole (104a)
于室温，将5-溴-2-氯吡啶(1.22g，6.44mmol)、2-(三正丁基甲锡烷基)噻唑(3.55g，9.66mmol)、Pd(PPh3)Cl2(445mg，0.644mmol)溶于DMF(20ml)中，于100℃反应过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得白色固体标题化合物810mg，收率：63.8％。At room temperature, 5-bromo-2-chloropyridine (1.22g, 6.44mmol), 2-(tri-n-butylstannyl)thiazole (3.55g, 9.66mmol), Pd(PPh 3 )Cl 2 (445mg, 0.644 mmol) was dissolved in DMF (20 ml), reacted at 100°C overnight, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=2:1) to obtain 810 mg of the title compound as a white solid. , Yield: 63.8%.
LC-MS：m/z＝197[M+H]+。LC-MS: m/z=197[M+H] + .
步骤2：5-(噻唑-2-基)吡啶-2-胺(104b)的制备Step 2: Preparation of 5-(thiazol-2-yl)pyridin-2-amine (104b)
于室温，将2-(6-氯吡啶-3-基)噻唑(104a)(810mg，4.11mmol)溶于氨水(10ml，25％)中，于150℃微波搅拌3h，减压浓缩，得黄色固体标题化合物620mg，收率：85.2％。Dissolve 2-(6-chloropyridin-3-yl)thiazole (104a) (810 mg, 4.11 mmol) in ammonia (10 ml, 25%) at room temperature, stir in microwave at 150°C for 3 hours, and concentrate under reduced pressure to obtain yellow color The title compound was 620 mg as a solid, yield: 85.2%.
LC-MS：m/z＝178[M+H]+。LC-MS: m/z=178[M+H] + .
步骤3：2-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)噻唑(104c)的制备Step 3: 2-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)thiazole (104c) Preparation
于室温，将5-(噻唑-2-基)吡啶-2-胺(104b)(300mg，1.70mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(501mg，1.70mmol)溶于二氧六环(10ml)中，加入碳酸氢钠(285mg，2.60mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物210mg，收率：34.2％。At room temperature, 5-(thiazol-2-yl)pyridin-2-amine (104b) (300 mg, 1.70 mmol), 1-bromo-3-(3-bromo-1-methyl-1H-pyrazole-4 -Propan-2-one (58b) (501 mg, 1.70 mmol) was dissolved in dioxane (10 ml), sodium bicarbonate (285 mg, 2.60 mmol) was added, stirred at room temperature overnight, concentrated under reduced pressure, and the residue Separate and purify by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 210 mg of the title compound as a brown solid, yield: 34.2%.
LC-MS：m/z＝374[M+H]+。LC-MS: m/z=374[M+H] + .
其他步骤与实施例12相同，除了用2-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1，2-a]吡啶-6-基)噻唑(104c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物104。Other steps are the same as Example 12, except using 2-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6 -yl)thiazole (104c) instead of 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(trifluoromethyl) in step 3 yl)imidazo[1,2-a]pyridine (12b) to obtain compound 104.
LC-MS：m/z 524[M+H]+。 LC-MS: m/z 524[M+H] + .
实施例105：(R)-1-(8-氨基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-14基)吡咯烷-2-酮(105)的制备
Example 105: (R)-1-(8-amino-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1] Pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-14yl ) Preparation of pyrrolidin-2-one (105)
步骤1：1-(6-溴吡啶-3-基)吡咯烷-2-酮(105a)的制备Step 1: Preparation of 1-(6-bromopyridin-3-yl)pyrrolidin-2-one (105a)
于室温，将2-溴-5-碘吡啶(2.00g，7.04mmol)、吡咯烷-2-酮(1.20g，14.1mmol)、碘化亚铜(134mg，0.700mmol)、乙二醇(44.0mg，0.700mmol)和磷酸钾(4.50g，21.1mmol)加入到异丙醇(20ml)中，于110℃搅拌72小时。将反应液减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：PE/EA＝2:1)，得白色固体标题化合物900mg，收率：53.1％。At room temperature, 2-bromo-5-iodopyridine (2.00g, 7.04mmol), pyrrolidin-2-one (1.20g, 14.1mmol), copper iodide (134mg, 0.700mmol), ethylene glycol (44.0 mg, 0.700mmol) and potassium phosphate (4.50g, 21.1mmol) were added to isopropyl alcohol (20ml), and stirred at 110°C for 72 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=2:1) to obtain 900 mg of the title compound as a white solid, yield: 53.1%.
LC-MS：m/z＝241[M+H]+。LC-MS: m/z=241[M+H] + .
步骤2：1-(6-氨基吡啶-3-基)吡咯烷-2-酮(105b)的制备Step 2: Preparation of 1-(6-aminopyridin-3-yl)pyrrolidin-2-one (105b)
于室温，将1-(6-溴吡啶-3-基)吡咯烷-2-酮(105a)(900mg，3.75mmol)溶于氨水(10ml，25％)中，于150℃微波搅拌3h，减压浓缩，得黄色固体标题化合物500mg，收率：75.3％。Dissolve 1-(6-bromopyridin-3-yl)pyrrolidin-2-one (105a) (900mg, 3.75mmol) in ammonia water (10ml, 25%) at room temperature, stir in microwave at 150°C for 3h, reduce Concentrate under pressure to obtain 500 mg of the title compound as a yellow solid, yield: 75.3%.
LC-MS：m/z＝178[M+H]+。LC-MS: m/z=178[M+H] + .
步骤3：1-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)吡咯烷-2-酮(105c)的制备Step 3: 1-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)pyrrolidine-2 -Preparation of ketone (105c)
于室温，将1-(6-氨基吡啶-3-基)吡咯烷-2-酮(105b)(500mg，2.82mmol)、1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(831mg，2.82mmol)溶于二氧六环(15ml)中，加入碳酸氢钠(347mg，4.18mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物320mg，收率：30.9％。 At room temperature, 1-(6-aminopyridin-3-yl)pyrrolidin-2-one (105b) (500 mg, 2.82 mmol), 1-bromo-3-(3-bromo-1-methyl-1H- Dissolve pyrazol-4-yl)propan-2-one (58b) (831 mg, 2.82 mmol) in dioxane (15 ml), add sodium bicarbonate (347 mg, 4.18 mmol), stir at room temperature overnight, and reduce pressure Concentrate, and the residue is separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 320 mg of the title compound as a brown solid, yield: 30.9%.
LC-MS：m/z＝374[M+H]+。LC-MS: m/z=374[M+H] + .
其他步骤与实施例12相同，除了用1-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)吡咯烷-2-酮(105c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物105。Other steps are the same as Example 12, except using 1-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6 -yl)pyrrolidin-2-one (105c) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6 in step 3 -(Trifluoromethyl)imidazo[1,2-a]pyridine (12b) to give compound 105.
LC-MS：m/z 524[M+H]+。LC-MS: m/z 524[M+H] + .
实施例106：(R)-N-(8-氨基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3-j]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-14基甲磺酰胺(106)的制备
Example 106: (R)-N-(8-amino-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l] Pyrazolo[4,3-j]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-14yl Preparation of methanesulfonamide (106)
步骤1：N-(6-氟吡啶-3-基)甲磺酰胺(106a)的制备Step 1: Preparation of N-(6-fluoropyridin-3-yl)methanesulfonamide (106a)
于室温，将6-氟吡啶-3-胺(2.00g，17.8mmol)、三乙胺(3.60g，35.6mmol)溶于乙腈(20ml)中，将反应体系降温到0℃加入甲磺酸酐(4.64g，26.7mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物1.21g，收率，35.5％。Dissolve 6-fluoropyridin-3-amine (2.00g, 17.8mmol) and triethylamine (3.60g, 35.6mmol) in acetonitrile (20ml) at room temperature, cool the reaction system to 0°C and add methanesulfonic anhydride ( 4.64g, 26.7mmol), stirred at room temperature overnight, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=20:1) to obtain 1.21g of the title compound as a brown solid, yield , 35.5%.
LC-MS：m/z＝191[M+H]+。LC-MS: m/z=191[M+H] + .
步骤2：N-(6-氨基吡啶-3-基)甲磺酰胺的制备(106b)Step 2: Preparation of N-(6-aminopyridin-3-yl)methanesulfonamide (106b)
于室温，将N-(6-氟吡啶-3-基)甲磺酰胺(1.20g，17.8mmol)，溶于氨水(20ml)中，于100℃搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物300mg，收率，25.4％。Dissolve N-(6-fluoropyridin-3-yl)methanesulfonamide (1.20g, 17.8mmol) in ammonia water (20ml) at room temperature, stir at 100°C overnight, concentrate under reduced pressure, and use the residue with a silica gel column After separation and purification by chromatography (mobile phase: DCM/MeOH=20:1), 300 mg of the title compound was obtained as a brown solid, with a yield of 25.4%.
LC-MS：m/z＝188[M+H]+。LC-MS: m/z=188[M+H] + .
步骤3：N-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1,2-a]吡啶-6-基)甲磺酰胺(106c)的制备Step 3: N-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridin-6-yl)methanesulfonamide ( Preparation of 106c)
于室温，将N-(6-氨基吡啶-3-基)甲磺酰胺(106b)(300mg，1.60mmol)/1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(472mg，1.60mmol)溶于二氧 六环(10ml)中，加入碳酸氢钠(269mg，3.20mmol)，于室温搅拌过夜，减压浓缩，残余物用硅胶柱层析色谱法分离纯化(流动相：DCM/MeOH＝20:1)，得棕色固体标题化合物400mg，收率，65.3％。At room temperature, N-(6-aminopyridin-3-yl)methanesulfonamide (106b) (300 mg, 1.60 mmol)/1-bromo-3-(3-bromo-1-methyl-1H-pyrazole- 4-yl)propan-2-one (58b) (472 mg, 1.60 mmol) dissolved in dioxygen To six rings (10 ml), add sodium bicarbonate (269 mg, 3.20 mmol), stir at room temperature overnight, concentrate under reduced pressure, and use silica gel column chromatography to separate and purify the residue (mobile phase: DCM/MeOH=20:1) , 400 mg of the title compound was obtained as a brown solid, yield 65.3%.
LC-MS：m/z＝384[M+H]+。LC-MS: m/z=384[M+H] + .
其他步骤与实施例12相同，除了用N-(2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)咪唑并[1，2-a]吡啶-6-基)甲磺酰胺(106c)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物106。Other steps are the same as Example 12, except using N-(2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)imidazo[1,2-a]pyridine-6 -yl)methanesulfonamide (106c) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(tris Fluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 106.
LC-MS：m/z 534[M+H]+。LC-MS: m/z 534[M+H] + .
实施例107：(R)-14-乙氧基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[1]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(107)的制备
Example 107: (R)-14-ethoxy-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[1]pyridine Azolo[4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine (107 ) preparation
步骤1：(5-(溴甲基)吡嗪-2-基)氨基甲酸叔丁酯(107a)的制备Step 1 Preparation of: (5-(bromomethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (107a)
于室温，向(5-甲基吡嗪-2-基)氨基甲酸叔丁酯(10.0g，47.8mmol，1.00equiv)的四氯化碳(100mL)溶液中加入NBS(10.2g，57.4mmol，1.20equiv)和AIBN(3.90g，23.9mmol，0.500equiv)，于85℃搅拌3h。反应液用水稀释。用二氯甲烷萃取(3X150毫升)。合并有机相，无水硫酸钠干燥。过滤，将滤液减压浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/石油醚/乙酸乙酯＝4：5：1)，得到黄色固体状的标题化合物9.0g，收率65.6％To a solution of (5-methylpyrazin-2-yl)carbamic acid tert-butyl ester (10.0g, 47.8mmol, 1.00equiv) in carbon tetrachloride (100mL) was added NBS (10.2g, 57.4mmol, 1.20 equiv) and AIBN (3.90 g, 23.9 mmol, 0.500 equiv), stirred at 85°C for 3 h. The reaction solution was diluted with water. Extract with dichloromethane (3X150 ml). The organic phases were combined and dried over anhydrous sodium sulfate. Filter, and concentrate the filtrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/petroleum ether/ethyl acetate=4:5:1) to obtain 9.0g of the title compound as a yellow solid, with a yield of 65.6%.
LC-MS：m/z 288.10[M+H]+。LC-MS: m/z 288.10[M+H] + .
步骤2：(5-(乙氧基甲基)吡嗪-2-基)氨基甲酸叔丁酯(107b)的制备Step 2 Preparation of: (5-(ethoxymethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (107b)
于室温，向(5-(溴甲基)吡嗪-2-基)氨基甲酸叔丁酯(3.00g，10.4mmol，1.00equiv)的无水乙醇(40.0mL)溶液中加入碳酸钾(2.16g，15.6mmol，1.50equiv)，于室温搅拌2小时。将反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：石油醚/乙酸乙酯＝5:1)，得到淡黄色油状的标题化合物700mg，收率26.5％。 To a solution of (5-(bromomethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (3.00g, 10.4mmol, 1.00equiv) in absolute ethanol (40.0mL) was added potassium carbonate (2.16g) at room temperature. , 15.6mmol, 1.50equiv), stirred at room temperature for 2 hours. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate = 5:1) to obtain 700 mg of the title compound as a light yellow oil, with a yield of 26.5%.
LC-MS：m/z 254.10[M+H]+。LC-MS: m/z 254.10[M+H] + .
步骤3：5-(乙氧基甲基)吡嗪-2-胺(107c)的制备Step 3: Preparation of 5-(ethoxymethyl)pyrazin-2-amine (107c)
于室温，向(5-(乙氧基甲基)吡嗪-2-基)氨基甲酸叔丁酯(900mg，3.55mmol，1.00equiv)的二氯甲烷(10.0mL)溶液中加入三氟乙酸(2.00mL)，于室温搅拌3小时。将反应液浓缩。加入碳酸氢钠调至碱性，残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物500mg，收率91.4％。To a solution of (5-(ethoxymethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (900 mg, 3.55 mmol, 1.00 equiv) in dichloromethane (10.0 mL) at room temperature was added trifluoroacetic acid ( 2.00 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated. Sodium bicarbonate was added to make it alkaline, and the residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 500 mg of the title compound as a light yellow oil, with a yield of 91.4%.
LC-MS：m/z 154.10[M+H]+。LC-MS: m/z 154.10[M+H] + .
步骤4：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(乙氧基甲基)咪唑并[1,2-a]吡嗪(107d)的制备Step 4: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(ethoxymethyl)imidazo[1,2-a]pyrazine ( Preparation of 107d)
于室温，向5-(乙氧基甲基)吡嗪-2-胺(500mg，3.24mmol，1.00equiv)的1,4-二氧六环(30.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(1.00g，3.57mmol，1.00equiv)和碳酸氢钠(818mg，9.74mmol，3.00equiv)，于80℃搅拌过夜。将反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物310mg，收率27.4％。To a solution of 5-(ethoxymethyl)pyrazin-2-amine (500 mg, 3.24 mmol, 1.00 equiv) in 1,4-dioxane (30.0 mL) at room temperature was added 1-bromo-3- (3-Bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (1.00g, 3.57mmol, 1.00equiv) and sodium bicarbonate (818mg, 9.74mmol, 3.00equiv) , stir overnight at 80°C. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 310 mg of the title compound as a light yellow oil, with a yield of 27.4%.
LC-MS：m/z 350.10[M+H]+。LC-MS: m/z 350.10[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(乙氧基甲基)咪唑并[1,2-a]吡嗪(107d)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物107。Other steps are the same as Example 12, except using 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(ethoxymethyl)imidazo[1, 2-a]pyrazine (107d) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-(tris Fluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 107.
LC-MS：m/z 500[M+H]+。LC-MS: m/z 500[M+H] + .
实施例108：(R)-3-氟-14-异丙氧基-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(108)的制备
Example 108: (R)-3-fluoro-14-isopropoxy-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l] Pyrazolo[4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine ( 108) Preparation
步骤1：5-(异丙氧基甲基)吡嗪-2-胺(108a)的制备Step 1: Preparation of 5-(isopropoxymethyl)pyrazin-2-amine (108a)
于室温，将(5-(溴甲基)吡嗪-2-基)氨基甲酸叔丁酯(1.00g，3.95mmol，1.00equiv)溶于无水异丙醇(10.0mL)中，于75℃搅拌24小时。将反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到黄色固体的标题化合物500mg，收率47.4％。Dissolve (5-(bromomethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (1.00g, 3.95mmol, 1.00equiv) in anhydrous isopropyl alcohol (10.0mL) at room temperature, at 75°C Stir for 24 hours. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 500 mg of the title compound as a yellow solid, with a yield of 47.4%.
LC-MS：m/z 168.10[M+H]+。LC-MS: m/z 168.10[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(异丙氧基甲基)咪唑并[1,2-a]吡嗪(108b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(isopropoxymethyl)imidazo[1,2-a]pyrazine Preparation of (108b)
于室温，向5-(异丙氧基甲基)吡嗪-2-胺(500mg，2.99mmol，1.00equiv)的1，4-二氧六环(30.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(880mg，2.99mmol，1.00equiv)和碳酸氢钠(754mg，8.98mmol，3.00equiv)，于80℃搅拌过夜。将反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物200mg，收率18.4％。To a solution of 5-(isopropoxymethyl)pyrazin-2-amine (500 mg, 2.99 mmol, 1.00 equiv) in 1,4-dioxane (30.0 mL) at room temperature was added 1-bromo-3 -(3-Bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (880 mg, 2.99 mmol, 1.00 equiv) and sodium bicarbonate (754 mg, 8.98 mmol, 3.00 equiv) , stir overnight at 80°C. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 200 mg of the title compound as a light yellow oil, with a yield of 18.4%.
LC-MS：m/z 364.10[M+H]+。LC-MS: m/z 364.10[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(异丙氧基甲基)咪唑并[1,2-a]吡嗪(108b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物108。Other steps are the same as in Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(isopropoxymethyl)imidazo[1 ,2-a]pyrazine (108b) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-( Trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 108.
LC-MS：m/z 514[M+H]+。LC-MS: m/z 514[M+H] + .
实施例109：(R)-14-环丙氧基-3-氟-5,20-二甲基-18,20-二氢-5H-7,11-(亚甲基)苯并[l]吡唑并[4,3]吡啶并[2',1':2,3]咪唑并[4,5-g][1]氧杂[4]氮杂环十四碳烯-8-胺(109)的制备
Example 109: (R)-14-cyclopropoxy-3-fluoro-5,20-dimethyl-18,20-dihydro-5H-7,11-(methylene)benzo[l] Pyrazolo[4,3]pyrido[2',1':2,3]imidazo[4,5-g][1]oxa[4]azacyclotetradecen-8-amine ( 109) Preparation
步骤1：5-(环丙氧基甲基)吡嗪-2-胺(109a)的制备Step 1: Preparation of 5-(cyclopropoxymethyl)pyrazin-2-amine (109a)
于室温，(5-(溴甲基)吡嗪-2-基)氨基甲酸叔丁酯(1.00g，3.95mmol，1.00equiv) 溶于无水环丙醇(5.00mL)中，于75℃搅拌24小时。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到黄色固体的标题化合物300mg，收率46.0％。(5-(bromomethyl)pyrazin-2-yl)carbamic acid tert-butyl ester (1.00g, 3.95mmol, 1.00equiv) at room temperature Dissolve in anhydrous cyclopropanol (5.00 mL) and stir at 75°C for 24 hours. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 300 mg of the title compound as a yellow solid, with a yield of 46.0%.
LC-MS：m/z 166.10[M+H]+。LC-MS: m/z 166.10[M+H] + .
步骤2：2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(环丙氧基甲基)咪唑并[1,2-a]吡嗪(109b)的制备Step 2: 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(cyclopropoxymethyl)imidazo[1,2-a]pyrazine Preparation of (109b)
于室温，向5-(环丙氧基甲基)吡嗪-2-胺(300mg，1.81mmol，1.00equiv)的1,4-二氧六环(10.0mL)溶液中加入1-溴-3-(3-溴-1-甲基-1H-吡唑-4-基)丙-2-酮(58b)(534mg，1.81mmol，1.00equiv)和碳酸氢钠(458mg，5.45mmol，3.00equiv)，于80℃搅拌过夜。反应液浓缩。残余物用硅胶柱层析色谱法分离纯化(流动相：二氯甲烷/甲醇＝10:1)，得到淡黄色油状的标题化合物180mg，收率27.5％。To a solution of 5-(cyclopropoxymethyl)pyrazin-2-amine (300 mg, 1.81 mmol, 1.00 equiv) in 1,4-dioxane (10.0 mL) at room temperature was added 1-bromo-3 -(3-Bromo-1-methyl-1H-pyrazol-4-yl)propan-2-one (58b) (534 mg, 1.81 mmol, 1.00 equiv) and sodium bicarbonate (458 mg, 5.45 mmol, 3.00 equiv) , stir overnight at 80°C. The reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (mobile phase: methylene chloride/methanol = 10:1) to obtain 180 mg of the title compound as a light yellow oil, with a yield of 27.5%.
LC-MS：m/z 362.10[M+H]+。LC-MS: m/z 362.10[M+H] + .
其他步骤与实施例12相同，除了用2-((3-溴-1-甲基-1H-吡唑-4-基)甲基)-6-(环丙氧基甲基)咪唑并[1,2-a]吡嗪(109b)代替步骤3中的2-((5-溴-2-甲基-2H-1,2,3-三唑-4-基)甲基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(12b)，得到化合物109。Other steps are the same as Example 12, except that 2-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-6-(cyclopropoxymethyl)imidazo[1 ,2-a]pyrazine (109b) replaces 2-((5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)-6-( Trifluoromethyl)imidazo[1,2-a]pyridine (12b) gave compound 109.
LC-MS:m/z 512[M+H]+。LC-MS: m/z 512[M+H] + .
生物学评价biological evaluation
试验例1：本发明化合物对肿瘤细胞增殖的抑制活性测试Test Example 1: Test of the inhibitory activity of the compound of the present invention on tumor cell proliferation
检测本发明化合物对BaF3-EML4-ALK-WT V1和BaF3-EML4-ALK-G1202R/L1196M稳转细胞株的抑制活性，根据检测指标IC50，筛选候选化合物。The inhibitory activity of the compounds of the present invention on BaF3-EML4-ALK-WT V1 and BaF3-EML4-ALK-G1202R/L1196M stably transfected cell lines is detected, and candidate compounds are screened according to the detection index IC 50 .
实验方法：experimental method:
亲本BaF3稳转细胞株(购自国家实验细胞资源共享服务平台)，转染EML4-ALK-WT、BaF3-EML4-ALK-G1202R/L1196M和BaF3 CD74-ROS1 G2032R获得稳定表达的细胞株。以上细胞均培养于RPMI1640(Invitrogen)，加入10％的FBS(Gbico)、1X Penicillin-Streptomycin(1％的青霉素和链霉素，Invitrogen)和Zeocin(1000μg/mL，Invitrogen)。待细胞生长至对数期，离心收集细胞，采用台盼蓝方法检测细胞活力，确保细胞活力大于90％。将细胞接种在白色透明底384孔板中(Corning，3570)，450个细胞/孔。加入待测化合物，化合物用DMSO溶解，稀释，起始浓度从10mM开始，3倍稀释，设置10个浓度梯度，每个梯度3个复孔。37℃，5％CO2共培养72小时。使用CELL Titer-GLO发光法，检测总的ATP含量来测定细胞增殖水平。将384孔板细胞取出，室温平衡30分钟，每孔加入20μL CellTiter Glo(Promega)，振荡混匀，室温孵育10分钟。The parental BaF3 stably transfected cell line (purchased from the National Experimental Cell Resource Sharing Service Platform) was transfected with EML4-ALK-WT, BaF3-EML4-ALK-G1202R/L1196M and BaF3 CD74-ROS1 G2032R to obtain a stably expressed cell line. The above cells were cultured in RPMI1640 (Invitrogen), and 10% FBS (Gbico), 1X Penicillin-Streptomycin (1% penicillin and streptomycin, Invitrogen) and Zeocin (1000 μg/mL, Invitrogen) were added. When the cells grow to the logarithmic phase, the cells are collected by centrifugation, and the cell viability is detected using the trypan blue method to ensure that the cell viability is greater than 90%. Cells were seeded in a white transparent bottom 384-well plate (Corning, 3570) at 450 cells/well. Add the compound to be tested, dissolve the compound in DMSO, and dilute it. The starting concentration starts from 10mM, dilute 3 times, and set up 10 concentration gradients, with 3 duplicate wells for each gradient. Incubate for 72 hours at 37°C, 5% CO2 . Use the CELL Titer-GLO luminescence method to detect total ATP content to determine cell proliferation levels. Remove the cells from the 384-well plate and equilibrate at room temperature for 30 minutes. Add 20 μL CellTiter Glo (Promega) to each well, shake to mix, and incubate at room temperature for 10 minutes.
使用多功能酶标仪(Biotek，型号Cytation 3)读取发光值。使用GraphPad Prism 6.0软件分析不同浓度下化合物反应的Log值，来测定IC50。 Luminescence values were read using a multifunctional microplate reader (Biotek, model Cytation 3). Use GraphPad Prism 6.0 software to analyze the Log values of compound reactions at different concentrations to determine IC 50 .
本发明化合物ALK相关稳转细胞株增殖抑制的IC50值见下表1。The IC 50 values of the compounds of the present invention that inhibit the proliferation of ALK-related stably transfected cell lines are shown in Table 1 below.
在表1中，A是指化合物对细胞增殖水平的抑制活性IC50<10nM；B是指10nM<IC50<100nM；C是指100nM<IC50<500nM；D是指IC50>500nM。In Table 1, A refers to the inhibitory activity of the compound on cell proliferation level, IC 50 <10nM; B refers to 10nM <IC 50 <100nM; C refers to 100nM <IC 50 <500nM; D refers to IC 50 >500nM.
表1本发明化合物对BaF3-EML4-ALK-WT、BaF3-EML4-ALK-G1202R/L1196M和BaF3 CD74-ROS1 G2032R细胞抑制的IC50值


Table 1 IC 50 values of compounds of the present invention inhibiting BaF3-EML4-ALK-WT, BaF3-EML4-ALK-G1202R/L1196M and BaF3 CD74-ROS1 G2032R cells


结论：本发明化合物对BaF3-EML4-ALK-WT、BaF3-EML4-ALK-G1202R/L1196M和BaF3-CD74-ROS1-G2032R细胞株的增殖具有显著抑制作用。Conclusion: The compounds of the present invention have a significant inhibitory effect on the proliferation of BaF3-EML4-ALK-WT, BaF3-EML4-ALK-G1202R/L1196M and BaF3-CD74-ROS1-G2032R cell lines.
试验例2：本发明化合物ICR小鼠体内药代动力学评价Test Example 2: Evaluation of the pharmacokinetics of the compound of the present invention in ICR mice
雄性7-8周龄ICR小鼠(北京市维通利华实验动物技术有限公司)饲养于SPF环境，温度20～26℃，每日温差不超过4℃，相对湿度40～70％RH，每日12h/12h交替照明。实验动物经过3-5天的适应期，其中口服给药动物于实验前1天禁食过夜(>12h)，不禁水，口服给予本发明化合物(称量2.5mg，加100％混合溶媒(10％NMP+49％PEG400+1％吐温80+40％水)定容至5mL，再用超声仪超声至均一溶液)。分别于给药前和给药后15min、30min、1h、2h、4h、6h、8h进行眼眶采血。血液经乙二胺四乙酸二钾抗凝，于4℃，3500rpm离心10分钟，获取血浆，并在-20℃保存直至测试。Male 7-8 week old ICR mice (Beijing Weitonglihua Experimental Animal Technology Co., Ltd.) were raised in an SPF environment at a temperature of 20-26°C, a daily temperature difference of no more than 4°C, and a relative humidity of 40-70% RH. Alternate lighting at 12h/12h day. After an adaptation period of 3-5 days, the experimental animals were given oral administration. The animals were fasted overnight (>12h) one day before the experiment and were not allowed to drink water. The compounds of the present invention were orally administered (weighing 2.5 mg, adding 100% mixed solvent (10 % NMP + 49% PEG400 + 1% Tween 80 + 40% water), adjust the volume to 5 mL, and then use an ultrasonicator to sonicate until a homogeneous solution). Orbital blood collection was performed before administration and at 15min, 30min, 1h, 2h, 4h, 6h, and 8h after administration. The blood was anticoagulated with dipotassium ethylenediaminetetraacetate, centrifuged at 3500 rpm for 10 minutes at 4°C, and the plasma was obtained and stored at -20°C until testing.
取血浆样品50μL于1.5mL EP管中，加入400μL含内标的乙腈溶液，涡旋1分钟充分混匀，10000rpm离心10分钟。移取上清液0.2mL，用0.22μM有机膜过滤后加入进样小瓶中，使用LC-MS/MS的分析方法检测样品中化合物浓度。采用MAS Studio(V1.3.1stable)软件计算并得到化合物在小鼠体内的血药浓度-时间曲线，以及主要的PK参数：AUC0-t、Cmax、Tmax、T1/2和F％，F％＝(AUCpo×Doseiv) /(AUCiv×Dosepo)×100％。Take 50 μL of plasma sample into a 1.5 mL EP tube, add 400 μL of acetonitrile solution containing internal standard, vortex for 1 minute to mix thoroughly, and centrifuge at 10,000 rpm for 10 minutes. Pipette 0.2 mL of the supernatant, filter it with a 0.22 μM organic membrane, and add it to the injection vial. Use the LC-MS/MS analysis method to detect the compound concentration in the sample. MAS Studio (V1.3.1stable) software was used to calculate and obtain the blood concentration-time curve of the compound in mice, as well as the main PK parameters: AUC 0-t , C max , T max , T 1/2 and F% , F%=(AUC po ×Dose iv ) /(AUC iv ×Dose po )×100%.
本发明化合物口服给药后药代实验数据见表2：The pharmacokinetic experimental data of the compounds of the present invention after oral administration are shown in Table 2:
在表2中，A是指化合物的AUC0-t(μg/L*h)<5000；B是指5000<AUC0-t(μg/L*h)<10000；C是指10000<AUC0-t(μg/L*h)<20000；D是指20000<AUC0-t(μg/L*h)。In Table 2, A refers to the AUC 0-t (μg/L*h)<5000 of the compound; B refers to 5000<AUC 0-t (μg/L*h)<10000; C refers to 10000<AUC 0 -t (μg/L*h)<20000; D means 20000<AUC 0-t (μg/L*h).
表2单次口服给予雄性ICR小鼠本发明化合物的药动学参数
Table 2 Pharmacokinetic parameters of the compounds of the present invention after a single oral administration to male ICR mice
结论：本发明化合物口服给予小鼠有良好的体内药代动力学性质。Conclusion: The compound of the present invention has good pharmacokinetic properties in vivo when administered orally to mice.
试验例3：本发明化合物小鼠皮下异种移植瘤药效实验Test Example 3: Experiment on the efficacy of the compound of the present invention on subcutaneous xenograft tumors in mice
小鼠原B细胞BaF3来源于协和细胞资源中心。载体构建委托苏州金唯智生物科技有限公司完成，本实验室通过电转，筛选阳性克隆等流程，得到BaF3 EML4-ALK-G1202R、BaF3 EML4-ALK-G1202R-L1196M和BaF3 CD74-ROS1 G2032R细胞。Mouse primary B cell BaF3 was obtained from Concordia Cell Resource Center. The vector construction was entrusted to Suzhou Jinweizhi Biotechnology Co., Ltd. Our laboratory obtained BaF3 EML4-ALK-G1202R, BaF3 EML4-ALK-G1202R-L1196M and BaF3 CD74-ROS1 G2032R cells through electroporation, screening of positive clones and other processes.
实验动物选用7-8周龄雌性Balb/c Nude小鼠，购自北京维通利华实验动物技术有限公司，饲养于SPF环境，温度20～26℃，每日温差不超过4℃，相对湿度40～70％RH，每日12h/12h交替照明。实验动物经过3-5天的适应期。Experimental animals were 7-8 week old female Balb/c Nude mice, purchased from Beijing Vitong Lihua Experimental Animal Technology Co., Ltd., and raised in an SPF environment at a temperature of 20 to 26°C, with a daily temperature difference of no more than 4°C and a relative humidity of 40~70%RH, 12h/12h alternating lighting every day. Experimental animals undergo an adaptation period of 3-5 days.
动物接种前2周，复苏靶细胞，采用RPMI-1640+10％FBS+1％PS+0.8μg/mL puro培养基，在37℃，5％CO2环境培养并扩增靶细胞。收集对数生长期的细胞，用PBS缓冲液洗两次后计数，细胞悬液离心后弃取上清。基质胶和PBS缓冲液按 1：1比例混匀，加入细胞沉淀中，配成浓度为5×107/ml的细胞悬液，置于冰上。用酒精棉球擦拭小鼠接种部位，用预冷的1mL注射器，在小鼠右前肢皮下接种细胞，接种体积100μL(接种量为5×106/只)。Two weeks before animal inoculation, target cells were resuscitated, and target cells were cultured and expanded using RPMI-1640+10% FBS+1% PS+0.8 μg/mL puro medium at 37°C in a 5% CO2 environment. Collect cells in the logarithmic growth phase, wash twice with PBS buffer and count, centrifuge the cell suspension and discard the supernatant. Matrigel and PBS buffer Mix evenly in a 1:1 ratio, add to the cell pellet to prepare a cell suspension with a concentration of 5×10 7 /ml, and place on ice. Use an alcohol cotton ball to wipe the mouse inoculation site, and use a pre-cooled 1mL syringe to subcutaneously inoculate cells into the right forelimb of the mouse with an inoculation volume of 100 μL (inoculation volume is 5×10 6 /mouse).
给药方式为灌胃，给药频率为一天两次。溶媒：20％HP-β-CD。小鼠每周秤重3次，并用游标卡尺测量肿瘤3次。根据公式V＝长径×短径2/2，计算肿瘤体积V；根据公式TGI(％)＝[1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％，计算化合物的肿瘤生长抑制率TGI。The administration method is intragastric administration, and the administration frequency is twice a day. Solvent: 20% HP-β-CD. Mice were weighed three times a week, and tumors were measured three times using vernier calipers. Calculate the tumor volume V according to the formula V = long diameter )/(average tumor volume at the end of treatment in the solvent control group - average tumor volume at the beginning of treatment in the solvent control group)] × 100%, calculate the tumor growth inhibition rate TGI of the compound.
本发明化合物对BaF3 EML4-ALK-G1202R小鼠皮下移植瘤的药效结果如图1A-图1C所示，小鼠体重如图2A-图2C所示；对BaF3 EML4-ALK-G1202R-L1196M小鼠皮下移植瘤的药效结果如图1D-图1F所示，小鼠体重如图2D-图2F所示；对BaF3 CD74-ROS1 G2032R小鼠皮下移植瘤的药效结果如图1G所示，小鼠体重如图2G所示。The efficacy results of the compound of the present invention on BaF3 EML4-ALK-G1202R mouse subcutaneous transplanted tumors are shown in Figure 1A-Figure 1C, and the mouse body weight is shown in Figure 2A-Figure 2C; on BaF3 EML4-ALK-G1202R-L1196M small The efficacy results of subcutaneous transplanted tumors in mice are shown in Figure 1D-Figure 1F, and the body weight of mice is shown in Figure 2D-Figure 2F; the efficacy results of subcutaneous transplanted tumors in BaF3 CD74-ROS1 G2032R mice are shown in Figure 1G. The body weight of mice is shown in Figure 2G.
结论：从图1A至图2G可以看出，本发明化合物对BaF3 EML4-ALK-G1202R、BaF3 EML4-ALK-G1202R-L1196M和BaF3 CD74-ROS1 G2032R小鼠皮下移植瘤模型有很好的抑瘤效果，且小鼠体重无异常。 Conclusion: It can be seen from Figure 1A to Figure 2G that the compounds of the present invention have good anti-tumor effects on BaF3 EML4-ALK-G1202R, BaF3 EML4-ALK-G1202R-L1196M and BaF3 CD74-ROS1 G2032R mouse subcutaneous transplant tumor models. , and the weight of the mice was normal.

Claims (24)

  1. 一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    A compound represented by general formula (I) or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof,
    其中，in,
    L选自-C(R3)(R4)-、-O-或-N(R5)-；L is selected from -C(R 3 )(R 4 )-, -O- or -N(R 5 )-;
    Y1和Y2各自独立地选自C或N；Y 1 and Y 2 are each independently selected from C or N;
    Z1和Z2各自独立地选自C或N；Z 1 and Z 2 are each independently selected from C or N;
    M1、M2和M3各自独立地选自C或N；M 1 , M 2 and M 3 are each independently selected from C or N;
    环A选自杂环基、杂芳基或芳基，其中所述杂环基、杂芳基或芳基任选进一步被一个或多个R6所取代；Ring A is selected from heterocyclyl, heteroaryl or aryl, wherein said heterocyclyl, heteroaryl or aryl is optionally further substituted by one or more R6 ;
    环B选自杂芳基、芳基、杂环基或环烷基，其中所述杂芳基、芳基、杂环基或环烷基任选进一步被一个或多个R7所取代；Ring B is selected from heteroaryl, aryl, heterocyclyl or cycloalkyl, wherein the heteroaryl, aryl, heterocyclyl or cycloalkyl is optionally further substituted by one or more R 7 ;
    R1选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；R 1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or Heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfide Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents of base, heterocyclyl, aryl and heteroaryl;
    R2选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；R 2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or Heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfide Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents of base, heterocyclyl, aryl and heteroaryl;
    R3和R4各自独立地选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环 基、芳基和杂芳基的一个或多个取代基所取代；R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, hetero Cyclic, aryl or heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from deuterium, halogen, amino , oxo group, thio group, nitro group, cyano group, hydroxyl group, mercapto group, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, deuterated alkoxy group, haloalkoxy group, hydroxyalkyl group, alkenyl group , alkynyl, cycloalkyl, heterocycle Substituted with one or more substituents of aryl, aryl and heteroaryl;
    R5选自氢、氘、烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基；所述烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；R 5 is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl or heteroaryl optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy Substituted with one or more substituents of base, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    每个R6各自独立地选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、硫代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；Each R is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, thio, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , - (CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O) R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R a ; the alkyl group, alkoxy group, alkenyl group, alkynyl group, ring Alkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl , one or more substituents of haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replace;
    或者，任意相邻的两个R6与其相连的原子一起形成环烷基、杂环基、芳基或杂芳基，其中所述环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa和-(CH2)qNRbS(O)pRa中的一个或多个取代基所取代；Alternatively, any two adjacent R 6 together with the atoms to which they are connected form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally Further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkyl Oxygen, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a and -(CH 2 ) q NR b S(O) p R a Substituted by one or more substituents;
    每个R7各自独立地选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、硫代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个取代基所取代；Each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, thio, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , - (CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O) R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R a ; the alkyl group, alkoxy group, alkenyl group, alkynyl group, ring Alkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl , one or more substituents of haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl replace;
    或者，相邻的两个R7与其相连的原子一起形成环烷基、杂环基、芳基或杂芳基，其中所述环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、 杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa和-(CH2)qNRbS(O)pRa中的一个或多个取代基所取代；Alternatively, two adjacent R 7s together with the atoms to which they are connected form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further Selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy base, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -( CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a and -(CH 2 ) q NR b S(O) p R a are substituted by one or more substituents;
    Ra选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
    Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic radical or heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者，Rb和Rc与它们相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted with one or more substituents in the heteroaryl group;
    p为0、1或2；p is 0, 1 or 2;
    q为0至6的整数。q is an integer from 0 to 6.
  2. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    The compound represented by the general formula (I) according to claim 1 or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutical Use a salt, which is a compound represented by the general formula (II) or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof ,
    其中，环A、环B、Y1、Y2、Z1、Z2、R1和R2如权利要求1所定义。Among them, Ring A, Ring B, Y 1 , Y 2 , Z 1 , Z 2 , R 1 and R 2 are as defined in claim 1.
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋 体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环B选自C6-C10芳基或5至10元杂芳基；优选5至10元杂芳基；进一步优选5元杂芳基；其中所述C6-C10芳基或5至10元杂芳基任选进一步被一个或多个R7所取代；R7如权利要求1所定义。The compound represented by the general formula (I) according to claim 1 or 2 or its meso, racemic isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is selected from C 6 -C 10 aryl or 5 to 10 membered heteroaryl; preferably 5 to 10-membered heteroaryl; further preferably 5-membered heteroaryl; wherein the C 6 -C 10 aryl or 5 to 10-membered heteroaryl is optionally further substituted by one or more R 7 ; R 7 is as as defined in claim 1.
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环B选自吡咯基、吡唑基、咪唑基、三唑基或四唑基，优选 更优选环B任选进一步被一个或多个R7所取代；R7如权利要求1所定义。The compound represented by the general formula (I) according to any one of claims 1 to 3, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl, preferably More preferred Ring B is optionally further substituted by one or more R7 ; R7 is as defined in claim 1.
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中每个R7各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基或C1-6卤代烷氧基；优选氢或C1-6烷基；更优选C1-6烷基。The compound represented by the general formula (I) according to any one of claims 1 to 4, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein each R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- 6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy or C 1-6 haloalkoxy; preferably hydrogen or C 1-6 alkyl; more preferably C 1-6 alkyl.
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自5至10元杂环基、5至10元杂芳基或C6-C10芳基；所述5至10元杂环基、5至10元杂芳基或C6-C10芳基任选进一步被一个或多个R6所取代；The compound represented by the general formula (I) according to any one of claims 1 to 5, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 5- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or a C 6 -C 10 aryl group; the 5- to 10-membered heterocyclyl group, 5 To a 10-membered heteroaryl or C 6 -C 10 aryl group is optionally further substituted by one or more R 6 ;
    每个R6各自独立地选自氢、氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基、5至6元杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa或-(CH2)qNRbS(O)pRa；所述C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基或5至6元杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基和5至6元杂芳基的一个或多个取代基所取代；Each R 6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, 6-10-membered aryl, 5- to 6-membered heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -( CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a or -(CH 2 ) q NR b S(O) p R a ; the C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group , 5 to 6 membered heterocyclyl, 6 to 10 membered aryl or 5 to 6 membered heteroaryl optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl , mercapto group, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy base, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl and 5 to 6 Substituted with one or more substituents of the heteroaryl group;
    Ra选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、烷氧基、烯基、炔 基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterium One or more of alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by substituents;
    Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic radical or heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者，Rb和Rc与它们相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
    p为0、1或2；p is 0, 1 or 2;
    q为0至6的整数。q is an integer from 0 to 6.
  7. 根据权利要求6所述的所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，每个R6各自独立地选自氢、氘、卤素、氨基、羟基、巯基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-6环烷基或5至6元杂环基；优选氢、卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基。The compound represented by the general formula (I) according to claim 6 or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or Its pharmaceutically acceptable salt, wherein each R 6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl base, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 3-6 cycloalkyl group or 5 to 6 membered heterocyclyl group ; Preferred are hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl.
  8. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自5至6元杂环基、5至6元杂芳基或苯基，所述5至6元杂环基、5至6元杂芳基或苯基进一步被一个或多个R6所取代；The compound represented by the general formula (I) according to any one of claims 1 to 5, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 5- to 6-membered heterocyclyl group, a 5- to 6-membered heteroaryl group, or a phenyl group. The base or phenyl group is further substituted by one or more R 6 ;
    其中，任意相邻的两个R6与其相连的原子一起形成C3-6环烷基、5至6元杂环基、苯基或5至6元杂芳基，其中所述C3-6环烷基、5至6元杂环基、苯基或5至6元杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基、5至6元杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、 -(CH2)qNRbC(O)ORa和-(CH2)qNRbS(O)pRa中的一个或多个取代基所取代；Wherein, any two adjacent R 6 and the atoms to which they are connected together form a C 3-6 cycloalkyl group, a 5- to 6-membered heterocyclyl group, a phenyl group or a 5- to 6-membered heteroaryl group, wherein the C 3-6 Cycloalkyl, 5 to 6 membered heterocyclyl, phenyl or 5 to 6 membered heteroaryl is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, Mercapto group, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 membered Heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -( CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a and -(CH 2 ) q NR b S(O) p R a are substituted by one or more substituents;
    Ra选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
    Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic radical or heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者，Rb和Rc与它们相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
    p为0、1或2；p is 0, 1 or 2;
    q为0至6的整数。q is an integer from 0 to 6.
  9. 根据权利要求8所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中任意相邻的两个R6与其相连的原子一起形成5至6元杂环基、苯基或5至6元杂芳基，其中所述5至6元杂环基、苯基或5至6元杂芳基任选进一步被选自氘、卤素、氨基、羟基、巯基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C3-6环烷基、5至6元杂环基的一个或多个取代基所取代；优选被选自氢、卤素、C1-6烷基、C1-6卤代烷基、C3-6环烷基的一个或多个基团所取代。The compound represented by the general formula (I) according to claim 8 or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutical Use salts, in which any two adjacent R 6 and the atoms to which they are connected together form a 5- to 6-membered heterocyclyl group, phenyl group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclyl group, phenyl group or 5 to 6 membered heteroaryl optionally further selected from deuterium, halogen, amino, hydroxyl, mercapto, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1- One or more of 6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl Substituted by substituents; preferably substituted by one or more groups selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl.
  10. 根据权利要求8所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中任意相邻的两个R6与其相连的原子一起形成5至6元杂环基、苯基或5至6元杂芳基，其中所述5至6元杂环基、苯基或5至6元杂芳基任选进一步被选自-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa和-(CH2)qNRbS(O)pRa中的一个或多个取代 基所取代；The compound represented by the general formula (I) according to claim 8 or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutical Use salts, in which any two adjacent R 6 and the atoms to which they are connected together form a 5- to 6-membered heterocyclyl group, phenyl group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclyl group, phenyl group Or the 5- to 6-membered heteroaryl group is optionally further selected from -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O )R a , -(CH 2 ) q NR b C(O)OR a and -(CH 2 ) q NR b S(O) p One or more substitutions in R a substituted by base;
    Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-6环烷基、5-6元杂环基、苯基或5-6元杂芳基，其中所述C3-6环烷基、5-6元杂环基、苯基或5-6元杂芳基任选进一步被选自氘、卤素、氨基、氰基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5-6杂环基、苯基和5-6元杂芳基中的一个或多个取代基所取代；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl Oxygen, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 3-6 cycloalkyl, 5 -6-membered heterocyclyl, phenyl or 5-6-membered heteroaryl optionally further selected from deuterium, halogen, amino, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, Substituted with one or more substituents in C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclyl, phenyl and 5-6 membered heteroaryl;
    Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5-6元杂环基、苯基或5-6元杂芳基，其中所述C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5-6元杂环基、苯基或5-6元杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy base, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl optionally further selected from deuterium, Halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl , substituted by one or more substituents in alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者，Rb和Rc与它们相连的氮原子一起形成5-8元杂环基，其中所述5-8元杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a 5-8 membered heterocyclyl group, wherein the 5-8 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
    p为1或2；p is 1 or 2;
    q为0或1，优选0。q is 0 or 1, preferably 0.
  11. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自 优选自 环A任选进一步被一个或多个R8所取代；The compound represented by the general formula (I) according to any one of claims 1 to 7, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from Preferred from Ring A is optionally further substituted by one or more R8 ;
    每个R8各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、ORa、C(O)Ra和-S(O)pRa中的一个或多个取代基所取代，所述C3-6环烷基、5至6元杂环基、6至10元芳基或5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基和C1-6卤代烷氧基中的一个或多个取代基所取代； Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a Substituted with one or more substituents, the C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl or 5 to 6 heteroaryl is optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy and C 1-6 haloalkoxy Substituted by one or more substituents;
    Ra选自C1-6烷基、C1-6氘代烷基和C1-6卤代烷基；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl and C 1-6 haloalkyl;
    p为1或2。p is 1 or 2.
  12. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环A选自 环A任选进一步被一个或多个R8所取代；The compound represented by the general formula (I) according to any one of claims 1 to 7, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from Ring A is optionally further substituted by one or more R8 ;
    每个R8各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、-(CH2)qRa、-(CH2)qORa、-C(O)Ra、-C(O)NRbRc、-S(O)pRa、-(CH2)qNRbRc和-(CH2)qNRbS(O)pRa，所述C3-6环烷基、5至6元杂环基、6至10元芳基或5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基和C1-6卤代烷氧基中的一个或多个取代基所取代；Each R 8 is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C (O)R a , -C(O)NR b R c , -S(O) p R a , -(CH 2 ) q NR b R c and -(CH 2 ) q NR b S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl or 5 to 6 heteroaryl is optionally further selected from deuterium, halogen, C 1-6 alkyl, One or more substituents of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy and C 1-6 haloalkoxy replace;
    Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-6环烷基和5-6元杂环基，所述C1-6烷基、C1-6氘代烷基和C1-6卤代烷基任选进一步被C1-6烷氧基取代；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 5-6 membered heterocyclyl, the C 1-6 alkyl The base, C 1-6 deuterated alkyl group and C 1-6 haloalkyl group are optionally further substituted by C 1-6 alkoxy group;
    Rb选自氢和C1-6烷基；R b is selected from hydrogen and C 1-6 alkyl;
    Rc选自氢、C1-6烷基、C3-6环烷基和5-6元杂环基；R c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and 5-6 membered heterocyclyl;
    或者，Rb和Rc与它们相连的氮原子一起形成5-6元杂环基，其中所述5-6元杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group, wherein the 5-6 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
    q为0或1；q is 0 or 1;
    p为1或2。p is 1 or 2.
  13. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    The compound represented by the general formula (I) according to claim 1 or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutical Use a salt, which is a compound represented by general formula (III) or its mesobody, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof ,
    其中，in,
    Y1、Y2、Y3、Y4、Y5各自独立地选自C或N；Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently selected from C or N;
    Z1、Z2、Z3、Z4、Z5各自独立地选自C或N；Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C or N;
    环C为C5-6环烷基、5至6元杂环基、5至6元杂芳基或苯基；Ring C is C 5-6 cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or phenyl;
    R9a和R9b各自独立地选自氢、氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6-10元芳基、5至6元杂芳基、-(CH2)qRa、-(CH2)qORa、-(CH2)qC(O)Ra、-(CH2)qC(O)ORa、-(CH2)qOC(O)Ra、-(CH2)qC(O)NRbRc、-(CH2)qS(O)pRa、-(CH2)qNRbRc、-(CH2)qS(O)pNRbRc、-NRaC(O)NRbRc、-(CH2)qNRbC(O)Ra、-(CH2)qNRbC(O)ORa和-(CH2)qNRbS(O)pRa；R 9a and R 9b are each independently selected from hydrogen, deuterium, halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl base, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl group, 5- to 6-membered heterocyclic group, 6-10-membered aryl group, 5- to 6-membered heteroaryl group, -(CH 2 ) q R a , -(CH 2 ) q OR a , -(CH 2 ) q C(O)R a , -(CH 2 ) q C(O)OR a , -(CH 2 ) q OC(O)R a , -(CH 2 ) q C(O)NR b R c , -(CH 2 ) q S(O) p R a , -(CH 2 ) q NR b R c , -(CH 2 ) q S(O) p NR b R c , -NR a C(O)NR b R c , -(CH 2 ) q NR b C(O)R a , -(CH 2 ) q NR b C(O)OR a and -(CH 2 ) q NR b S(O) p R a ;
    Ra选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R a is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, Wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium, halogen, amino, oxo, thio, Nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, hetero Substituted by one or more substituents in cyclic group, aryl group and heteroaryl group;
    Rb和Rc各自独立地选自氢、氘、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R b and R c are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic and heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, halogen, amino, oxo base, thio, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl , substituted by one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;
    或者，Rb和Rc与它们相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a heterocyclyl group, wherein the heterocyclyl group is optionally further selected from deuterium, halogen, amino, oxo, thio, nitro, cyano , hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and substituted by one or more substituents in the heteroaryl group;
    p为0、1或2；p is 0, 1 or 2;
    q为0至6的整数； q is an integer from 0 to 6;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    s为0、1或2；s is 0, 1 or 2;
    R1、R2、R7如权利要求1所定义。R 1 , R 2 and R 7 are as defined in claim 1.
  14. 根据权利要求13所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：The compound represented by the general formula (I) according to claim 13 or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutical Use salt where:
    选自 Selected from
    每个R9b各自独立地选自氘、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、-(CH2)qRa、-(CH2)qORa、-C(O)Ra、-C(O)NRbRc、-S(O)pRa、-(CH2)qNRbRc和-(CH2)qNRbS(O)pRa，所述C3-6环烷基、5至6元杂环基、6至10元芳基或5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基和C1-6卤代烷氧基中的一个或多个取代基所取代；Each R 9b is independently selected from deuterium, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl Base, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl, 5 to 6 membered heterocyclyl, 6 to 10 membered aryl, 5 to 6 heteroaryl, -(CH 2 ) q R a , -(CH 2 ) q OR a , -C (O)R a , -C(O)NR b R c , -S(O) p R a , -(CH 2 ) q NR b R c and -(CH 2 ) q NR b S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl or 5 to 6 heteroaryl is optionally further selected from deuterium, halogen, C 1-6 alkyl, One or more substituents of C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy and C 1-6 haloalkoxy replace;
    Ra选自C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C3-6环烷基和5-6元杂环基，所述C1-6烷基、C1-6氘代烷基或C1-6卤代烷基任选进一步被C1-6烷氧基取代；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 5-6 membered heterocyclyl, the C 1-6 alkyl The base, C 1-6 deuterated alkyl group or C 1-6 haloalkyl group is optionally further substituted by C 1-6 alkoxy group;
    Rb选自氢、C1-6烷基；R b is selected from hydrogen, C 1-6 alkyl;
    Rc选自氢、C1-6烷基、C3-6环烷基、5-6元杂环基；R c is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-6 membered heterocyclyl;
    或者，Rb和Rc与它们相连的氮原子一起形成5-6元杂环基，其中所述5-6元杂环基任选进一步被选自氘、卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、氘代烷基、卤代烷基、烷氧基、氘代烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, R b and R c together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclyl group, wherein the 5-6 membered heterocyclyl group is optionally further selected from the group consisting of deuterium, halogen, amino, oxo, sulfur Substitute, nitro, cyano, hydroxyl, mercapto, alkyl, deuterated alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl Substituted with one or more substituents among base, heterocyclyl, aryl and heteroaryl;
    m为0、1或2；m is 0, 1 or 2;
    q为0或1；q is 0 or 1;
    p为1或2。p is 1 or 2.
  15. 根据权利要求13或14所述的通式(I)所示的化合物或其内消旋体、外消 旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：The compound represented by the general formula (I) according to claim 13 or 14 or its meso or racemic form spin isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:
    选自 Selected from
    R7a和R7b各自独立地选自氢和C1-6烷基。R 7a and R 7b are each independently selected from hydrogen and C 1-6 alkyl.
  16. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IVA)或通式(IVB)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    The compound represented by the general formula (I) according to claim 1 or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutical Use a salt, which is a compound represented by general formula (IVA) or general formula (IVB) or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt,
    其中，in,
    Y3、Y4各自独立地选自CH或N；优选地，Y3和Y4均为N，或者Y3和Y4之一为N，另一个为CH；Y 3 and Y 4 are each independently selected from CH or N; preferably, Y 3 and Y 4 are both N, or one of Y 3 and Y 4 is N and the other is CH;
    环C为5至6元杂环基；优选四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基；Ring C is a 5- to 6-membered heterocyclic group; preferably tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, or piperazinyl;
    R9a选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基和C1-6羟烷基；优选氢或C1-6烷基；更优选氢；R 9a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen;
    R9b各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、ORa、C(O)Ra和-S(O)pRa， 所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；R 9b is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a , The C 3-6 cycloalkyl group, 5 to 6 membered heterocyclyl group, 6 to 10 membered aryl group, and 5 to 6 heteroaryl group are optionally further selected from deuterium, halogen, C 1-6 alkyl group, C 1 Substituted with one or more substituents of -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy;
    Ra选自C1-6烷基、C1-6氘代烷基和C1-6卤代烷基；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl and C 1-6 haloalkyl;
    R7a选自氢、氘、C1-6烷基、C1-6氘代烷基和C1-6卤代烷基；优选氢或C1-6烷基；R 7a is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl and C 1-6 haloalkyl; preferably hydrogen or C 1-6 alkyl;
    R7b选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基和C1-6羟烷基；R 7b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl;
    m为0、1或2；优选1或2；m is 0, 1 or 2; preferably 1 or 2;
    R1、R2如权利要求1所定义。R 1 and R 2 are as defined in claim 1.
  17. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(VA)、通式(VB)或通式(VC)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    The compound represented by the general formula (I) according to claim 1 or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutical Use salts, which are compounds represented by general formula (VA), general formula (VB) or general formula (VC) or their meso, racemate, enantiomers and diastereomers. , or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中，in,
    Y3、Y4各自独立地选自CH或N；优选地，Y3和Y4均为N，或者Y3和Y4之一为N， 另一个为CH；Y 3 and Y 4 are each independently selected from CH or N; preferably, Y 3 and Y 4 are both N, or one of Y 3 and Y 4 is N, The other is CH;
    X1选自CR9c或N；X 1 is selected from CR 9c or N;
    X2选自CR9c或N；X 2 is selected from CR 9c or N;
    X3选自N且X4选自CR9c；或者X3选自CR9c且X4选自N；X 3 is selected from N and X 4 is selected from CR 9c ; or X 3 is selected from CR 9c and X 4 is selected from N;
    R9a选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基和C1-6羟烷基；优选氢或C1-6烷基；更优选氢；R 9a is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen;
    R9b各自独立地选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基、ORa、C(O)Ra和-S(O)pRa，所述C3-6环烷基、5至6元杂环基、6至10元芳基、5至6杂芳基任选进一步被选自氘、卤素、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基中的一个或多个取代基所取代；R 9b is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl, OR a , C(O)R a and -S(O) p R a , the C 3-6 cycloalkyl, 5 to 6-membered heterocyclyl, 6 to 10-membered aryl, 5 to 6 heteroaryl optionally further selected from deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- Substituted with one or more substituents of 6 deuterated alkoxy and C 1-6 haloalkoxy;
    Ra选自C1-6烷基、C1-6氘代烷基和C1-6卤代烷基；R a is selected from C 1-6 alkyl, C 1-6 deuterated alkyl and C 1-6 haloalkyl;
    R9c选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基和C1-6羟烷基；优选氢、C1-6烷基和C1-6卤代烷基；R 9c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; preferably hydrogen, C 1-6 alkyl and C 1-6 haloalkyl;
    R7a选自氢、氘、C1-6烷基、C1-6氘代烷基和C1-6卤代烷基；优选氢或C1-6烷基；R 7a is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuterated alkyl and C 1-6 haloalkyl; preferably hydrogen or C 1-6 alkyl;
    R7b选自氢、氘、卤素、氨基、羟基、巯基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基和C1-6羟烷基；R 7b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl;
    n为0、1或2；优选1或2；更优选1；n is 0, 1 or 2; preferably 1 or 2; more preferably 1;
    R1、R2如权利要求1所定义。R 1 and R 2 are as defined in claim 1.
  18. 根据权利要求1至17中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R1选自氢、氘、卤素、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6氘代烷氧基、C1-C6卤代烷氧基和氨基；优选氢、氘和卤素。The compound represented by the general formula (I) according to any one of claims 1 to 17, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 deuterated alkoxy, C 1 -C 6 haloalkoxy and amino; hydrogen, deuterium and halogen are preferred.
  19. 根据权利要求1至18中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R2选自氢、氘、卤素、C1-C6烷基、C1-C6氘代烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6氘代烷氧基、C1-C6卤代烷氧基和氨基；优选氢、氘、卤素、C1-C6烷基、C1-C6氘代烷基和C1-C6卤代烷基；更优选C1-C6烷基。The compound represented by the general formula (I) according to any one of claims 1 to 18, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof Form, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 haloalkyl, C 1 - C 6 alkoxy, C 1 -C 6 deuterated alkoxy, C 1 -C 6 haloalkoxy and amino; preferably hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 deuterated Alkyl and C 1 -C 6 haloalkyl; more preferably C 1 -C 6 alkyl.
  20. 根据权利要求1至19中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐， 其选自：


    The compound represented by the general formula (I) according to any one of claims 1 to 19, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, It is selected from:


  21. 一种制备通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
    A method for preparing the compound represented by the general formula (II) or its mesobody, racemate, enantiomer, diastereomer, or mixture form thereof, or its pharmaceutically acceptable salt , which includes the following steps:
    在催化剂存在下，式IIi的化合物发生分子内偶联反应得到通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐；所述催化剂优选醋酸钯；In the presence of a catalyst, the compound of formula IIi undergoes an intramolecular coupling reaction to obtain the compound represented by the general formula (II) or its meso, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof; the catalyst is preferably palladium acetate;
    其中，环A、环B、Y1、Y2、Z1、Z2、R1和R2如权利要求2所定义。Among them, Ring A, Ring B, Y 1 , Y 2 , Z 1 , Z 2 , R 1 and R 2 are as defined in claim 2.
  22. 一种药物组合物，其包含根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及药学上可接受的载体或赋形剂。A pharmaceutical composition comprising the compound represented by the general formula (I) according to any one of claims 1 to 20 or its meso, racemate, enantiomer, non-enantiomer enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers or excipients.
  23. 根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求22所述的药物组合物在制备ALK激酶抑制剂中的用途。The compound represented by the general formula (I) according to any one of claims 1 to 20, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22 for the preparation of an ALK kinase inhibitor.
  24. 根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求22所述的药物组合物在制备预防或/和治疗与ALK激酶活性相关的疾病的药物中的用途，所述疾病优选恶性肿瘤疾病，所述恶性肿瘤疾病例如非小细胞肺癌、炎性成肌纤维母细胞瘤和乳腺癌。 The compound represented by the general formula (I) according to any one of claims 1 to 20, or its mesobody, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 22 in the preparation of a medicament for preventing or/and treating diseases related to ALK kinase activity, the disease is preferably a malignant tumor disease, the malignant Neoplastic diseases such as non-small cell lung cancer, inflammatory myofibroblastoma and breast cancer.
PCT/CN2023/135839 2022-12-01 2023-12-01 Nitrogen-containing macrocyclic compound, and preparation method therefor and medical use thereof WO2024046512A2 (en)

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