WO2024046512A2 - Composé macrocyclique contenant de l'azote, et son procédé de préparation et son utilisation médicale - Google Patents

Composé macrocyclique contenant de l'azote, et son procédé de préparation et son utilisation médicale 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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WO2024046512A3 (fr
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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/fr
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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

La présente invention concerne un composé macrocyclique contenant de l'azote, et son procédé de préparation et son utilisation médicale. Spécifiquement, la présente invention concerne un composé macrocyclique contenant de l'azote représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique le contenant, et son utilisation en tant qu'inhibiteur de kinase ALK pour le traitement de maladies associées à l'activité kinase ALK. La définition de chaque substituant dans la formule générale (I) est identique à celle donnée dans la description.
PCT/CN2023/135839 2022-12-01 2023-12-01 Composé macrocyclique contenant de l'azote, et son procédé de préparation et son utilisation médicale WO2024046512A2 (fr)

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