WO2023134765A1 - Five-membered-ring-containing derivatives, preparation method therefor, and uses thereof - Google Patents

Five-membered-ring-containing derivatives, preparation method therefor, and uses thereof Download PDF

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WO2023134765A1
WO2023134765A1 PCT/CN2023/072393 CN2023072393W WO2023134765A1 WO 2023134765 A1 WO2023134765 A1 WO 2023134765A1 CN 2023072393 W CN2023072393 W CN 2023072393W WO 2023134765 A1 WO2023134765 A1 WO 2023134765A1
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alkyl
alkoxy
aryl
deuterated
cycloalkyl
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PCT/CN2023/072393
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French (fr)
Chinese (zh)
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董加强
邓欣贤
俞文胜
金芳芳
龚珍
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上海翰森生物医药科技有限公司
江苏豪森药业集团有限公司
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Publication of WO2023134765A1 publication Critical patent/WO2023134765A1/en

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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to a five-membered ring-containing derivative, its preparation method and application.
  • MK2 MAPK activated protein kinase 2, MAPK activated protein kinase 2
  • MAPK MAPK activated protein kinase 2
  • MAPK a protein kinase, as an important downstream molecule of the classic inflammatory signal transduction pathway MAPK, it regulates the expression of inflammatory factors.
  • the activated p38 MAPK protein phosphorylates and activates MK2, leading to the phosphorylation of MK2 substrate TTP, promoting the stability of pro-inflammatory cytokine mRNA, thereby increasing the protein expression level of inflammatory cytokines.
  • MK2 is activated. Inhibition of the p38-MK2 pathway through genetic or pharmacological means can inhibit the expression of inflammatory factors, indicating that MK2 is involved in mediating the development of arthritis. Inflammation regulation. Inhibitors of p38-MK2 hold promise for the treatment of patients with relapsed, refractory rheumatoid arthritis who have poor response to existing therapies.
  • ATI-450 of Aclaris Therapeutics has entered the clinical phase IIb of rheumatoid arthritis.
  • Other clinical MK2 inhibitors include CC-99677 from BMS and MMI-0100 from Moerae Matrix, both of which can directly inhibit the activity of MK2, which is different from ATI-450.
  • the published patent applications for p38-MK2 (or MK2) inhibitors include: Aclaris Therapeutics patents (WO-2012078684, WO-2013086208, WO-2014197846, WO-2021022186, WO-2012078687, WO2012078673, WO2012078674) ; BMS patent (WO -2020236636, WO-2018170199, WO-2016044463, WO-2018170201, WO-2018170200, WO-2018170203, US20210198276, US20210139501, US20200148701, US20200 102326); Moerae Matrix patents (WO-2016112292, WO-2016145234, US-10336788, WO- 2014040074, WO-2018231722, WO-2012142320, WO-2016033432, WO-2013134636, WO-2011149964) etc.
  • the p38-MK2 inhibitor has a good application prospect as a drug in the pharmaceutical industry.
  • p38-MK2 inhibitors provide a safer and more effective treatment for rheumatoid arthritis patients with relapsed, refractory, and poor responses to existing therapies;
  • p38-MK2 inhibitors have broad-spectrum anti-inflammatory effects (TNF/IL- 6/IL-1), theoretically can be used to treat a variety of inflammatory diseases and autoimmune diseases;
  • p38-MK2 inhibitors are small molecule inhibitors, compared with macromolecular drugs such as TNF monoclonal antibody, it has oral convenience and patient compliance good advantage, while There are no reports of side effects of JAK inhibitors, such as infection, tumor, thrombus, and cardiotoxicity, in the clinical practice of p38-MK2 inhibitors. Therefore, there is a huge clinical need to develop novel p38-MK2 inhibitors.
  • the object of the present invention is to provide a compound shown in general formula (I-2), its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound structure shown in general formula (I-2) is as follows:
  • Ring C is selected from phenyl, thiazolyl, pyrazolyl, pyrimidinyl or pyridyl;
  • L 1 is selected from a bond or -(CH 2 ) n O(CR aa R bb ) n1 -;
  • R aa and R bb are each independently selected from hydrogen, deuterium, halogen, C 1-8 alkyl or C 1-8 deuterated alkyl, said C 1-8 alkyl or C 1-8 deuterated alkyl , optionally can be further substituted;
  • M 5 is selected from CR 5 , N, NR 5 , O or S;
  • M 6 is selected from CR 6 , N, NR 6 , O or S;
  • M 7 is selected from CR 7 or NR 7 ;
  • M 8 is selected from CR 8 , N, NR 8 , O or S;
  • M9 is selected from C or N;
  • R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-8 alkyl, C 1- 8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclic
  • R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 He
  • R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, bridged cycloalkyl, C 1-8 deuterated alkyl, C 1-8 haloalkane C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff )
  • R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkanes C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy , C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
  • any two adjacent or non-adjacent substituents of R 5 , R 6 , R 7 and R 8 are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclic radical, aryl and heteroaryl, optionally further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2
  • any two adjacent or non-adjacent substituents are linked to form a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group containing 1-3 N, O, or S atoms, a C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, the C 3-8 cycloalkyl, 3-8 containing 1-3 N, O, or S atoms Membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group containing 1-3 N, O, or S atoms, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, Cyano, amino, oxo, thio, carboxyl, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 Alkoxy, C 1-4 deuterated alkoxy, C 1-4 deuter
  • x is an integer from 0 to 6;
  • y is an integer from 0 to 6;
  • z is an integer from 0 to 6;
  • n 0, 1, 2 or 3;
  • n1 0, 1, 2 or 3;
  • n4 is 0, 1, 2, 3 or 4.
  • M 5 is selected from CR 5 , N, NR 5 , O or S;
  • M 6 is selected from CR 6 , N, NR 6 , O or S;
  • M 7 is selected from CR 7 or NR 7 ;
  • M 8 is selected from CR 8 , N, NR 8 , O or S;
  • M9 is selected from C or N;
  • R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-8 alkyl, C 1- 8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclic
  • R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-8 cycloalkyl, 3-8 membered
  • R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 Haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, - (CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)
  • R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkanes C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy , C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n4 is 0, 1, 2, 3 or 4;
  • L 1 is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)(CR aa R bb ) n1 - , -(CH 2 ) n C(O)NR cc (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH 2 ) n1 - , -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH 2 ) n1 -, -(CH 2 ) n S(CR aa R bb ) n1 -, - (CR aa R b
  • R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkane radical, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterium Alkylkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally can be further superseded;
  • any two of R aa , R bb and R cc are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally can be further replaced;
  • R a is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
  • any two adjacent or non-adjacent R a links to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further replaced;
  • L is linked with Ra to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted;
  • R b are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
  • L and R are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted;
  • R a is linked with R b to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl can optionally be further substituted;
  • R c are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
  • R b is linked with R c to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl may optionally be further substituted;
  • x is an integer from 0 to 6;
  • y is an integer from 0 to 6;
  • z is an integer from 0 to 6;
  • n 0, 1, 2, or 3;
  • n1 0, 1, 2, or 3;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2 or 3.
  • the compound is further shown in general formula (VI-1) or (VI-2), (XI-1) or (XI-2):
  • the compound is further shown in general formula (VIII-1) or (VIII-2):
  • said compound is further shown in general formula (IX-1) or (IX-2):
  • said compound is further shown in general formula (VI-3) or (XI-3):
  • R aa and R bb are each independently selected from hydrogen, deuterium, halogen, C 1-8 alkyl or C 1-8 deuterated alkyl, said C 1-8 alkyl or C 1-8 deuterated alkyl , optionally can be further substituted.
  • L 1 described in the present invention is selected from bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR cc (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH 2 ) n1 -, -( CH 2 ) n S(CR aa R bb ) n1 -
  • L 1 is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)-, -(CR aa R bb ) n O-, -O(CR aa R bb ) n1 -, -(CR aa R bb ) n S-, -S(CR aa R bb ) n1 -, -(CH 2 ) n1 NR cc - , -NR cc (CR aa R bb ) n1 -or -NR cc C(O)-;
  • L 1 is selected from a bond, -CH 2 -, -OCH 2 -, -OCD 2 -, -NH-, -C(O)NH-, -OCH(CH 3 )-, -OC(CH 3 ) 2 -, -NH-CH 2 -or
  • R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C
  • R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2 -4 alkenyl, C 2-4 alkyn
  • any two of R aa , R bb and R cc are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo group, thiol group, carboxyl group, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy and C 1-6 haloalkoxy in one or more substituents;
  • any two of R aa , R bb and R cc are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, so
  • the C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano , amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy
  • X 1 is selected from N or CR a5 ;
  • X 3 is selected from N or CR b1 ;
  • R a1 , R a2 , R a3 , R a4 or R a5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, all Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl
  • R aa or R bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12
  • R aa and R bb are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated Alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5 -One or more substituents in the
  • R b1 , R b2 or R b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C
  • R b1 and R b2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base
  • 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group
  • R c1 , R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C
  • R c1 and R c2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group
  • the R c1 and R b2 substituents are linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, and the 3-12 membered heterocyclic group and the 5-14 membered heteroaryl group can optionally be further replaced by Deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- Substituted by one or more substituents in 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
  • R da , R db , R' da or R' db are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkane Oxygen, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 al
  • R 6 or R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycloalkyl
  • R 6 and R 8 are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio group, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkane Oxygen, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5- Substituted by one or more substituents in
  • n7 is 0, 1, 2 or 3;
  • the compound is further shown in general formula (XIII-B) or (XIII-B'):
  • X 1 is selected from N or CR a5 ;
  • R a1 , R a2 , R a3 , R a4 or R a5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, all Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl
  • R aa or R bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycl
  • R aa and R bb are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated Alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5 -One or more substituents in the
  • R b2 or R b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12
  • R c1 , R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C
  • R c1 and R c2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group
  • the R c1 and R b2 substituents are linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, and the 3-12 membered heterocyclic group and the 5-14 membered heteroaryl group can optionally be further replaced by Deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- Substituted by one or more substituents in 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
  • R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1 -6 bridged cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 NR hh OR gg
  • R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
  • One or more substituents in the heteroaryl group
  • R 6 or R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycloalkyl
  • any two adjacent or non-adjacent R 6 , R 7 and R 8 are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heterocyclic group Aryl, the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1 -6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 members
  • n4 is 0, 1, 2, 3 or 4.
  • said compound is further such as general formula (XII-D-1), (XII-D-2), (XIII-B-1), (XIII-B-2), ( XIII-B'-1) or (XIII-B'-2):
  • R a described in the present invention is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl base, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl,
  • each R a is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloal
  • R b described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl base, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl,
  • each R b is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloal
  • R c described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl group, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl,
  • each Rc is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, the
  • R b is linked with R c to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkyl group, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated Alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and
  • R in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl base or -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O) 2
  • R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkanes C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n4 is 0, 1, 2, 3 or 4.
  • R 5 , R 6 and R 8 described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterium alkanes Oxygen, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5- 10-membered heteroaryl, the amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 1-3 alkyl, C 1-3
  • R in the present invention is selected from halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3
  • R is selected from halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
  • R6 is selected from fluorine.
  • R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R c1 , R c2 , R c3 , R da , R db , R' da and R' db are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membere
  • the present invention further provides a method for preparing the aforementioned compound of general formula (XII-D) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the general formula (M-1) reacts with the general formula (M-2) to obtain the target compound shown in the general formula (XII-D);
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients Forming agent; further the compound, its stereoisomer or its pharmaceutically acceptable salt, the percentage by weight in the composition is 0.1% ⁇ 95%, preferably 0.5% ⁇ 85%, more preferably 1% ⁇ 60%, more preferably 10%-50%, even more preferably 15-40%, even more preferably 20-30%, even more preferably 20-25% (based on the total weight of the pharmaceutical composition).
  • the present invention further relates to the application of the compound, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of medicines for treating diseases mediated by p38 kinase.
  • the present invention further relates to the application of said compound, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of medicines for treating autoimmune diseases, metabolic diseases and tumors, etc.
  • Autoimmune diseases are selected from Selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases and atherosclerosis; metabolic diseases selected from diabetes and fibrotic diseases; tumors selected from leukemia and lymphoma.
  • the present invention also relates to a method for preventing and/or treating autoimmune diseases, metabolic diseases and tumors, etc., which comprises administering to patients a therapeutically effective dose of the compound of the present invention or its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof; wherein the autoimmune disease is selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, and atherosclerosis; metabolic diseases are selected from diabetes and fibrotic diseases; tumors are selected from Leukemia and Lymphoma etc.
  • the invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions including, but not limited to, conditions associated with p38 kinase-mediated diseases.
  • 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 8 carbon atoms atom, more preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Base, 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-methyl Amylpentyl, 2,3-dimethylbutyl, n-heptyl, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhex
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-Dimethylbutyl, 1,2-Dimethylbutyl, 2,2-Dimethylbutyl, 1,3-Dimethylbutyl, 2-Ethylbutyl, 2-Methylbutyl pentyl, 3-methylpentyl, 4-methylpentyl,
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
  • alkylene refers to a divalent alkyl group formed by further substituting one hydrogen atom of the alkyl group, wherein the alkyl group is as defined above.
  • methylene refers to -CH 2 -
  • ethylene refers to -(CH 2 ) 2 -
  • propylene refers to -(CH 2 ) 3 -
  • butylene refers to -(CH 2 ) 4 -etc.
  • the point of attachment of the alkylene chain to the rest of the molecule and to the group can be through one carbon or any two carbons within the chain.
  • Alkylene groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyclo Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkane in the present invention radical, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably containing 2 An alkenyl group having to 12 carbon atoms, more preferably an alkenyl group having 2 to 8 carbon atoms, further preferably an alkenyl group having 2 to 6 carbon atoms, and most preferably an alkenyl group having 2 to 4 carbon atoms.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkenylene refers to a divalent alkenyl group in which one hydrogen atom of the alkenyl group is further substituted, wherein the alkenyl group is as defined above, for example: vinylene, propenylene, butenylene, etc.
  • Alkenylene may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably containing 2 to 20 carbon atoms.
  • ethynyl, propynyl, 1-butynyl, 2-butynyl or 3-butynyl and the like are examples of the alkynyl group having 2 to 4 carbon atoms.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynylene refers to a divalent alkynyl group in which one hydrogen atom of an alkynyl group is further substituted, wherein alkynyl is as defined above. For example, ethynylene, propynylene, butynylene and the like.
  • Alkynylene may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene group, cyclooctyl group, etc.; polycyclic cycloalkyl group includes spiro ring, fused ring and bridged ring cycloalkyl group, preferably cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group and cycloheptyl group.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include: wait;
  • spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include: wait.
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include: wait.
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan or 5 to 14 yuan, more preferably 7 to 10 yuan or 5 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 may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, wait.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkane radical, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • cycloalkylene refers to a divalent cycloalkyl group formed by further substitution of one hydrogen atom of the cycloalkyl group, wherein the cycloalkylene group is optionally substituted or unsubstituted, and the definition of cycloalkyl group is as above.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, C(O) or A heteroatom of S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contain 3 to 8 ring atoms; most preferably contain 3 to 6 ring atoms; further preferably contain 1-3 nitrogen atoms 3-8
  • the membered heterocyclic group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including monocyclic heterocyclic group, spiro heterocyclic group or fused heterocyclic group.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl Base, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1,4-diazepanyl, pyridonyl, pyranyl, tetrahydrothiopyranyl dioxide, wait.
  • Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups; the spiro rings, condensed rings and bridged ring heterocyclic groups involved are optionally connected to other groups through single bonds, or through rings Any two or more atoms on the ring are further linked with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 8 to 12 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyls include: wait.
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which 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 bond, but none of the rings has a fully conjugated ⁇ -electron system, where 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
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 8 to 12 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 4-membered/5-membered, 5-membered/5-membered, 5-membered/6-membered , 6-membered/6-membered 6-membered/7-membered bicyclic condensed heterocyclic group.
  • fused heterocyclic groups include: wait.
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocyclyl groups include: wait.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include: wait.
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclylalkylene refers to a heterocyclyl group linked to an alkylene group to form a “heterocyclyl-alkylene-", wherein the heterocyclyl or alkyl group can be optionally substituted or unsubstituted, Heterocyclyl and alkylene are as defined above.
  • heterocyclic group refers to a divalent heterocyclic group formed by further substituting a hydrogen atom of a cycloalkyl group, wherein the heterocyclic group can be optionally substituted or unsubstituted, and the definition of heterocyclic group is as above .
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group with a sulfur atom; or a three-membered nitrogen-containing condensed ring containing a benzene ring.
  • ring attached to the parent structure is an aryl ring, non-limiting examples of which include: wait.
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • arylene refers to a divalent aryl group in which one hydrogen atom of a cycloalkyl group is further substituted, wherein the arylene group is optionally substituted or unsubstituted, and the definition of aryl is as described above.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5-6 membered monocyclic heteroaryl or 8-12 membered bicyclic heteroaryl, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazole Base, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl , pyrimidyl or thiazolyl; more preferably tetrazolyl, pyridyl,
  • Non-limiting examples of such bicyclic heteroaryl groups include:
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include: wait.
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • heteroarylene refers to a divalent heteroaryl group in which one hydrogen atom of a cycloalkyl group is further substituted, wherein the heteroarylene group is optionally substituted or unsubstituted, and the definition of heteroaryl group is as described above.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, alkoxy can is optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Thio group, carboxyl
  • Haloalkyl means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Non-limiting examples of such haloalkyl groups include: trifluoromethyl, -CH 2 CF 3 ,
  • Haloalkoxy means an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • Hydroalkyl means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • alkenylcarbonyl refers to -C(O)-(alkenyl), wherein alkenyl is as defined above.
  • alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl.
  • Alkenylcarbonyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl , cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups, which independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl ,
  • Aminocarbonyl refers to NH2 -C(O)-.
  • Alkylaminocarbonyl means that one or both of the two hydrogens on an aminocarbonyl group (NH 2 -C(O)-) is replaced by an alkyl group, wherein the definition of alkyl group is as above.
  • Alkylamino means that one or both of the two hydrogens on the amino group are replaced by an alkyl group, wherein the definition of alkyl group is as above.
  • Alkylcarbonyl or "acyl” means (alkyl)-C(O)-, wherein alkyl is as defined above.
  • Haldroxy means an -OH group.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Carbonyl refers to -C(O)-.
  • Carboxy refers to -C(O)OH.
  • THF tetrahydrofuran
  • Ethyl acetate means ethyl acetate.
  • MeOH means methanol
  • DMF N,N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • TAA triethylamine
  • MeCN refers to acetonitrile
  • DMA refers to N,N-dimethylacetamide.
  • Et2O means diethyl ether
  • DCM dichloromethane
  • DMAP refers to 4-dimethylaminopyridine.
  • DCC dicyclohexylcarbodiimide
  • DCE 1,2 dichloroethane
  • DIPEA N,N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris(dibenzylideneacetone)dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
  • HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamide.
  • MeLi means methyllithium
  • n-BuLi refers to n-butyllithium
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with 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 by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the determination of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or deuterium water (D 2 O), and the internal standard was tetramethylsilane (TMS).
  • Agilent 1200 Infinity Series mass spectrometer was used for liquid chromatography-mass chromatography LC-MS determination.
  • the determination of HPLC used Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 ⁇ 4.6mm column).
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates.
  • the specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
  • the eluent system of the silica gel column chromatography and the developing agent system of the thin layer chromatography used in the intermediate and the purified compound in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: Dichloromethane and acetone system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • the ratios in the mobile phase in the HPLC chiral resolution conditions and HPLC chiral analysis conditions are volume ratios.
  • the preparation method of intermediate 2 refers to WO2014197846A1 for synthesis.
  • intermediate 1 500mg, 1.21mmol
  • hexa-n-butylditin 1.06g, 1.82mmol
  • lithium chloride 51mg, 1.21mmol
  • tricyclohexylphosphine 68mg, 0.24mmol
  • three two Benzylideneacetonate dipalladium (111 mg, 0.12 mmol) was dispersed in 1,4-dioxane (8 mL). The reaction was heated to 130°C and stirred for 12 hours.
  • Methyl 4-bromothiazole-2-carboxylate 5B (970 mg, 4.37 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C. Methylmagnesium bromide (3M, 4.37 mL) was added dropwise to the reaction solution, returned to room temperature, and stirred for 5 hours.
  • 2,2,6-Trimethyl-4H-1,3-dioxin-4-one 6A (8.16 g, 57.40 mmol) was dissolved in tetrahydrofuran (60 mL), and cooled to -78°C. Lithium bistrimethylsilylamide (1M, 63 mL) was added dropwise to the reaction solution, and after the addition was complete, the reaction was stirred at -78°C for 1 hour. A solution of cyclopropylformyl chloride (3 g, 28.70 mmol, 2.60 mL) in tetrahydrofuran (10 mL) was added dropwise to the reaction solution, and the reaction was stirred at -78°C for 16 hours.
  • intermediate 1 (50mg, 0.12mmol), intermediate 5 (50.8mg, 0.17mmol, purity: 62%), 1,1-bis(diphenylphosphine) 1,1'-bisdiphenyl Phosphinoferrocenepalladium dichloride (8.9 mg, 0.01 mmol) and cesium carbonate (79 mg, 0.24 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.3 mL). The reaction was heated to 100°C and stirred for 3 hours.
  • Embodiment 1-1 MS m/z (ESI): 519.1[M+H] + ;
  • 2,2,6-Trimethyl-4H-1,3-dioxin-4-one (10.04 g, 70.66 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to -78°C. Lithium bistrimethylsilylamide (1M, 71 mL) was added dropwise to the reaction solution. The reaction was stirred at -78°C for 1 hour. A tetrahydrofuran (10 mL) solution of 2,2,2-trideuteroacetyl chloride (2.88 g, 35.33 mmol) was added dropwise to the reaction liquid. The reaction was stirred at -78°C for 16 hours.
  • reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)- 5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridyl]-2-one 2d (560 mg), yield: 78.9%.
  • Embodiment 2-1 MS m/z (ESI): 522.1[M+H] + ;
  • the target product 2'-chloro-4-hydroxyl-6-methyl-5'-(methyl-d 3 )-2H-[1,4'-dipyridin]-2-one 3c can be obtained through Example 2 for the second Prepared in a similar process.
  • Target product 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'–(methyl-d3)-2H-[1,4' -Dipyridin]-2-one 3d can be prepared by a similar process to the third step of Example 2.
  • the target product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'–(methyl-d3)-2H-[1 , 4'-dipyridin]-2-one 3e can be prepared by the similar process of the fourth step of Example 2.
  • reaction solution was concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl )methoxy)-6-methyl-2H-[1,4'-bipyridyl]-2-one 4d (83 mg), yield: 63%
  • Embodiment 4-1 MS m/z (ESI): 539.0[M+H] + ;
  • reaction solution was concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system A) to obtain the product 2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl )ethoxy)-6-methyl-2H-[1,4'-bipyridyl]-2-one 5b (110 mg), yield: 84%.
  • intermediate 1 (40mg, 0.1mmol), 6d (102.7mg, 0.22mmol, about 40% purity), 1,1-bis(diphenylphosphine)ferrocenepalladium dichloride (7.1mg , 0.01mmol) and cesium carbonate (94.8mg, 0.29mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.2mL) and water (0.1mL). The reaction was heated to 90°C and stirred for 0.5 hours.
  • Embodiment 6-1 MS m/z (ESI): 516.1[M+H] + ;
  • Lithium aluminum deuteride (388 mg, 9.24 mmol) was added in portions to a solution of methyl 3,5-difluoropyridine-2-carboxylate (1.00 g, 5.78 mmol) in tetrahydrofuran (20 mL) under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with ice cubes, and the reaction solution was filtered. The filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product (3,5-difluoropyridin-2-yl)methane-d2-ol 7a (345 mg), yield: 40.6%.
  • Embodiment 7-1 MS m/z (ESI): 521.1[M+H] + ;
  • Embodiment 8-1 MS m/z (ESI): 533.1[M+H] + ;
  • Embodiment 8-2 MS m/z (ESI): 533.1[M+H] + ;
  • Embodiment 8-3 MS m/z (ESI): 533.1[M+H] + ;
  • Embodiment 8-4 MS m/z (ESI): 533.1[M+H] + ;
  • reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2-((tert-butyl Oxycarbonyl)amino)thiazole-4-carboxylic acid ethyl ester 9b (6.1 g), yield: 77.2%.
  • reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-( 4-(2-Hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 9 (25mg,), yield Rate: 53.5%.
  • Embodiment 9-1 MS m/z (ESI): 519.1[M+H] + ;
  • Embodiment 10-1 MS m/z (ESI): 545.1[M+H] + ;
  • 11b (55mg, 0.438mmol), 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl Base-2H-[1,4'-bipyridyl]-2-one 11f (100mg, 0.219mmol), cuprous iodide (8mg, 0.044mmol), N,N'-dimethyl-1,2-cyclo Hexamethylenediamine (13mg, 0.088mmol) and cesium carbonate (143mg, 0.438mmol) were dissolved in N,N-dimethylformamide (5mL) and heated to 100°C and stirred for 16 hours.
  • N,N-dimethylformamide 5mL
  • Embodiment 11-1 MS m/z (ESI): 501.8[M+H] + ;
  • intermediate 4 (100mg, 0.150mmol), 12b (70mg, 0.3mmol) and bis(triphenylphosphine)palladium dichloride (11mg, 0.015mmol) were dissolved in 1,4-dioxane (3 mL). The reaction was heated to 130° C. with microwave and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated.
  • 2-cyano-2-methylpropansulfamide 13c (0.5g, 3.90mmol), bromoacetaldehyde diethyl acetal (845mg, 4.29mmol) and p-toluenesulfonic acid (67mg, 0.39mmol) were dissolved in ethanol ( 6 mL) and water (0.6 mL), heated to 100°C in a sealed tube and stirred for 20 hours. After the reaction solution was concentrated, a black residue was obtained. Silica gel column chromatography (elution system B) gave compound 2-methyl-2-(thiazol-2-yl)propionitrile 13d (94 mg), yield: 16%.
  • 2-(5-Bromothiazol-2-yl)-2-methylpropionitrile 13d (0.312g, 1.35mmol) was dissolved in anhydrous tetrahydrofuran (6mL), protected by nitrogen replacement, cooled to -78°C in a dry ice bath, passed Slowly add lithium diisopropylamide (2M, 1.35mL) into the syringe, after the addition is complete, keep stirring at -78°C for 3 hours.
  • reaction solution was quenched with saturated ammonium chloride solution, stirred for 5 minutes, diluted with ethyl acetate (40mL), washed with saturated brine, dried, and the concentrated residue was subjected to silica gel column chromatography (elution system B) to obtain the product 2-(4 -Bromothiazol-2-yl)-2-methylpropionitrile 13f (0.147 g), 47% yield.
  • reaction solution was diluted with ethyl acetate (25 mL), filtered through celite, concentrated, and the residue was purified by preparative silica gel chromatography (elution system A) to obtain the title product 2-(4-(3-chloro-4- ((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridine]-2)'-yl )thiazol-2-yl)-2-methylpropionitrile 13 (30 mg), yield: 47%.
  • 2-Amino-4,6-difluorobenzoic acid 14a (5 g, 28.9 mmol) and potassium carbonate (5.98 g, 43.3 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature. Methane iodide (4.92 g, 34.7 mmol) was slowly added dropwise to the reaction solution with stirring. The reaction solution was stirred at 25°C for 2 hours. Water (180 mL) was added to the reaction solution, and stirring was continued for 1 hour. The reaction solution was filtered to obtain the title product 2-amino-4,6-difluorobenzoic acid methyl ester 14b (3.9 g), which was directly used in the next reaction without purification.
  • Methyl 2-amino-4,6-difluorobenzoate 14b (1 g, 5.34 mmol) was dissolved in 20% sulfuric acid solution (30 mL), cooled to 0°C.
  • Sodium nitrite (442 mg, 6.41 mmol) aqueous solution (4 mL) and potassium iodide (1.78 g, 10.7 mmol) aqueous solution (4 mL) were added dropwise in sequence.
  • the reaction solution was stirred at 25°C for 4 hours.
  • Saturated sodium sulfite (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3).
  • the organic phases were combined, dried and concentrated to give the crude product.
  • the crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 2,4-difluoro-6-iodobenzoic acid methyl ester 14c (1.1 g
  • Methyl 2,4-difluoro-6-iodobenzoate 14c (2 g, 6.71 mmol) and cuprous cyanide (1.26 g, 13.4 mmol) were dissolved in N,N-dimethylformamide (10 mL), The reaction was heated to 120° C. with microwave and stirred for 1 hour. Ethyl acetate (10mL) was added to the reaction solution, filtered, water (30mL) was added, and the filtrate was washed with acetic acid Ethyl ester (10 mL ⁇ 3) was extracted. The organic phases were combined, dried and concentrated to give the crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 2-cyano-4,6-difluorobenzoic acid methyl ester 14d (740 mg), yield: 56%.
  • Methyl 2-cyano-4,6-difluorobenzoate 14d (700 mg, 3.55 mmol) and anhydrous calcium chloride (394 mg, 3.55 mmol) were dissolved in ethanol (10 mL) and tetrahydrofuran (10 mL), and stirred Sodium borohydride (296 mg, 7.81 mmol) was added portionwise. The reaction solution was stirred at 25°C for 16 hours. The reaction solution was concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the title product 3,5-difluoro-2-(hydroxymethyl)benzonitrile 14e (340 mg, colorless liquid), yield: 57%.
  • Example 14-2 MS m/z (ESI): 543.1[M+H] + .
  • reaction solution was diluted with ethyl acetate and washed with saturated brine, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried and concentrated.
  • the residue was subjected to silica gel column chromatography (elution system B) to obtain the product 2-(4-bromothiazol-2-yl)-2-methylpropanoic acid ethyl ester 34d (3.15g), the yield: 57%.
  • reaction solution was quenched with saturated ammonium chloride solution, concentrated and the crude product was subjected to silica gel column chromatography (elution system B) to obtain the product 2-(4-bromothiazol-2-yl)-N,2-dimethylpropanamide 34f (225 mg), Yield: 11%.
  • intermediate 4 (135 mg, 0.202 mmol), 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (50 mg, 0.202 mmol) and tetrakistriphenylphosphine palladium (35 mg , 0.030mmol) was dissolved in dioxane (2mL). The reaction was heated to 105°C and stirred for 16 hours. The reaction solution was filtered through diatomaceous earth and then concentrated under reduced pressure.
  • the target product (4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl yl-2-oxyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropanamide 37.
  • Embodiment 37-2 MS m/z (ESI): 548.1[M+H] + ;
  • the target product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6 was synthesized -(Methyl-d3)-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropylamine 38.
  • Embodiment 38-2 MS m/z (ESI): 549.1[M+H] + ;
  • 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (116mg, 0.45mmol), pinacol diboronate (137.2mg, 0.54mmol), tris(diethylene Benzylacetone) dipalladium (20.6mg, 0.02mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25.8mg, 0.05mmol) and potassium acetate (88.4mg, 0.9 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL). The reaction was heated to 110°C and stirred for 2 hours.
  • the target product 2-(4-(3,5'-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-6 was synthesized -Methyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropanamide 42.
  • Embodiment 45-1 MS m/z (ESI): 562.1[M+H] + ;
  • reaction solution was quenched with saturated ammonium chloride solution, concentrated and separated by silica gel column chromatography (elution system B) to obtain the title product 2-(4-bromothiazol-2-yl)-N,N,2-trimethylpropane Amide 46a (489 mg, pale yellow solid), yield: 23%.
  • reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2) -2'-(2-(2-Hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 47 (65mg), yield Rate: 52.2% yield.
  • Embodiment 47-1 MS m/z (ESI): 541.1[M+H] + ;
  • Embodiment 47-2 MS m/z (ESI): 541.1[M+H] + ;
  • Embodiment 48-1 MS m/z (ESI): 504.1[M+H] + ;
  • reaction solution was concentrated, and the residue was separated by a reverse-phase column (formic acid system) to obtain 2',3,5'-trichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridine]-2- Ketone 49a (5.1 g), yield: 45.3%.
  • Example 49 the target product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3- (2-Hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 50.
  • the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-(2-hydroxypropane) was synthesized -2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 51.
  • Embodiment 51-1 MS m/z (ESI): 521.1[M+H] + ;
  • Embodiment 51-2 MS m/z (ESI): 521.1[M+H] + ;
  • ethyl 4-methyl-1H-pyrazole-3-carboxylate 53a (2.5 g, 16.2 mmol) was dissolved in tetrahydrofuran (25 mL). Under ice cooling, methylmagnesium bromide (3M, 16.2 mL) was added dropwise to the reaction solution with stirring. opposite Stirring was continued for 1 hour after warming to room temperature. The reaction solution was quenched with saturated ammonium chloride, concentrated under reduced pressure to half volume, extracted with ethyl acetate, and the aqueous layer was extracted once more with ethyl acetate.
  • reaction solution was purified by reverse-phase HPLC (formic acid system) to obtain the title product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-( 2-Hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 53 (70 mg), Yield: 67%.
  • Example 53 the target product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3- (2-Hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 54.
  • Example 54-2 MS m/z (ESI): 538.1[M+H] + ;
  • N-(2-(4-bromothiazol-2-yl)propan-2-yl)acetamide 56a (100mg, 0.38mmol), pinacol diborate (106mg, 0.418mmol), three (Dibenzylideneacetone) dipalladium (17mg, 0.019mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (22mg, 0.046mmol) and potassium acetate (112mg, 1.14 mmol) was dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100° C. and stirred for 1 hour.
  • reaction solution was filtered, and the filtrate was concentrated to obtain the crude product (2-(2-acetylaminopropan-2-yl)thiazol-4-yl)boronic acid 56b (83 mg), which was directly used in the next reaction without further purification.
  • (2-(2-acetylaminopropan-2-yl)thiazol-4-yl)boronic acid 56b (83mg, 0.362mmol), 48a (100mg, 0.241mmol), 1,1-bis(diphenyl Phosphine) ferrocene palladium dichloride (18 mg, 0.024mmol) and cesium carbonate (157mg, 0.483mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5mL) and water (0.5mL), and the reaction was heated to 100°C and stirred for 1.5 hours.
  • reaction solution was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy) Base-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide 56 (103 mg), yield: 75.91%.
  • Embodiment 56-1 MS m/z (ESI): 562.1[M+H] + ;
  • the target product 3-chloro-4-((2,4-difluorobenzyl) oxo)-2'-(3-(2-hydroxypropan-2-yl)- 1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 58.
  • Example 57 the target product 3-chloro-4-((3,5-dichloropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropane-2 -yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 59.
  • the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized yl-4-((3-(trifluoromethyl)benzyl)oxo)-2H-[1,4'-bipyridyl]-2-one 60.
  • the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized yl-4-((2,4,5-trifluorobenzyl)oxo)-2H-[1,4'-bipyridyl]-2-one 62.
  • the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized yl-4-((2,3,4-trifluorobenzyl)oxo)-2H-[1,4'-bipyridyl]-2-one 63.
  • the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxyl Propan-2-yl)-4-methyl-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 64.
  • Embodiment 64-1 MS m/z (ESI): 518.1 [M+H] + ;
  • Embodiment 64-2 MS m/z (ESI): 518.1[M+H] + ;
  • the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentyl) was synthesized Alk-3-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 66.
  • Embodiment 66-1 MS m/z (ESI): 532.2[M+H] + ;

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Abstract

The present invention relates to five-membered-ring-containing derivatives, a preparation method therefor, and the uses thereof. In particular, the present invention relates to compounds represented by a general formula, a preparation method therefor, a pharmaceutical composition containing the compounds, and the uses of the compounds as biological regulators in preparation of drugs for treatment of autoimmune diseases, chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, atherosclerosis, diabetes, fibrotic diseases, metabolic diseases, cancers, tumors, leukemia and lymphoma, wherein each substituent in the general formula is same as that defined in the specification.

Description

含五元环类衍生物、其制备方法和应用Derivatives containing five-membered rings, their preparation methods and applications 技术领域technical field
本发明属于生物医药领域，具体涉及一种含五元环类衍生物、其制备方法和应用。The invention belongs to the field of biomedicine, and specifically relates to a five-membered ring-containing derivative, its preparation method and application.
背景技术Background technique
MK2(MAPK activated protein kinase 2，MAPK激活蛋白激酶2)是一种蛋白激酶，作为经典炎症信号转导途径MAPK的重要下游分子，调控炎症因子的表达。细胞受炎性刺激后，激活的p38 MAPK蛋白磷酸化并活化MK2，导致MK2底物TTP磷酸化，促进促炎细胞因子mRNA的稳定性，从而提高炎症细胞因子的蛋白表达水平。MK2 (MAPK activated protein kinase 2, MAPK activated protein kinase 2) is a protein kinase, as an important downstream molecule of the classic inflammatory signal transduction pathway MAPK, it regulates the expression of inflammatory factors. After the cells are stimulated by inflammation, the activated p38 MAPK protein phosphorylates and activates MK2, leading to the phosphorylation of MK2 substrate TTP, promoting the stability of pro-inflammatory cytokine mRNA, thereby increasing the protein expression level of inflammatory cytokines.
在小鼠关节炎模型和骨关节炎病人软骨细胞中，MK2都表现激活状态，通过遗传学或者药理学手段抑制p38-MK2通路均可以抑制炎症因子表达水平，说明MK2参与介导了关节炎的炎症调控。p38-MK2抑制剂有望治疗复发、难治、对现有疗法响应差的类风湿性关节炎病人。In mouse arthritis models and chondrocytes of osteoarthritis patients, MK2 is activated. Inhibition of the p38-MK2 pathway through genetic or pharmacological means can inhibit the expression of inflammatory factors, indicating that MK2 is involved in mediating the development of arthritis. Inflammation regulation. Inhibitors of p38-MK2 hold promise for the treatment of patients with relapsed, refractory rheumatoid arthritis who have poor response to existing therapies.
目前全球仅Aclaris Therapeutics公司的p38-MK2抑制剂ATI-450进入类风湿性关节炎临床IIb，初步临床实验结果表明ATI-450在类风湿性关节炎病人中安全耐受，药效出众持续。其他在临床的MK2抑制剂还有BMS公司的CC-99677和Moerae Matrix的MMI-0100，均可直接抑制MK2的活性，与ATI-450机制不同。At present, only the p38-MK2 inhibitor ATI-450 of Aclaris Therapeutics has entered the clinical phase IIb of rheumatoid arthritis. The preliminary clinical trial results show that ATI-450 is safe and tolerated in patients with rheumatoid arthritis, and its efficacy is outstanding and sustained. Other clinical MK2 inhibitors include CC-99677 from BMS and MMI-0100 from Moerae Matrix, both of which can directly inhibit the activity of MK2, which is different from ATI-450.
现已公开的p38-MK2(或MK2)抑制剂专利申请包括：Aclaris Therapeutics专利(WO-2012078684，WO-2013086208，WO-2014197846，WO-2021022186，WO-2012078687，WO2012078673，WO2012078674)；BMS专利(WO-2020236636，WO-2018170199，WO-2016044463，WO-2018170201，WO-2018170200，WO-2018170203，US20210198276，US20210139501，US20200148701，US20200102326)；Moerae Matrix专利(WO-2016112292，WO-2016145234，US-10336788，WO-2014040074，WO-2018231722，WO-2012142320，WO-2016033432，WO-2013134636，WO-2011149964)等。The published patent applications for p38-MK2 (or MK2) inhibitors include: Aclaris Therapeutics patents (WO-2012078684, WO-2013086208, WO-2014197846, WO-2021022186, WO-2012078687, WO2012078673, WO2012078674) ; BMS patent (WO -2020236636, WO-2018170199, WO-2016044463, WO-2018170201, WO-2018170200, WO-2018170203, US20210198276, US20210139501, US20200148701, US20200 102326); Moerae Matrix patents (WO-2016112292, WO-2016145234, US-10336788, WO- 2014040074, WO-2018231722, WO-2012142320, WO-2016033432, WO-2013134636, WO-2011149964) etc.
p38-MK2抑制剂作为药物在医药行业具有良好的应用前景。p38-MK2抑制剂为复发、难治、对现有疗法响应差的类风湿性关节炎病人提供了更安全更有效的治疗方法；p38-MK2抑制剂具有广谱抑炎效果(TNF/IL-6/IL-1)，理论上可以用于治疗多种炎症疾病和自身免疫疾病；p38-MK2抑制剂为小分子抑制剂，相比与大分子药物如TNF单抗具有口服便利、病人依从性好等优势，同时 p38-MK2抑制剂临床未见有JAK抑制剂毒副作用如感染、肿瘤、血栓、心脏毒性等报道。因此，研发新型的p38-MK2抑制剂有巨大的临床需求。The p38-MK2 inhibitor has a good application prospect as a drug in the pharmaceutical industry. p38-MK2 inhibitors provide a safer and more effective treatment for rheumatoid arthritis patients with relapsed, refractory, and poor responses to existing therapies; p38-MK2 inhibitors have broad-spectrum anti-inflammatory effects (TNF/IL- 6/IL-1), theoretically can be used to treat a variety of inflammatory diseases and autoimmune diseases; p38-MK2 inhibitors are small molecule inhibitors, compared with macromolecular drugs such as TNF monoclonal antibody, it has oral convenience and patient compliance good advantage, while There are no reports of side effects of JAK inhibitors, such as infection, tumor, thrombus, and cardiotoxicity, in the clinical practice of p38-MK2 inhibitors. Therefore, there is a huge clinical need to develop novel p38-MK2 inhibitors.
发明内容Contents of the invention
本发明的目的在于提供一种通式(I-2)所示的化合物、其立体异构体或其药学上可接受盐，其中通式(I-2)所示的化合物结构如下：
The object of the present invention is to provide a compound shown in general formula (I-2), its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound structure shown in general formula (I-2) is as follows:
其中：in:
环C选自苯基、噻唑基、吡唑基、嘧啶基或吡啶基；Ring C is selected from phenyl, thiazolyl, pyrazolyl, pyrimidinyl or pyridyl;
L1选自键或-(CH2)nO(CRaaRbb)n1-；L 1 is selected from a bond or -(CH 2 ) n O(CR aa R bb ) n1 -;
Raa和Rbb各自独立地选自氢、氘、卤素、C1-8烷基或C1-8氘代烷基，所述的C1-8烷基或C1-8氘代烷基，任选地可以进一步被取代；R aa and R bb are each independently selected from hydrogen, deuterium, halogen, C 1-8 alkyl or C 1-8 deuterated alkyl, said C 1-8 alkyl or C 1-8 deuterated alkyl , optionally can be further substituted;
M5选自CR5、N、NR5、O或S；M 5 is selected from CR 5 , N, NR 5 , O or S;
M6选自CR6、N、NR6、O或S；M 6 is selected from CR 6 , N, NR 6 , O or S;
M7选自CR7或NR7；M 7 is selected from CR 7 or NR 7 ;
M8选自CR8、N、NR8、O或S；M 8 is selected from CR 8 , N, NR 8 , O or S;
M9选自C或N； M9 is selected from C or N;
R5、R6和R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8羟烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-8 alkyl, C 1- 8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano group, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterium Substituted alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or Substituted by one or more substituents in the 5-14 membered heteroaryl;
优选地，R5、R6和R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、 3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基中的一个或多个取代基所取代；Preferably, R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 Heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl replaced by a substituent;
R7选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、桥环烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基、5-14元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；所述的氨基、C1-8烷基、桥环烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8羟烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基中的一个或多个取代基所取代； R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, bridged cycloalkyl, C 1-8 deuterated alkyl, C 1-8 haloalkane C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ; said amino, C 1-8 alkyl, bridged cycloalkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1- 8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1- 8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2- One or more substituents in 8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl replace;
优选氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基中的一个或多个取代基所取代；Preferably hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkane Base, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C( O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ; said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered hetero Aryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3 One or more substituents in -8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl;
Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基；R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkanes C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy , C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
优选地，Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、 C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；Preferably, R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- 8-membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group;
或者，R5、R6、R7和R8任意两个相邻或不相邻的取代基链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, any two adjacent or non-adjacent substituents of R 5 , R 6 , R 7 and R 8 are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclic radical, aryl and heteroaryl, optionally further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 One or more substituents in -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl replaced by
优选地，任意两个相邻或不相邻的取代基链接形成C3-8环烷基、含1-3个N、O、或S原子的3-8元杂环基、C6-10芳基或含1-3个N、O、或S原子的5-10元杂芳基，所述C3-8环烷基、含1-3个N、O、或S原子的3-8元杂环基、C6-10芳基或含1-3个N、O、或S原子的5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、C1-4羟烷基、C1-4烷氧基、C1-4氘代烷氧基、C1-4卤代烷氧基、C2-3烯基、C2-3炔基、C5-8环烷基、5-8元杂环基、C6-8芳基和5-8元杂芳基中的一个或多个取代基所取代；更优选地，任意两个相邻或不相邻的取代基链接形成 任选地可进一步被氘、氟、氯、溴、羟基、巯基、氰基、氧代基、硫代基、羧基、甲基、乙基、丙基、丁基、氘代甲基、氘代乙基、氘代丙基、氘代丁基、羟甲基、羟乙基、羟丙基或羟丁基中的一个或多个所取代；Preferably, any two adjacent or non-adjacent substituents are linked to form a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group containing 1-3 N, O, or S atoms, a C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, the C 3-8 cycloalkyl, 3-8 containing 1-3 N, O, or S atoms Membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group containing 1-3 N, O, or S atoms, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, Cyano, amino, oxo, thio, carboxyl, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 Alkoxy, C 1-4 deuterated alkoxy, C 1-4 haloalkoxy, C 2-3 alkenyl, C 2-3 alkynyl, C 5-8 cycloalkyl, 5-8 membered heterocycle One or more substituents in radical, C 6-8 aryl and 5-8 membered heteroaryl; more preferably, any two adjacent or non-adjacent substituents link to form Optionally can be further substituted by deuterium, fluorine, chlorine, bromine, hydroxyl, mercapto, cyano, oxo, thio, carboxyl, methyl, ethyl, propyl, butyl, deuteromethyl, deuterium One or more of ethyl, deuterated propyl, deuterated butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl;
x为0～6的整数；x is an integer from 0 to 6;
y为0～6的整数；y is an integer from 0 to 6;
z为0～6的整数；z is an integer from 0 to 6;
n为0、1、2或3；n is 0, 1, 2 or 3;
n1为0、1、2或3；n1 is 0, 1, 2 or 3;
n4为0、1、2、3或4。n4 is 0, 1, 2, 3 or 4.
在本发明进一步优选的实施方案中，所述化合物进一步如通式(VI)、(X)或(XI)所示：
In a further preferred embodiment of the present invention, said compound is further shown in general formula (VI), (X) or (XI):
其中：in:
M5选自CR5、N、NR5、O或S；M 5 is selected from CR 5 , N, NR 5 , O or S;
M6选自CR6、N、NR6、O或S；M 6 is selected from CR 6 , N, NR 6 , O or S;
M7选自CR7或NR7；M 7 is selected from CR 7 or NR 7 ;
M8选自CR8、N、NR8、O或S；M 8 is selected from CR 8 , N, NR 8 , O or S;
M9选自C或N； M9 is selected from C or N;
R5、R6和R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8羟烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-8 alkyl, C 1- 8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano group, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterium Substituted alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or Substituted by one or more substituents in the 5-14 membered heteroaryl;
优选地，R5、R6和R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基中的一个或多个取代基所取代；Preferably, R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substituents in aryl or 5-10 membered heteroaryl;
R7选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8 卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基、5-14元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；所述的氨基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8羟烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基中的一个或多个取代基所取代； R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 Haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl, - (CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ; said amino, C 1-8 alkyl, C 1-8 deuterated Alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino , carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 One or more substituents in the heteroaryl group are substituted;
优选氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基中的一个或多个取代基所取代；Preferably hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkane Base, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C( O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ; said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered hetero Aryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3 One or more substituents in -8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl;
Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基；R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkanes C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy , C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
优选地，Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；Preferably, R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
n4为0、1、2、3或4；n4 is 0, 1, 2, 3 or 4;
L1选自键、取代或未取代的亚烯基、取代或未取代的亚炔基、-(CH2)n-、-(CH2)nC(O)(CRaaRbb)n1-、-(CH2)nC(O)NRcc(CH2)n1-、-(CH2)n(CRaaRbb)n1-、-(CRaaRbb)nO(CH2)n1-、-(CH2)nO(CRaaRbb)n1-、-(CRaaRbb)nS(CH2)n1-、-(CH2)nS(CRaaRbb)n1-、-(CRaaRbb)n(CH2)n1NRcc-、-(CH2)nNRcc(CRaaRbb)n1-、-(CH2)nNRccC(O)-、-(CH2)nP(O)pRaa-、-(CH2)nS(O)m-、-(CH2)nS(O)mNRcc-和-(CH2)nNRccS(O)m-； L 1 is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)(CR aa R bb ) n1 - , -(CH 2 ) n C(O)NR cc (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH 2 ) n1 - , -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH 2 ) n1 -, -(CH 2 ) n S(CR aa R bb ) n1 -, - (CR aa R bb ) n (CH 2 ) n1 NR cc -, -(CH 2 ) n NR cc (CR aa R bb ) n1 -, -(CH 2 ) n NR cc C(O)-, -(CH 2 ) n P(O) p R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR cc -and-(CH 2 ) n NR cc S( O) m -;
Raa、Rbb和Rcc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkane radical, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterium Alkylkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally can be further superseded;
或者，Raa、Rbb和Rcc中的任意两个链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选地可以进一步被取代；Alternatively, any two of R aa , R bb and R cc are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally can be further replaced;
Ra各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；R a is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
或者，任意两个相邻或不相邻的Ra链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选地可以进一步被取代；Alternatively, any two adjacent or non-adjacent R a links to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further replaced;
或者，L1与Ra链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选地可以进一步被取代；Alternatively, L is linked with Ra to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted;
Rb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；R b are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
或者，任意两个相邻或不相邻的Rb链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, any two adjacent or non-adjacent R b link to form cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally can be further replaced;
或者，L1与Rb链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, L and R are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted;
或者，Ra与Rb链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, R a is linked with R b to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl can optionally be further substituted;
Rc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；R c are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
或者，任意两个相邻或不相邻的Rc链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, any two adjacent or non-adjacent R c link to form cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally can be further replaced;
或者，Rb与Rc链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代； Alternatively, R b is linked with R c to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl may optionally be further substituted;
x为0～6的整数；x is an integer from 0 to 6;
y为0～6的整数；y is an integer from 0 to 6;
z为0～6的整数；z is an integer from 0 to 6;
n为0、1、2、或3；n is 0, 1, 2, or 3;
n1为0、1、2、或3；n1 is 0, 1, 2, or 3;
m为0、1、2或3；m is 0, 1, 2 or 3;
p为0、1、2或3。p is 0, 1, 2 or 3.
在本发明进一步优选的实施方案中，所述化合物进一步如通式(VI-1)或(VI-2)、(XI-1)或(XI-2)所示：
In a further preferred embodiment of the present invention, the compound is further shown in general formula (VI-1) or (VI-2), (XI-1) or (XI-2):
在本发明进一步优选的实施方案中，所述化合物进一步如通式(VIII)所示：
In a further preferred embodiment of the present invention, the compound is further represented by general formula (VIII):
在本发明进一步优选的实施方案中，所述化合物进一步如通式(VIII-1)或(VIII-2)所示：
In a further preferred embodiment of the present invention, the compound is further shown in general formula (VIII-1) or (VIII-2):
在本发明进一步优选的实施方案中，所述化合物进一步如通式(IX)所示：
In a further preferred embodiment of the present invention, said compound is further shown in general formula (IX):
在本发明进一步优选的实施方案中，所述化合物进一步如通式(IX-1)或(IX-2)所示：
In a further preferred embodiment of the present invention, said compound is further shown in general formula (IX-1) or (IX-2):
在本发明进一步优选的实施方案中，所述化合物进一步如通式(VI-3)或(XI-3)所示：
In a further preferred embodiment of the present invention, said compound is further shown in general formula (VI-3) or (XI-3):
其中：in:
Raa和Rbb各自独立地选自氢、氘、卤素、C1-8烷基或C1-8氘代烷基，所述的C1-8烷基或C1-8氘代烷基，任选地可以进一步被取代。 R aa and R bb are each independently selected from hydrogen, deuterium, halogen, C 1-8 alkyl or C 1-8 deuterated alkyl, said C 1-8 alkyl or C 1-8 deuterated alkyl , optionally can be further substituted.
在本发明进一步优选的实施方案中，本发明所述的L1选自键、取代或未取代的亚烯基、取代或未取代的亚炔基、-(CH2)n-、-(CH2)nC(O)(CRaaRbb)n1-、-(CH2)nC(O)NRcc(CH2)n1-、-(CH2)n(CRaaRbb)n1-、-(CRaaRbb)nO(CH2)n1-、-(CH2)nO(CRaaRbb)n1-、-(CRaaRbb)nS(CH2)n1-、-(CH2)nS(CRaaRbb)n1-、-(CRaaRbb)n(CH2)n1NRcc-、-(CH2)nNRcc(CRaaRbb)n1-、-(CH2)nNRccC(O)-、-(CH2)nP(O)pRaa-、-(CH2)nS(O)m-、-(CH2)nS(O)mNRcc-和-(CH2)nNRccS(O)m-；In a further preferred embodiment of the present invention, L 1 described in the present invention is selected from bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR cc (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH 2 ) n1 -, -( CH 2 ) n S(CR aa R bb ) n1 -, -(CR aa R bb ) n (CH 2 ) n1 NR cc -, -(CH 2 ) n NR cc (CR aa R bb ) n1 -, -( CH 2 ) n NR cc C(O)-, -(CH 2 ) n P(O) p R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR cc - and - (CH 2 ) n NR cc S(O) m -;
优选地，L1选自键、取代或未取代的亚烯基、取代或未取代的亚炔基、-(CH2)n-、-(CH2)nC(O)-、-(CRaaRbb)nO-、-O(CRaaRbb)n1-、-(CRaaRbb)nS-、-S(CRaaRbb)n1-、-(CH2)n1NRcc-、-NRcc(CRaaRbb)n1-或-NRccC(O)-；Preferably, L 1 is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)-, -(CR aa R bb ) n O-, -O(CR aa R bb ) n1 -, -(CR aa R bb ) n S-, -S(CR aa R bb ) n1 -, -(CH 2 ) n1 NR cc - , -NR cc (CR aa R bb ) n1 -or -NR cc C(O)-;
更优选地，L1选自键、-CH2-、-OCH2-、-OCD2-、-NH-、-C(O)NH-、-OCH(CH3)-、-OC(CH3)2-、-NH-CH2-或 More preferably, L 1 is selected from a bond, -CH 2 -, -OCH 2 -, -OCD 2 -, -NH-, -C(O)NH-, -OCH(CH 3 )-, -OC(CH 3 ) 2 -, -NH-CH 2 -or
Raa、Rbb和Rcc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
优选地，Raa、Rbb和Rcc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；Preferably, R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further deuterized , halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1 -3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are substituted by one or more substituents;
或者，Raa、Rbb和Rcc中的任意两个链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代 基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基和C1-6卤代烷氧基中的一个或多个取代基所取代；Alternatively, any two of R aa , R bb and R cc are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo group, thiol group, carboxyl group, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy and C 1-6 haloalkoxy in one or more substituents;
优选地，Raa、Rbb和Rcc中的任意两个链接形成C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基和C1-3卤代烷氧基中的一个或多个取代基所取代。Preferably, any two of R aa , R bb and R cc are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, so The C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano , amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy One or more substituents in radical, C 1-3 deuterated alkoxy and C 1-3 haloalkoxy.
在本发明进一步优选的实施方案中，所述化合物进一步如通式(XII-D)所示：
In a further preferred embodiment of the present invention, the compound is further shown in general formula (XII-D):
其中：in:
X1选自N或者CRa5；X 1 is selected from N or CR a5 ;
X3选自N或者CRb1；X 3 is selected from N or CR b1 ;
Ra1、Ra2、Ra3、Ra4或Ra5各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R a1 , R a2 , R a3 , R a4 or R a5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, all Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can Further deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C One or more substituents in 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
或者，任意两个相邻或不相邻的Ra1、Ra2、Ra3、Ra4和Ra5链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、 C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Or, any two adjacent or non-adjacent R a1 , R a2 , R a3 , R a4 and R a5 link to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl Or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen , nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
Raa或Rbb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R aa or R bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- Substituted by one or more substituents in 12-membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group;
或者，Raa和Rbb链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R aa and R bb are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated Alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5 -One or more substituents in the 14-membered heteroaryl;
Rb1、Rb2或Rb3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R b1 , R b2 or R b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
或者，Rb1和Rb2取代基链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代； Alternatively, R b1 and R b2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and Substituted by one or more substituents in the 5-14 membered heteroaryl;
Rc1、Rc2或Rc3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R c1 , R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
或者，Rc1和Rc2取代基链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R c1 and R c2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and Substituted by one or more substituents in the 5-14 membered heteroaryl;
或者，Rc1和Rb2取代基链接形成3-12元杂环基或5-14元杂芳基，所述3-12元杂环基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, the R c1 and R b2 substituents are linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, and the 3-12 membered heterocyclic group and the 5-14 membered heteroaryl group can optionally be further replaced by Deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- Substituted by one or more substituents in 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
Rda、Rdb、R’da或R’db各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R da , R db , R' da or R' db are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkane Oxygen, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally further By deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
或者，任意两个相邻的或者不相邻的Rda、Rdb、R’da和R’db链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6 卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Or, any two adjacent or non-adjacent R da , R db , R' da and R' db link to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl Or 5-14 membered heteroaryl, the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, Halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 Haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
R6或R8各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R 6 or R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- Substituted by one or more substituents in 12-membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group;
或者，R6和R8链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R 6 and R 8 are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio group, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkane Oxygen, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5- Substituted by one or more substituents in the 14-membered heteroaryl;
n7为0、1、2或3；n7 is 0, 1, 2 or 3;
优选地，所述的不为 Preferably, the not for
在本发明进一步优选的实施方案中，所述化合物进一步如通式(XIII-B)或(XIII-B’)所示：
In a further preferred embodiment of the present invention, the compound is further shown in general formula (XIII-B) or (XIII-B'):
其中：in:
X1选自N或者CRa5； X 1 is selected from N or CR a5 ;
Ra1、Ra2、Ra3、Ra4或Ra5各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R a1 , R a2 , R a3 , R a4 or R a5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, all Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can Further deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C One or more substituents in 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
或者，任意两个相邻或不相邻的Ra1、Ra2、Ra3、Ra4和Ra5链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Or, any two adjacent or non-adjacent R a1 , R a2 , R a3 , R a4 and R a5 link to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl Or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen , nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkane One or more substituents in radical, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
Raa或Rbb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R aa or R bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- Substituted by one or more substituents in 12-membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group;
或者，Raa和Rbb链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R aa and R bb are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated Alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5 -One or more substituents in the 14-membered heteroaryl;
Rb2或Rb3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、 C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R b2 or R b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclic group, C 6-14 aryl or 5-14-membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered hetero Cyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl One or more substituents in the group are substituted;
Rc1、Rc2或Rc3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R c1 , R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
或者，Rc1和Rc2取代基链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R c1 and R c2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and Substituted by one or more substituents in the 5-14 membered heteroaryl;
或者，Rc1和Rb2取代基链接形成3-12元杂环基或5-14元杂芳基，所述3-12元杂环基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, the R c1 and R b2 substituents are linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, and the 3-12 membered heterocyclic group and the 5-14 membered heteroaryl group can optionally be further replaced by Deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- Substituted by one or more substituents in 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
R7选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6桥环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基、5-14元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4NRhhORgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4S(O)Rgg、-(CReeRff)n4SRgg、-(CReeRff)n4C(O)NRhhRgg、 -(CReeRff)n4S(O)NRhhRgg、-(CReeRff)n4SNRhhRgg或-(CReeRff)n4S(O)2NRhhRgg，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6桥环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代； R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1 -6 bridged cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 NR hh OR gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 S(O)R gg , -(CR ee R ff ) n4 SR gg , -(CR ee R ff ) n4 C(O)NR hh R gg , -(CR ee R ff ) n4 S(O)NR hh R gg , -(CR ee R ff ) n4 SNR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg , the Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 bridged cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkane One of oxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl or multiple substituents;
Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基；R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
或者Ree、Rff链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Or R ee and R ff link to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio , carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 One or more substituents in the heteroaryl group are substituted;
R6或R8各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R 6 or R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- Substituted by one or more substituents in 12-membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group;
或者，任意两个相邻或不相邻的R6、R7和R8链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, any two adjacent or non-adjacent R 6 , R 7 and R 8 are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heterocyclic group Aryl, the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1 -6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 members One or more substituents in heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
n4为0、1、2、3或4。 n4 is 0, 1, 2, 3 or 4.
在本发明进一步优选的实施方案中，所述化合物进一步如通式(XII-D-1)、(XII-D-2)、(XIII-B-1)、(XIII-B-2)、(XIII-B’-1)或(XIII-B’-2)所示：
In a further preferred embodiment of the present invention, said compound is further such as general formula (XII-D-1), (XII-D-2), (XIII-B-1), (XIII-B-2), ( XIII-B'-1) or (XIII-B'-2):
在本发明进一步优选的实施方案中，本发明所述的Ra各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代； In a further preferred embodiment of the present invention, R a described in the present invention is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl base, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, any Optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkyne One or more substituents in radical, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
优选地，Ra各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代。Preferably, each R a is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- One or more substituents in 8-membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group.
在本发明进一步优选的实施方案中，本发明所述的Rb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；In a further preferred embodiment of the present invention, R b described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl base, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 Hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, any Optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkyne One or more substituents in radical, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
优选地，Rb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代。Preferably, each R b is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- One or more substituents in 8-membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group.
在本发明进一步优选的实施方案中，本发明所述的Rc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、 C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；In a further preferred embodiment of the present invention, R c described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl group, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, One or more of C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl Substituents are substituted;
优选地，Rc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；Preferably, each Rc is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- One or more substituents in 8-membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group;
或者，Rb与Rc链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。Alternatively, R b is linked with R c to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkyl group, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated Alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5 -Substituted by one or more substituents in the 14-membered heteroaryl.
在本发明进一步优选的实施方案中，本发明所述的R7各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基或-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；In a further preferred embodiment of the present invention, R in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl base or -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ;
Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkanes C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
n4为0、1、2、3或4。n4 is 0, 1, 2, 3 or 4.
在本发明进一步优选的实施方案中，本发明所述的R5、R6及R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷 氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代。In a further preferred embodiment of the present invention, R 5 , R 6 and R 8 described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterium alkanes Oxygen, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5- 10-membered heteroaryl, the amino, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered hetero Aryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl , C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C One or more substituents in 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl.
在本发明进一步优选的实施方案中，本发明所述的R6选自卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；In a further preferred embodiment of the present invention, R in the present invention is selected from halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, Halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1- 6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 ring One or more substituents in alkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
优选地，R6选自卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基；Preferably, R is selected from halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
更优选地，R6选自氟。More preferably, R6 is selected from fluorine.
在本发明进一步优选的实施方案中，本发明所述的Ra1、Ra2、Ra3、Ra4、Ra5、Rb1、Rb2、Rb3、Rc1、Rc2、Rc3、Rda、Rdb、R’da及R’db各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代。In a further preferred embodiment of the present invention, R a1 , R a2 , R a3 , R a4 , R a5 , R b1 , R b2 , R b3 , R c1 , R c2 , R c3 , R da , R db , R' da and R' db are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further deuterized , halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1 -3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are substituted by one or more substituents.
本发明进一步提供前述通式(XII-D)化合物或其立体异构体及其药学上可接受的盐的制备方法，包含如下步骤：
The present invention further provides a method for preparing the aforementioned compound of general formula (XII-D) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, comprising the following steps:
通式(M-1)与通式(M-2)反应，得到通式(XII-D)所示的目标化合物；The general formula (M-1) reacts with the general formula (M-2) to obtain the target compound shown in the general formula (XII-D);
所述X1、X3、Ra1、Ra2、Ra3、Ra4、Raa、Rbb、Rb2、Rb3、Rc1、Rc2、Rc3、Rda、Rdb、R’da、R’db、R6、R8、n7如前所述。Said X 1 , X 3 , R a1 , R a2 , R a3 , R a4 , R aa , R bb , R b2 , R b3 , R c1 , R c2 , R c3 , R da , R db , R' da , R' db , R 6 , R 8 , and n7 are as described above.
本发明进一步涉及一种药物组合物，其包括治疗有效剂量的所述化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂；进一步地所述化合物、其立体异构体或其药学上可接受盐，在组合物中所占的重量百分比为0.1％～95％，优选0.5％～85％，更优选1％～60％，进一步优选10％～50％，更进一步优选15-40％，更进一步优选20-30％，更进一步优选20-25％(以药物组合物总重计)。The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients Forming agent; further the compound, its stereoisomer or its pharmaceutically acceptable salt, the percentage by weight in the composition is 0.1%～95%, preferably 0.5%～85%, more preferably 1%～ 60%, more preferably 10%-50%, even more preferably 15-40%, even more preferably 20-30%, even more preferably 20-25% (based on the total weight of the pharmaceutical composition).
本发明进一步涉及所述化合物、其立体异构体或其药学上可接受的盐，或所述的药物组合物在制备治疗p38激酶介导的疾病药物中的应用。The present invention further relates to the application of the compound, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of medicines for treating diseases mediated by p38 kinase.
本发明进一步涉及所述的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备治疗自身免疫疾病、代谢疾病和肿瘤等的药物中的应用，自身免疫疾病选自慢性炎性疾病、急性炎症性疾病、自身炎性疾病及动脉粥样硬化等；代谢性疾病选自糖尿病及纤维变性疾病等；肿瘤选自白血病及淋巴瘤等。The present invention further relates to the application of said compound, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of medicines for treating autoimmune diseases, metabolic diseases and tumors, etc. Autoimmune diseases are selected from Selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases and atherosclerosis; metabolic diseases selected from diabetes and fibrotic diseases; tumors selected from leukemia and lymphoma.
本发明还涉及一种治疗预防和/或治疗自身免疫疾病、代谢疾病和肿瘤等的方法，其包括向患者施用治疗有效剂量的本发明所述化合物其立体异构体或其药学上可接受的盐，或其药物组合物；其中自身免疫疾病选自慢性炎性疾病、急性炎症性疾病、自身炎性疾病及动脉粥样硬化等；代谢性疾病选自糖尿病及纤维变性疾病等；肿瘤选自白血病及淋巴瘤等。The present invention also relates to a method for preventing and/or treating autoimmune diseases, metabolic diseases and tumors, etc., which comprises administering to patients a therapeutically effective dose of the compound of the present invention or its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof; wherein the autoimmune disease is selected from chronic inflammatory diseases, acute inflammatory diseases, autoinflammatory diseases, and atherosclerosis; metabolic diseases are selected from diabetes and fibrotic diseases; tumors are selected from Leukemia and Lymphoma etc.
本发明还提供了使用本发明的化合物或药物组合物治疗疾病状况的方法，该疾病状况包括但不限于与p38激酶介导的疾病有关的状况。The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions including, but not limited to, conditions associated with p38 kinase-mediated diseases.
发明的详细说明Detailed Description of the Invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至8个碳原子的烷基，进一步优选1至6个碳原子的烷基，最优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁 基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、4-庚基、1-丙基丁基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、正庚基、4-庚基、1-丙基丁基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms atom, more preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Base, 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-methyl Amylpentyl, 2,3-dimethylbutyl, n-heptyl, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- Methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl , 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3, 3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl -3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3, 3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-Dimethylbutyl, 1,2-Dimethylbutyl, 2,2-Dimethylbutyl, 1,3-Dimethylbutyl, 2-Ethylbutyl, 2-Methylbutyl pentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
术语“亚烷基”是指烷基的一个氢原子进一步被取代形成的二价烷基，其中烷基如上所定义。例如：“亚甲基”指-CH2-、“亚乙基”指-(CH2)2-、“亚丙基”指-(CH2)3-、“亚丁基”指-(CH2)4-等。亚烷基链与分子其余部分及与基团的连接点可经由该链内的一个碳或任何两个碳。亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "alkylene" refers to a divalent alkyl group formed by further substituting one hydrogen atom of the alkyl group, wherein the alkyl group is as defined above. For example: "methylene" refers to -CH 2 -, "ethylene" refers to -(CH 2 ) 2 -, "propylene" refers to -(CH 2 ) 3 -, "butylene" refers to -(CH 2 ) 4 -etc. The point of attachment of the alkylene chain to the rest of the molecule and to the group can be through one carbon or any two carbons within the chain. Alkylene groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyclo Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkane in the present invention radical, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，其为包含2至20个碳原子的直链或支链基团，优选含有2至12个碳原子的烯基，更优选含有2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基，最优选2至4个碳原子的烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、 烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably containing 2 An alkenyl group having to 12 carbon atoms, more preferably an alkenyl group having 2 to 8 carbon atoms, further preferably an alkenyl group having 2 to 6 carbon atoms, and most preferably an alkenyl group having 2 to 4 carbon atoms. For example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl or 3-butenyl and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“亚烯基”是指烯基的一个氢原子进一步被取代形成的二价烯基，其中烯基如上所定义例如：亚乙烯基、亚丙烯基、亚丁烯基等。亚烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkenylene" refers to a divalent alkenyl group in which one hydrogen atom of the alkenyl group is further substituted, wherein the alkenyl group is as defined above, for example: vinylene, propenylene, butenylene, etc. Alkenylene may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio.
术语“炔基”指至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，其为包含2至20个碳原子的直链或支链基团，优选含有2至12个碳原子的炔基，更优选含有2至8个碳原子的炔基，进一步优选2至6个碳原子的炔基，最优选2至4个碳原子的炔基。例如乙炔基、丙炔基、1-丁炔基、2-丁炔基或3-丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably containing 2 to 20 carbon atoms. An alkynyl group having 12 carbon atoms, more preferably an alkynyl group having 2 to 8 carbon atoms, further preferably an alkynyl group having 2 to 6 carbon atoms, and most preferably an alkynyl group having 2 to 4 carbon atoms. For example, ethynyl, propynyl, 1-butynyl, 2-butynyl or 3-butynyl and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“亚炔基”是指炔基的一个氢原子进一步被取代形成的二价炔基，其中炔基如上所定义。例如亚乙炔基、亚丙炔基、亚丁炔基等。亚炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkynylene" refers to a divalent alkynyl group in which one hydrogen atom of an alkynyl group is further substituted, wherein alkynyl is as defined above. For example, ethynylene, propynylene, butynylene and the like. Alkynylene may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个碳原子，进一步优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene group, cyclooctyl group, etc.; polycyclic cycloalkyl group includes spiro ring, fused ring and bridged ring cycloalkyl group, preferably cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group and cycloheptyl group.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/6元、3元/5元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
等；The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. More preferably, it is a 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:
wait;
也包含单螺环烷基与杂环烷基共用螺原子的螺环烷基，非限制性实例包括：
等。Also included are spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include:
wait.
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
等。The term "fused cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:
wait.
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元或5至14元，更优选为7至10元或5至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron systems. Preferably it is 6 to 14 yuan or 5 to 14 yuan, more preferably 7 to 10 yuan or 5 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基、等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷 基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, wait. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkane radical, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“亚环烷基”是指环烷基的一个氢原子进一步被取代形成的二价环烷基，其中，亚环烷基是任选取代的或非取代的，环烷基定义如上所述。The term "cycloalkylene" refers to a divalent cycloalkyl group formed by further substitution of one hydrogen atom of the cycloalkyl group, wherein the cycloalkylene group is optionally substituted or unsubstituted, and the definition of cycloalkyl group is as above.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子选自氮、氧、C(O)或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至6个环原子；进一步优选包含1-3氮原子的3-8元杂环基，任选地，被1-2个氧原子、硫原子、氧代基取代，包括单环杂环基、螺杂环基或稠杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, C(O) or A heteroatom of S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contain 3 to 8 ring atoms; most preferably contain 3 to 6 ring atoms; further preferably contain 1-3 nitrogen atoms 3-8 The membered heterocyclic group is optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including monocyclic heterocyclic group, spiro heterocyclic group or fused heterocyclic group.
单环杂环基的非限制性实例包括氧杂环丁基、氮杂环丁烷基、硫杂环丁基、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吖庚基、1,4-二氮杂环庚基、吡啶酮基、吡喃基、四氢噻喃二氧化物基、等。Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl Base, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1,4-diazepanyl, pyridonyl, pyranyl, tetrahydrothiopyranyl dioxide, wait.
多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups; the spiro rings, condensed rings and bridged ring heterocyclic groups involved are optionally connected to other groups through single bonds, or through rings Any two or more atoms on the ring are further linked with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为8至12元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
等。 The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 8 to 12 yuan. According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyls include:
wait.
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为8至12元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为4元/5元、5元/5元、5元/6元、6元/6元6元/7元双环稠杂环基。稠杂环基的非限制性实例包括：

等。The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which 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 bond, but none of the rings has a fully conjugated π-electron system, where 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 The atom is carbon. Preferably it is 6 to 14 yuan, more preferably 8 to 12 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 4-membered/5-membered, 5-membered/5-membered, 5-membered/6-membered , 6-membered/6-membered 6-membered/7-membered bicyclic condensed heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

wait.
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
等。The term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond. A pi-electron system of a yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
wait.
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
等。The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
wait.
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。 Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“杂环基亚烷基”是指杂环基与亚烷基相连形成“杂环基-亚烷基-”，其中的杂环基或烷基可以是任选取代的或非取代的，杂环基和亚烷基的定义如上所述。The term "heterocyclylalkylene" refers to a heterocyclyl group linked to an alkylene group to form a "heterocyclyl-alkylene-", wherein the heterocyclyl or alkyl group can be optionally substituted or unsubstituted, Heterocyclyl and alkylene are as defined above.
术语“亚杂环基”是指环烷基的一个氢原子进一步被取代形成的二价杂环基，其中，亚杂环基可以是任选取代的或非取代的，杂环基定义如上所述。The term "heterocyclic group" refers to a divalent heterocyclic group formed by further substituting a hydrogen atom of a cycloalkyl group, wherein the heterocyclic group can be optionally substituted or unsubstituted, and the definition of heterocyclic group is as above .
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并5-10元杂芳基、苯并3-8元环烷基和苯并3-8元杂烷基，优选苯并5-6元杂芳基、苯并3-6元环烷基和苯并3-6元杂烷基，其中杂环基为含1-3氮原子、氧原子、硫原子的杂环基；或者还包含含苯环的三元含氮稠环。The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group with a sulfur atom; or a three-membered nitrogen-containing condensed ring containing a benzene ring.
其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
等。Where the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
wait.
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
术语“亚芳基”是指环烷基的一个氢原子进一步被取代形成的二价芳基，其中，亚芳基是任选取代的或非取代的，芳基定义如上所述。The term "arylene" refers to a divalent aryl group in which one hydrogen atom of a cycloalkyl group is further substituted, wherein the arylene group is optionally substituted or unsubstituted, and the definition of aryl is as described above.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5-6元单环杂芳基或8-12元双环杂芳基，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选吡啶基、噁二唑基、三唑基、噻吩基、咪唑基、吡唑基、噁唑基、噻唑基、嘧啶基或噻唑基；更优选四氮唑基、吡啶基、噁二唑基、吡唑基、吡咯基、噻唑基和噁唑基。The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-6 membered monocyclic heteroaryl or 8-12 membered bicyclic heteroaryl, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazole Base, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl , pyrimidyl or thiazolyl; more preferably tetrazolyl, pyridyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl.
所述双环杂芳基非限制性实例包括：

Non-limiting examples of such bicyclic heteroaryl groups include:

所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
等。The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
wait.
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
术语“亚杂芳基”是指环烷基的一个氢原子进一步被取代形成的二价杂芳基，其中，亚杂芳基是任选取代的或非取代的，杂芳基定义如上所述。The term "heteroarylene" refers to a divalent heteroaryl group in which one hydrogen atom of a cycloalkyl group is further substituted, wherein the heteroarylene group is optionally substituted or unsubstituted, and the definition of heteroaryl group is as described above.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基，烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, alkoxy can is optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkane Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Thio group, carboxyl group or carboxylate group.
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。所述卤代烷基非限制性实例包括：三氟甲基、-CH2CF3、 "Haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples of such haloalkyl groups include: trifluoromethyl, -CH 2 CF 3 ,
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。"Haloalkoxy" means an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。"Hydroxyalkyl" means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
术语“烯基羰基”指-C(O)-(烯基)，其中烯基的定义如上所述。烯基羰基的非限制性实例包括：乙烯基羰基、丙烯基羰基、丁烯基羰基。烯基羰基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地 选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl , cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
“氨基羰基”指NH2-C(O)-。"Aminocarbonyl" refers to NH2 -C(O)-.
“烷基氨基羰基”指氨基羰基(NH2-C(O)-)上的两个氢中的一个或全部被烷基取代，其中烷基的定义如上所述。"Alkylaminocarbonyl" means that one or both of the two hydrogens on an aminocarbonyl group (NH 2 -C(O)-) is replaced by an alkyl group, wherein the definition of alkyl group is as above.
“烷基氨基”指氨基上的两个氢中的一个或全部被烷基取代，其中烷基的定义如上所述。"Alkylamino" means that one or both of the two hydrogens on the amino group are replaced by an alkyl group, wherein the definition of alkyl group is as above.
“烷基羰基”或“酰基”指(烷基)-C(O)-，其中烷基的定义如上所述。"Alkylcarbonyl" or "acyl" means (alkyl)-C(O)-, wherein alkyl is as defined above.
“羟基”指-OH基团。"Hydroxy" means an -OH group.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“氨基”指-NH2。"Amino" refers to -NH2 .
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO2。"Nitro" refers to -NO2 .
“羰基”指-C(O)-。"Carbonyl" refers to -C(O)-.
“羧基”指-C(O)OH。"Carboxy" refers to -C(O)OH.
“THF”指四氢呋喃。"THF" means tetrahydrofuran.
“乙酸乙酯”指乙酸乙酯。"Ethyl acetate" means ethyl acetate.
“MeOH”指甲醇。"MeOH" means methanol.
“DMF”指N,N-二甲基甲酰胺。"DMF" refers to N,N-dimethylformamide.
“DIPEA”指二异丙基乙胺。"DIPEA" means diisopropylethylamine.
“TFA”指三氟乙酸。"TFA" means trifluoroacetic acid.
“TEA”指三乙胺。"TEA" means triethylamine.
“MeCN”指乙晴。"MeCN" refers to acetonitrile.
“DMA”指N,N-二甲基乙酰胺。"DMA" refers to N,N-dimethylacetamide.
“Et2O”指乙醚。" Et2O " means diethyl ether.
“DCM”指二氯甲烷。"DCM" means dichloromethane.
“DMAP”指4-二甲氨基吡啶。"DMAP" refers to 4-dimethylaminopyridine.
“DCC”指二环己基碳二亚胺。"DCC" means dicyclohexylcarbodiimide.
“DCE”指1,2二氯乙烷。"DCE" means 1,2 dichloroethane.
“DIPEA”指N,N-二异丙基乙胺。"DIPEA" refers to N,N-diisopropylethylamine.
“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.
“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.
“Cbz-Cl”指氯甲酸苄酯。"Cbz-Cl" refers to benzyl chloroformate.
“Pd2(dba)3”指三(二亚苄基丙酮)二钯。"Pd 2 (dba) 3 " refers to tris(dibenzylideneacetone)dipalladium.
“Dppf”指1,1’-双二苯基膦二茂铁。 "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。"HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
“KHMDS”指六甲基二硅基胺基钾。"KHMDS" refers to potassium hexamethyldisilazide.
“LiHMDS”指双三甲基硅基胺基锂。"LiHMDS" refers to lithium bistrimethylsilylamide.
“MeLi”指甲基锂。"MeLi" means methyllithium.
“n-BuLi”指正丁基锂。"n-BuLi" refers to n-butyllithium.
“NaBH(OAc)3”指三乙酰氧基硼氢化钠。"NaBH(OAc) 3 " refers to sodium triacetoxyborohydride.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。Different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, and C" all express the same The meaning means that X can be any one or several of A, B, and C.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
具体实施方式Detailed ways
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention is further described below in conjunction with examples, but these examples do not limit the scope of the present invention.
实施例Example
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代甲醇(CD3OD)，氘代氯仿(CDCl3)或氘水(D2O)，内标为四甲基硅烷(TMS)。 The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The determination of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or deuterium water (D 2 O), and the internal standard was tetramethylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Agilent 1200 Infinity Series mass spectrometer was used for liquid chromatography-mass chromatography LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150×4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150×4.6mm column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all the reactions in the present invention are carried out under a dry nitrogen or argon atmosphere under continuous magnetic stirring, the solvent is a dry solvent, and the unit of the reaction temperature is Celsius.
中间体及实施例中纯化化合物采用的硅胶柱色谱法的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和丙酮体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The eluent system of the silica gel column chromatography and the developing agent system of the thin layer chromatography used in the intermediate and the purified compound in the examples include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: Dichloromethane and acetone system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
除非特别说明，本发明实施例中，HPLC手性拆分条件和HPLC手性分析条件中的流动相中的比值为体积比。Unless otherwise specified, in the examples of the present invention, the ratios in the mobile phase in the HPLC chiral resolution conditions and HPLC chiral analysis conditions are volume ratios.
中间体1Intermediate 1
2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
2',3-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridine]- 2-keto
第一步first step
将2'-氯-4-羟基-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮a(200mg,0.8mmol，其合成方法参考WO2014197846A1)，2-(氯甲基)-3,5-二氟-吡啶(157mg,0.96mmol)，碳酸钾(276mg,1.99mmol)和18-冠-6(21mg,0.08mmol)溶解于N,N-二甲基甲酰胺(4mL)中。反应加热至60℃搅拌16小时。向反应液中加入水(20mL)，水相用乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩。残余物用硅胶柱色谱法(洗 脱剂体系A)分离得到产物2'-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮b(301mg)，产率：99％。2'-Chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one a (200mg, 0.8mmol, its synthesis method refers to WO2014197846A1), 2- (Chloromethyl)-3,5-difluoro-pyridine (157mg, 0.96mmol), potassium carbonate (276mg, 1.99mmol) and 18-crown-6 (21mg, 0.08mmol) were dissolved in N,N-dimethyl formamide (4 mL). The reaction was heated to 60°C and stirred for 16 hours. Water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×2), and the organic phases were combined, dried and concentrated. The residue was chromatographed on a silica gel column (washing Removal system A) The product 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4' was isolated -Bipyridyl]-2-one b (301 mg), yield: 99%.
MS m/z(ESI):378.1[M+H]+.MS m/z(ESI):378.1[M+H] + .
第二步second step
将2'-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮b(301mg,0.8mmol)和N-氯代丁二酰亚胺(117mg,0.88mmol)溶解于异丙醇(6mL)中，反应加热至60℃搅拌16小时。冷却至室温，反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮中间体1(190mg)，产率：57.9％。2'-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2H-[1,4'-bipyridine]-2- Ketone b (301 mg, 0.8 mmol) and N-chlorosuccinimide (117 mg, 0.88 mmol) were dissolved in isopropanol (6 mL), and the reaction was heated to 60° C. and stirred for 16 hours. Cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methanol Oxy)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one intermediate 1 (190 mg), yield: 57.9%.
MS m/z(ESI):412.1[M+H]+.MS m/z(ESI):412.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.54(s,1H),8.07-8.13(m,1H),7.69(s,1H),6.80(s,1H),5.48(s,2H),1.98(s,3H),1.96(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(s,1H),8.54(s,1H),8.07-8.13(m,1H),7.69(s,1H),6.80(s,1H), 5.48(s,2H),1.98(s,3H),1.96(s,3H).
中间体2Intermediate 2
2’-乙酰基-3-氯-4-羟基-5’,6-二甲基-2H-[1,4’-联吡啶]-2-酮
2'-Acetyl-3-chloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
中间体2的制备方法参考WO2014197846A1进行合成。The preparation method of intermediate 2 refers to WO2014197846A1 for synthesis.
MS m/z(ESI):293.0[M+H]+.MS m/z(ESI):293.0[M+H] + .
中间体3Intermediate 3
2',3-二氯-4-羟基-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮

2',3-Dichloro-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one

第一步first step
将a(10g，40mmol)溶解在二氯乙烷(600mL)和异丙醇(400mL)的混合液中。反应液加热到60℃，向反应液中分批加N-氯代丁二酰胺(6.4g，50mmol)，反应在60℃下继续搅拌2小时。反应液浓缩，向残余物中加入异丙醇(50mL)，混合液在60℃下搅拌1小时。混合液冷却，过滤，滤饼用异丙醇洗涤。滤饼干燥得到产物2',3-二氯-4-羟基-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮中间体3(8.0g)，产率：71％。Dissolve a (10 g, 40 mmol) in a mixture of dichloroethane (600 mL) and isopropanol (400 mL). The reaction solution was heated to 60° C., N-chlorosuccinamide (6.4 g, 50 mmol) was added in batches to the reaction solution, and the reaction was stirred at 60° C. for 2 hours. The reaction solution was concentrated, isopropanol (50 mL) was added to the residue, and the mixture was stirred at 60° C. for 1 hour. The mixture was cooled, filtered, and the filter cake was washed with isopropanol. The filter cake was dried to obtain the product 2',3-dichloro-4-hydroxyl-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one intermediate 3 (8.0g), producing Rate: 71%.
MS m/z(ESI):285.0[M+H]+；MS m/z(ESI):285.0[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.52(s,1H),7.64(s,1H),6.17(d,1H),1.97(s,3H),1.86(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.61(s,1H),8.52(s,1H),7.64(s,1H),6.17(d,1H),1.97(s,3H),1.86( s,3H).
中间体4Intermediate 4
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2'-(三丁基甲锡烷基)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2'-(tributylstannyl)-2H-[1, 4'-Bipyridyl]-2-one
第一步first step
氮气保护下，将中间体1(500mg，1.21mmol)，六正丁基二锡(1.06g，1.82mmol)，氯化锂(51mg，1.21mmol)，三环己基膦(68mg，0.24mmol)和三(二 亚苄基丙酮)二钯(111mg，0.12mmol)分散到1,4-二氧六环(8mL)中。反应加热至130℃搅拌12小时。反应液过滤，滤液浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2'-(三丁基甲锡烷基)-2H-[1,4'-联吡啶]-2-酮中间体4(400mg)，产率：49.4％。Under nitrogen protection, intermediate 1 (500mg, 1.21mmol), hexa-n-butylditin (1.06g, 1.82mmol), lithium chloride (51mg, 1.21mmol), tricyclohexylphosphine (68mg, 0.24mmol) and three two Benzylideneacetonate) dipalladium (111 mg, 0.12 mmol) was dispersed in 1,4-dioxane (8 mL). The reaction was heated to 130°C and stirred for 12 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5 ',6-Dimethyl-2'-(tributylstannyl)-2H-[1,4'-bipyridyl]-2-one intermediate 4 (400 mg), yield: 49.4%.
MS m/z(ESI):668.2[M+H]+.MS m/z(ESI):668.2[M+H] + .
1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.40(d,1H),7.32(td,1H),7.12(s,1H),6.35(s,1H),5.39(d,2H),2.07(s,3H),1.92(s,3H),1.71–1.42(m,6H),1.31(h,6H),1.13(t,6H),0.96–0.83(m,9H). 1 H NMR (400MHz, CDCl 3 )δ8.78(s,1H),8.40(d,1H),7.32(td,1H),7.12(s,1H),6.35(s,1H),5.39(d, 2H),2.07(s,3H),1.92(s,3H),1.71–1.42(m,6H),1.31(h,6H),1.13(t,6H),0.96–0.83(m,9H).
中间体5Intermediate 5
(2-(2-羟基丙烷-2-基)噻唑-4-基)硼酸
(2-(2-Hydroxypropan-2-yl)thiazol-4-yl)boronic acid
第一步first step
将4-溴噻唑-2-羧酸5A(1g,4.81mmol)溶解于甲醇(10mL)中，室温下向反应液中缓慢滴加氯化亚砜(1.72g，14.42mmol)。滴加完成后，反应加热至50℃,搅拌3.5小时。反应恢复至室温，直接浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物4-溴噻唑-2-羧酸甲酯5B(1.02g)，产率：95.6％。4-Bromothiazole-2-carboxylic acid 5A (1 g, 4.81 mmol) was dissolved in methanol (10 mL), and thionyl chloride (1.72 g, 14.42 mmol) was slowly added dropwise to the reaction solution at room temperature. After the addition was complete, the reaction was heated to 50 °C and stirred for 3.5 hours. The reaction was returned to room temperature, concentrated directly, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 4-bromothiazole-2-carboxylic acid methyl ester 5B (1.02 g), yield: 95.6%.
MS m/z(ESI):222.1,224.1[M+H]+.MS m/z(ESI):222.1,224.1[M+H] + .
第二步second step
将4-溴噻唑-2-羧酸甲酯5B(970mg,4.37mmol)溶解于四氢呋喃(30mL)中，冷却至0℃。向反应液中滴加甲基溴化镁(3M,4.37mL)，恢复至室温，继续搅拌5小时。向反应液中加入饱和氯化铵(15mL)溶液，乙酸乙酯(15mL×2)萃取，有机相合并，干燥，浓缩，残余物用用硅胶柱色谱法(洗脱剂体系A)分离得到产物2-(4-溴噻唑-2-基)丙烷-2-醇5C(805mg,)，产率：83.0％。Methyl 4-bromothiazole-2-carboxylate 5B (970 mg, 4.37 mmol) was dissolved in tetrahydrofuran (30 mL), cooled to 0°C. Methylmagnesium bromide (3M, 4.37 mL) was added dropwise to the reaction solution, returned to room temperature, and stirred for 5 hours. Add saturated ammonium chloride (15mL) solution to the reaction solution, extract with ethyl acetate (15mL×2), combine the organic phases, dry and concentrate, and the residue is separated by silica gel column chromatography (eluent system A) to obtain the product 2-(4-Bromothiazol-2-yl)propan-2-ol 5C (805 mg,), yield: 83.0%.
MS m/z(ESI):222.1,224.1[M+H]+.MS m/z(ESI):222.1,224.1[M+H] + .
第三步third step
将2-(4-溴噻唑-2-基)丙烷-2-醇5C(100mg,0.45mmol)，联硼酸频那醇酯(137.2mg,0.54mmol)，三(二亚苄基丙酮)二钯(20.6mg,0.02mmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(25.8mg,0.05mmol)和醋酸钾(88.4mg,0.9mmol)溶解于无水1，4-二氧六环(9mL)中，氮气置换1分钟，反应加热至110C搅拌2 小时。冷却至室温，反应液过滤，滤液浓缩，残余物经反相HPLC(甲酸体系)制备得到标题产物(2-(2-羟基丙烷-2-基)噻唑-4-基)硼酸中间体5(65mg)，产率：77.2％。2-(4-Bromothiazol-2-yl)propan-2-ol 5C (100mg, 0.45mmol), pinacol diboronate (137.2mg, 0.54mmol), tris(dibenzylideneacetone)dipalladium (20.6mg, 0.02mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25.8mg, 0.05mmol) and potassium acetate (88.4mg, 0.9mmol) were dissolved in In water 1,4-dioxane (9mL), nitrogen replacement for 1 minute, the reaction was heated to 110C and stirred for 2 Hour. Cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated, and the residue was prepared by reverse phase HPLC (formic acid system) to obtain the title product (2-(2-hydroxypropan-2-yl)thiazol-4-yl)boronic acid intermediate 5 (65mg ), yield: 77.2%.
MS m/z(ESI):188.1[M+H]+.MS m/z(ESI):188.1[M+H] + .
中间体6Intermediate 6
2'-氯-6-环丙基-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-2H-[1,4'-联吡啶]-2-酮
2'-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-2H-[1,4'-bipyridine]- 2-keto
第一步first step
将2,2,6-三甲基-4H-1,3-二噁英-4-酮6A(8.16g,57.40mmol)溶解于四氢呋喃(60mL)中，冷却至-78℃。向反应液中滴加双三甲基硅基胺基锂(1M,63mL)，滴加完成后，反应在-78℃搅拌1小时。向反应液中滴加环丙基甲酰氯(3g,28.70mmol,2.60mL)的四氢呋喃(10mL)溶液，反应在-78℃搅拌16小时。冰浴下向反应液中加入饱和氯化铵溶液(30mL)淬灭反应，并用稀盐酸调节pH至弱酸性，有机相分离，水相用乙酸乙酯(30mL×2)萃取。有机相合并，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物6-(2-环丙基-2-羰基乙基)-2,2-二甲基-4H-1,3-二噁英-4-酮6B(2.93g)，产率：48％。2,2,6-Trimethyl-4H-1,3-dioxin-4-one 6A (8.16 g, 57.40 mmol) was dissolved in tetrahydrofuran (60 mL), and cooled to -78°C. Lithium bistrimethylsilylamide (1M, 63 mL) was added dropwise to the reaction solution, and after the addition was complete, the reaction was stirred at -78°C for 1 hour. A solution of cyclopropylformyl chloride (3 g, 28.70 mmol, 2.60 mL) in tetrahydrofuran (10 mL) was added dropwise to the reaction solution, and the reaction was stirred at -78°C for 16 hours. Saturated ammonium chloride solution (30 mL) was added to the reaction solution under ice-cooling to quench the reaction, and the pH was adjusted to weak acidity with dilute hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to obtain the product 6-(2-cyclopropyl-2-carbonylethyl)-2,2-dimethyl-4H-1,3-dioxin -4-Kone 6B (2.93 g), yield: 48%.
MS m/z(ESI):211.1[M+H]+.MS m/z(ESI):211.1[M+H] + .
第二步second step
将6-(2-环丙基-2-羰基乙基)-2,2-二甲基-4H-1,3-二噁英-4-酮6B(700mg,3.33mmol)和2-氯-4-氨基-5-甲基吡啶(617mg,4.33mmol)溶解于1,4-二氧六环(10mL)中，反应加热至90℃搅拌3.5小时。向反应液中加入浓硫酸(0.25mL)，反应在90℃搅拌1小时。向反应液中加入水(10mL)，经反相HPLC制备分离(甲酸体系)得到产物2'-氯-6-环丙基-4-羟基-5'-甲基-2H-[1,4'-联吡啶]-2-酮6C(318mg)，产率：34.5％。 Mix 6-(2-cyclopropyl-2-carbonylethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one 6B (700mg, 3.33mmol) and 2-chloro- 4-Amino-5-picoline (617 mg, 4.33 mmol) was dissolved in 1,4-dioxane (10 mL), and the reaction was heated to 90° C. and stirred for 3.5 hours. Concentrated sulfuric acid (0.25 mL) was added to the reaction solution, and the reaction was stirred at 90° C. for 1 hour. Water (10mL) was added to the reaction solution, and the product 2'-chloro-6-cyclopropyl-4-hydroxyl-5'-methyl-2H-[1,4' was prepared and separated by reverse phase HPLC (formic acid system) -Bipyridyl]-2-one 6C (318 mg), yield: 34.5%.
MS m/z(ESI):277.1[M+H]+.MS m/z(ESI):277.1[M+H] + .
第三步third step
将2'-氯-6-环丙基-4-羟基-5'-甲基-2H-[1,4'-联吡啶]-2-酮1c(318mg,1.15mmol)，2-(氯甲基)-3,5-二氟-吡啶(226mg,1.38mmol)，碳酸钾(397mg,2.87mmol)和18-冠-6(30mg,0.11mmol)溶解于N,N-二甲基甲酰胺(5mL)中。反应加热至60℃搅拌3小时。向反应液中加入水(20mL)，水相用乙酸乙酯(20mL×2)萃取。有机相合并，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物2'-氯-6-环丙基-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-2H-[1,4'-联吡啶]-2-酮中间体6(380mg)，产率：81％。2'-Chloro-6-cyclopropyl-4-hydroxy-5'-methyl-2H-[1,4'-bipyridine]-2-one 1c (318 mg, 1.15 mmol), 2-(chloromethyl base)-3,5-difluoro-pyridine (226mg, 1.38mmol), potassium carbonate (397mg, 2.87mmol) and 18-crown-6 (30mg, 0.11mmol) were dissolved in N,N-dimethylformamide ( 5mL). The reaction was heated to 60°C and stirred for 3 hours. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2'-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5 '-Methyl-2H-[1,4'-bipyridyl]-2-one intermediate 6 (380 mg), yield: 81%.
MS m/z(ESI):404.1[M+H]+.MS m/z(ESI):404.1[M+H] + .
实施例1Example 1
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
第一步first step
氮气保护下，将中间体1(50mg,0.12mmol)，中间体5(50.8mg,0.17mmol，纯度：62％)，1,1-双(二苯基膦)1,1'-双二苯基膦二茂铁二氯化钯(8.9mg,0.01mmol)和碳酸铯(79mg,0.24mmol)溶解于1，4-二氧六环(1mL)和水(0.3mL)混合溶剂中。反应加热至100℃搅拌3小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到标题产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮1(32mg)，产率：50.8％。Under nitrogen protection, intermediate 1 (50mg, 0.12mmol), intermediate 5 (50.8mg, 0.17mmol, purity: 62%), 1,1-bis(diphenylphosphine) 1,1'-bisdiphenyl Phosphinoferrocenepalladium dichloride (8.9 mg, 0.01 mmol) and cesium carbonate (79 mg, 0.24 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.3 mL). The reaction was heated to 100°C and stirred for 3 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'- (2-(2-Hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 1 (32 mg), producing Rate: 50.8%.
MS m/z(ESI):519.1[M+H]+. MS m/z(ESI):519.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.15-8.05(m,1H),7.86(s,1H),6.80(s,1H),6.06(s,1H),5.48(d,2H),2.03(s,3H),1.97(s,3H),1.55(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.15-8.05(m,1H),7.86(s,1H), 6.80(s,1H),6.06(s,1H),5.48(d,2H),2.03(s,3H),1.97(s,3H),1.55(d,6H).
实施例1的拆分Splitting of Example 1
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl )-5',6-Dimethyl-2H-[1,4'-bipyridyl]-2-one and (R)-3-chloro-4-((3,5-difluoropyridin-2-yl )methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]- 2-keto
将实施例1(30mg,0.06mmol)经手性拆分(OD柱)得到标题产物1-1(12.0mg，R.T＝3.597min)，产率：40％；1-2(11.7mg，R.T＝4.320min)，产率：39.0％。Example 1 (30mg, 0.06mmol) was subjected to chiral resolution (OD column) to obtain the title product 1-1 (12.0mg, R.T=3.597min), yield: 40%; 1-2 (11.7mg, R.T=4.320 min), yield: 39.0%.
实施例1-1：MS m/z(ESI):519.1[M+H]+；Embodiment 1-1: MS m/z (ESI): 519.1[M+H] + ;
实施例1-2：MS m/z(ESI):519.1[M+H]+.Example 1-2: MS m/z (ESI): 519.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例2 Example 2
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5'-Methyl-6-(methyl-d3)-2H-[1,4'-bipyridyl]-2-one
第一步first step
将2,2,6-三甲基-4H-1,3-二噁英-4-酮(10.04g,70.66mmol)溶解于四氢呋喃(60mL)中，冷却至-78C。向反应液中滴加双三甲基硅基胺基锂(1M,71mL)。反应在-78℃下搅拌1小时。向反应液中滴加2，2，2-三氘乙酰氯(2.88g,35.33mmol)的四氢呋喃(10mL)溶液。反应在-78℃下搅拌16小时。冰浴下向反应液中加入饱和氯化铵溶液(30mL)，用稀盐酸调节pH至弱酸性。有机相分离，水相用乙酸乙酯(30mL×2)萃取。有机相合并，干燥，浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物2,2-二甲基-6-(2-羰基丙基-3,3,3-d3)-4H-1,3-二噁英-4-酮2a(2.66g)，产率：40％。2,2,6-Trimethyl-4H-1,3-dioxin-4-one (10.04 g, 70.66 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to -78°C. Lithium bistrimethylsilylamide (1M, 71 mL) was added dropwise to the reaction solution. The reaction was stirred at -78°C for 1 hour. A tetrahydrofuran (10 mL) solution of 2,2,2-trideuteroacetyl chloride (2.88 g, 35.33 mmol) was added dropwise to the reaction liquid. The reaction was stirred at -78°C for 16 hours. Saturated ammonium chloride solution (30 mL) was added to the reaction solution under ice cooling, and the pH was adjusted to weak acidity with dilute hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2,2-dimethyl-6-(2-carbonylpropyl-3,3,3-d3) -4H-1,3-dioxin-4-one 2a (2.66 g), yield: 40%.
MS m/z(ESI):188.1[M+H]+.MS m/z(ESI):188.1[M+H] + .
第二步second step
将2,2-二甲基-6-(2-羰基丙基-3,3,3-d3)-4H-1,3-二噁英-4-酮2a(2.66g,14.21mmol)和2-氯-4-氨基-5-甲基吡啶(2.63g,18.47mmol)溶解于1,4-二氧六环(20mL)中。反应加热至90℃搅拌2小时。向反应液中加入浓硫酸(1.06mL)，反应在90℃下继续搅拌1小时。反应液浓缩，残余物用冰水打浆得到产物2'-氯-4-羟基-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮2b(2.66g)，产率：73.9％。2,2-Dimethyl-6-(2-carbonylpropyl-3,3,3-d3)-4H-1,3-dioxin-4-one 2a (2.66g, 14.21mmol) and 2 -Chloro-4-amino-5-methylpyridine (2.63 g, 18.47 mmol) was dissolved in 1,4-dioxane (20 mL). The reaction was heated to 90°C and stirred for 2 hours. Concentrated sulfuric acid (1.06 mL) was added to the reaction solution, and the reaction was stirred at 90° C. for 1 hour. The reaction solution was concentrated, and the residue was beaten with ice water to obtain the product 2'-chloro-4-hydroxy-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridine]-2- Ketone 2b (2.66 g), yield: 73.9%.
MS m/z(ESI):254.1[M+H]+.MS m/z(ESI):254.1[M+H] + .
第三步 third step
将2'-氯-4-羟基-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮2b(500mg,1.97mmol)，2-(氯甲基)-3,5-二氟-吡啶(419mg,2.56mmol)，碳酸钾(544mg,3.94mmol)和18-冠-6(521mg,1.97mmol)溶解于N,N-二甲基甲酰胺(10mL)中。反应加热至60℃搅拌4小时。反应液冷却至室温，向反应液中加入水(20mL),水相用乙酸乙酯(20mL×2)萃取。有机相合并，干燥，浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物2'-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮2c(660mg)，产率：87.9％。2'-Chloro-4-hydroxyl-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridine]-2-one 2b (500mg, 1.97mmol), 2- (Chloromethyl)-3,5-difluoro-pyridine (419mg, 2.56mmol), potassium carbonate (544mg, 3.94mmol) and 18-crown-6 (521mg, 1.97mmol) were dissolved in N,N-dimethyl formamide (10 mL). The reaction was heated to 60°C and stirred for 4 hours. The reaction solution was cooled to room temperature, water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy) -5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridyl]-2-one 2c (660 mg), yield: 87.9%.
MS m/z(ESI):381.1[M+H]+.MS m/z(ESI):381.1[M+H] + .
第四步the fourth step
将2'-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮2c(651mg,1.71mmol)和N-氯代丁二酰亚胺(251mg,1.88mmol)溶解于异丙醇(2mL)中。反应加热至60℃搅拌3小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮2d(560mg)，产率：78.9％。2'-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2H-[1,4'- Bipyridyl]-2-one 2c (651 mg, 1.71 mmol) and N-chlorosuccinimide (251 mg, 1.88 mmol) were dissolved in isopropanol (2 mL). The reaction was heated to 60°C and stirred for 3 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)- 5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridyl]-2-one 2d (560 mg), yield: 78.9%.
MS m/z(ESI):415.0[M+H]+.MS m/z(ESI):415.0[M+H] + .
第五步the fifth step
将油浴预热到100℃。氮气保护下，将2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮2d(50mg，0.12mmol)，[2-(1-羟基-1-甲基-乙基)噻唑-4-基]硼酸中间体5(45mg,0.24mmol)，碳酸铯(78mg，0.24mmol)，和1,1-双(二苯基膦)二荗铁二氯化钯(9mg，0.012mmol)溶解到1，4-二氧六环(3mL)中。反应用微波加热至100℃搅拌3小时。反应液过滤，滤液使用反相HPLC制备分离(甲酸体系)分离得到标题产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮2(46mg)，产率：76.2％。Preheat the oil bath to 100 °C. Under nitrogen protection, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2H -[1,4'-bipyridyl]-2-one 2d (50mg, 0.12mmol), [2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]boronic acid intermediate 5 (45mg , 0.24mmol), cesium carbonate (78mg, 0.24mmol), and 1,1-bis(diphenylphosphine) dioxonium dichloride palladium (9mg, 0.012mmol) were dissolved in 1,4-dioxane ( 3mL). The reaction was heated to 100° C. with microwave and stirred for 3 hours. The reaction solution was filtered, and the filtrate was separated by reverse phase HPLC (formic acid system) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2- (2-Hydroxypropane-2-yl)thiazol-4-yl)-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridine]-2-one 2(46mg ), yield: 76.2%.
MS m/z(ESI):522.1[M+H]+.MS m/z(ESI):522.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.10(s,1H),7.86(s,1H),6.80(s,1H),6.07(s,1H),5.48(s,2H),2.03(s,3H),1.55(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.10(s,1H),7.86(s,1H),6.80( s,1H),6.07(s,1H),5.48(s,2H),2.03(s,3H),1.55(d,6H).
实施例2的拆分Splitting of Example 2
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5'-甲基-6-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl )-5'-methyl-6-(methyl-d3)-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-di Fluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-5'-methyl-6-(methyl-d3)- 2H-[1,4'-bipyridyl]-2-one
实施例2(110mg,0.21mmol)通过手性拆分(OD柱)得到实施例2-1(42mg，R.T＝3.633min，产率：38.2％)和实施例2-2(36mg，R.T＝4.360min，产率：36.7％)，Example 2 (110mg, 0.21mmol) was obtained by chiral resolution (OD column) Example 2-1 (42mg, R.T=3.633min, yield: 38.2%) and Example 2-2 (36mg, R.T=4.360 min, yield: 36.7%),
实施例2-1：MS m/z(ESI):522.1[M+H]+；Embodiment 2-1: MS m/z (ESI): 522.1[M+H] + ;
实施例2-2：MS m/z(ESI):522.1[M+H]+.Example 2-2: MS m/z (ESI): 522.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例3Example 3
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙-2-基)噻唑-4-基)-6-甲基-5'-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6- Methyl-5'-(methyl-d 3 )-2H-[1,4'-bipyridyl]-2-one
第一步first step
将2-氯-5-碘吡啶-4-胺(2g,7.86mmol)和三乙酰丙酮铁(416mg,1.18mmol)置于二口烧瓶，氮气置换，加入无水四氢呋喃(30mL)，冰浴10分钟后，搅拌下通过注射器缓慢滴加1mol/L的甲基-d3-碘化镁溶液(27.5mL)，滴毕，转至室温反应1小时。冰浴下滴加饱和氯化铵溶液淬灭反应，用乙酸乙酯(50mL)萃取，干燥，浓缩后用硅胶柱层析(洗脱体系B)得产物2-氯-5-(甲基-d3)吡啶-4-胺3b(0.140g)，收率：12％。2-Chloro-5-iodopyridin-4-amine (2g, 7.86mmol) and iron triacetylacetonate (416mg, 1.18mmol) were placed in a two-necked flask, nitrogen replacement was added, and anhydrous tetrahydrofuran (30mL) was added, and ice bathed for 10 Minutes later, 1 mol/L methyl-d3-magnesium iodide solution (27.5 mL) was slowly added dropwise through a syringe under stirring. Add saturated ammonium chloride solution dropwise under ice bath to quench the reaction, extract with ethyl acetate (50mL), dry, concentrate and use silica gel column chromatography (elution system B) to obtain the product 2-chloro-5-(methyl- d 3 ) Pyridin-4-amine 3b (0.140 g), yield: 12%.
MS m/z(ESI):146.1[M+H]+.MS m/z(ESI):146.1[M+H] + .
1H NMR(400MHz,CDCl3)δ7.85(s,1H),6.53(s,1H),4.24(s,2H). 1 H NMR (400MHz, CDCl 3 )δ7.85(s,1H),6.53(s,1H),4.24(s,2H).
第二步second step
目标产物2'-氯-4-羟基-6-甲基-5'–(甲基-d3)-2H-[1,4'-二吡啶]-2-酮3c可通过实施例2第二步类似过程制备。The target product 2'-chloro-4-hydroxyl-6-methyl-5'-(methyl-d 3 )-2H-[1,4'-dipyridin]-2-one 3c can be obtained through Example 2 for the second Prepared in a similar process.
MS m/z(ESI):253.8[M+H]+.MS m/z(ESI):253.8[M+H] + .
第三步third step
目标产物2'-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-5'–(甲基-d3)-2H-[1,4'-二吡啶]-2-酮3d可通过实施例2第三步类似过程制备。Target product 2'-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'–(methyl-d3)-2H-[1,4' -Dipyridin]-2-one 3d can be prepared by a similar process to the third step of Example 2.
MS m/z(ESI):381.1[M+H]+.MS m/z(ESI):381.1[M+H] + .
第四步the fourth step
目标产物2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-5'–(甲基-d3)-2H-[1,4'-二吡啶]-2-酮3e可通过实施例2第四步类似过程由制备。 The target product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'–(methyl-d3)-2H-[1 , 4'-dipyridin]-2-one 3e can be prepared by the similar process of the fourth step of Example 2.
MS m/z(ESI):414.8[M+H]+.MS m/z(ESI):414.8[M+H] + .
第五步the fifth step
氮气保护下，将2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-5'–(甲基-d3)-2H-[1,4'-二吡啶]-2-酮3e(40mg,0.096mmol)，[2-(1-羟基-1-甲基-乙基)噻唑-4-基]硼酸中间体5(82mg,0.241mmol，纯度：55％)和1,1'-二(二苯膦基)二茂铁二氯化钯(14mg,0.019mmol)和碳酸铯(94mg,0.289mmol)溶于二氧六环(0.75mL)和水(0.25mL)的混合液中。反应加热至100℃搅拌3.5小时。向反应液加入乙酸乙酯(25mL)，经硅藻土过滤后，滤液浓缩。残留物用制备型硅胶色谱板纯化(洗脱体系A)得标题产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙-2-基)噻唑-4-基)-6-甲基-5'-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮3(44mg)，收率：87％。Under nitrogen protection, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-5'–(methyl-d3)-2H -[1,4'-dipyridin]-2-one 3e (40mg, 0.096mmol), [2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]boronic acid intermediate 5 (82mg , 0.241mmol, purity: 55%) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (14mg, 0.019mmol) and cesium carbonate (94mg, 0.289mmol) were dissolved in dioxane (0.75mL) and water (0.25mL) mixture. The reaction was heated to 100°C and stirred for 3.5 hours. Ethyl acetate (25 mL) was added to the reaction solution, and after filtration through celite, the filtrate was concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to give the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-( 2-Hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-5'-(methyl-d 3 )-2H-[1,4'-bipyridine]-2-one 3(44mg ), yield: 87%.
MS m/z(ESI):521.8[M+H]+.MS m/z(ESI):521.8[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.66(d,J＝27.0Hz,1H),8.60(s,1H),8.15(d,J＝19.1Hz,1H),8.10(s,1H),7.86(s,1H),6.80(s,1H),6.05(s,1H),5.48(s,2H),1.97(s,3H),1.55(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.66(d,J=27.0Hz,1H),8.60(s,1H),8.15(d,J=19.1Hz,1H),8.10(s,1H) ,7.86(s,1H),6.80(s,1H),6.05(s,1H),5.48(s,2H),1.97(s,3H),1.55(s,6H).
实施例3的拆分Splitting of Example 3
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙-2-基)噻唑-4-基)-6-甲基-5'-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙-2-基)噻唑-4-基)-6-甲基-5'-(甲基-d3)-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl )-6-methyl-5'-(methyl-d 3 )-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5- Difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-5'-(methyl-d 3 )-2H-[1,4'-bipyridine]-2-one
实施例3(66mg，0.126mmol)经手性拆分(OD柱)得到标题产物3-1(25mg，R.T＝3.623min)，产率：38％；3-2(25mg，R.T＝4.420min)，产率：38％。Example 3 (66mg, 0.126mmol) was subjected to chiral resolution (OD column) to obtain the title product 3-1 (25mg, R.T=3.623min), yield: 38%; 3-2 (25mg, R.T=4.420min), Yield: 38%.
实施例3-1，MS m/z(ESI):521.8[M+H]+；Embodiment 3-1, MS m/z (ESI): 521.8[M+H] + ;
实施例3-2，MS m/z(ESI):521.8[M+H]+；Embodiment 3-2, MS m/z (ESI): 521.8[M+H] + ;
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例4Example 4
3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl )-6-Methyl-2H-[1,4'-bipyridine]-2-one
第一步first step
将2,2-二甲基-6-(2-羰基丙基)-4H-1,3-二噁英-4-酮(2.26g，12.3mmol)和2,5-二氯-4-氨基吡啶4a(1g，6.13mmol)溶于1,4-二氧六环(15mL)中。反应液加热至100℃搅拌3小时。向反应体系中加入浓硫酸(842mg，8.59mmol)，并继续在100℃下搅拌2小时。浓缩得粗品，粗品用硅胶柱色谱法(洗脱剂体系 A)分离，得产物2',5'-二氯-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮4b(700mg)，产率：42％。2,2-Dimethyl-6-(2-carbonylpropyl)-4H-1,3-dioxin-4-one (2.26g, 12.3mmol) and 2,5-dichloro-4-amino Pyridine 4a (1 g, 6.13 mmol) was dissolved in 1,4-dioxane (15 mL). The reaction solution was heated to 100°C and stirred for 3 hours. Concentrated sulfuric acid (842mg, 8.59mmol) was added to the reaction system, and stirring was continued at 100°C for 2 hours. Concentrate to get the crude product, and the crude product is subjected to silica gel column chromatography (eluent system A) Separation to obtain the product 2',5'-dichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 4b (700mg), yield: 42%.
MS m/z(ESI):271.0[M+H]+.MS m/z(ESI):271.0[M+H] + .
第二步second step
将2',5'-二氯-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮4b(400mg，1.48mmol)、2-(氯甲基)-3,5-二氟吡啶(313mg，1.92mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入碳酸钾(509mg，3.69mmol)和18-冠醚-6(585mg，2.21mmol)。反应液加热至70℃搅拌4小时。向反应液加入饱和氯化钠(20mL)，水相用乙酸乙酯(20mL×3)萃取，有机相合并，干燥，浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到产物2',5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-2H-[1,4'-联吡啶]-2-酮4c(500mg)，产率：85％。2',5'-dichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridine]-2-one 4b (400mg, 1.48mmol), 2-(chloromethyl)- 3,5-Difluoropyridine (313 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (509 mg, 3.69 mmol) and 18-crown-6 (585 mg, 2.21 mmol) were added ). The reaction solution was heated to 70°C and stirred for 4 hours. Saturated sodium chloride (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the product 2',5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methanol yl-2H-[1,4'-bipyridyl]-2-one 4c (500 mg), yield: 85%.
MS m/z(ESI):398.0[M+H]+.MS m/z(ESI):398.0[M+H] + .
第三步third step
将2',5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-2H-[1,4'-联吡啶]-2-酮4c(120mg，0.301mmol)溶于异丙醇(2mL)中，加入N-氯代丁二酰亚胺(45mg，0.331mmol)。反应液于60℃下搅拌4小时。将反应液浓缩得粗品,粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到产物2',3,5'-三氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-2H-[1,4'-联吡啶]-2-酮4d(83mg)，产率：63％2',5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridine]-2- Ketone 4c (120 mg, 0.301 mmol) was dissolved in isopropanol (2 mL), and N-chlorosuccinimide (45 mg, 0.331 mmol) was added. The reaction solution was stirred at 60°C for 4 hours. The reaction solution was concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl )methoxy)-6-methyl-2H-[1,4'-bipyridyl]-2-one 4d (83 mg), yield: 63%
MS m/z(ESI):431.9[M+H]+.MS m/z(ESI):431.9[M+H] + .
第四步the fourth step
将2',3,5'-三氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-2H-[1,4'-联吡啶]-2-酮4d(40mg，0.092mmol)，中间体5(44mg，0.231mmol)，1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(7.5mg，0.009mmol)和碳酸铯(60mg，0.184mmol)溶于1，4-二氧六环/水(5:1,1mL)中，氮气保护下将反应加热至100℃搅拌3小时。向反应液加入饱和氯化钠(10mL)，水相用乙酸乙酯(10mL×3)萃取。有机相合并,干燥,浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到标题产物3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮4(27mg)，产率：54％。2',3,5'-Trichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2H-[1,4'-bipyridine]- 2-Kone 4d (40mg, 0.092mmol), intermediate 5 (44mg, 0.231mmol), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium dichloromethane complex (7.5mg, 0.009 mmol) and cesium carbonate (60 mg, 0.184 mmol) were dissolved in 1,4-dioxane/water (5:1, 1 mL), and the reaction was heated to 100° C. and stirred for 3 hours under nitrogen protection. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried and concentrated to obtain the crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the title product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'- (2-(2-Hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 4 (27 mg), yield: 54% .
MS m/z(ESI):539.0[M+H]+.MS m/z(ESI):539.0[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.10(m,1H),6.98–6.79(m,1H),6.10(s,1H),5.50(d,2H),2.01(s,3H),1.56(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.93(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.10(m,1H),6.98– 6.79(m,1H),6.10(s,1H),5.50(d,2H),2.01(s,3H),1.56(d,6H).
实施例4的拆分 Splitting of Example 4
(S)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazole -4-yl)-6-methyl-2H-[1,4'-bipyridine]-2-one and (R)-3,5'-dichloro-4-((3,5-difluoropyridine -2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridine]- 2-keto
实施例4(27mg,0.050mmol)通过手性拆分(OD柱)得到实施例4-1(9.1mg，R.T＝3.413min，产率：34％)和实施例4-2(11mg，R.T＝4.960min，产率：41％)。Example 4 (27mg, 0.050mmol) was obtained by chiral resolution (OD column) Example 4-1 (9.1mg, R.T = 3.413min, yield: 34%) and Example 4-2 (11mg, R.T = 4.960 min, yield: 41%).
实施例4-1：MS m/z(ESI):539.0[M+H]+；Embodiment 4-1: MS m/z (ESI): 539.0[M+H] + ;
实施例4-2：MS m/z(ESI):539.0[M+H]+.Example 4-2: MS m/z (ESI): 539.0[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例5Example 5
3,5'-二氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
3,5'-Dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazole-4 -yl)-6-methyl-2H-[1,4'-bipyridine]-2-one
第一步first step
将2',5'-二氯-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮4b(100mg，0.369mmol)，2-(1-氯乙基)-3,5-二氟吡啶(98mg，0.553mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入碳酸钾(127mg，0.922mmol)和18-冠醚-6(146mg，0.553mmol)。反应液加热至70℃搅拌4小时。向反应液中加入饱和氯化钠(10mL)，水相用乙酸乙酯(10mL×3)萃取，有机相合并，干燥，浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到产物2',5'-二氯-4-((3,5-二氟吡啶-2-基)乙氧基)-6-甲基-2H-[1,4'-联吡啶]-2-酮5a(120mg)，产率：78％。2',5'-dichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridine]-2-one 4b (100mg, 0.369mmol), 2-(1-chloroethyl )-3,5-difluoropyridine (98mg, 0.553mmol) was dissolved in N,N-dimethylformamide (2mL), potassium carbonate (127mg, 0.922mmol) and 18-crown-6 (146mg, 0.553 mmol). The reaction solution was heated to 70°C and stirred for 4 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the product 2',5'-dichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-6-methanol Ethyl-2H-[1,4'-bipyridyl]-2-one 5a (120 mg), yield: 78%.
MS m/z(ESI):412.0[M+H]+.MS m/z(ESI):412.0[M+H] + .
第二步second step
将2',5'-二氯-4-((3,5-二氟吡啶-2-基)乙氧基)-6-甲基-2H-[1,4'-联吡啶]-2-酮5a(120mg，0.291mmol)溶于异丙醇(2mL)中，加入N-氯代丁二酰亚胺(43mg，0.321mmol)。反应液于60℃下搅拌4小时。将反应液浓缩得粗品，粗品用硅胶柱色谱法(洗脱剂体系A)分离，得到产物2',3,5'-三氯-4-((3,5-二氟吡啶-2-基)乙氧基)-6-甲基-2H-[1,4'-联吡啶]-2-酮5b(110mg)，产率：84％。2',5'-dichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2H-[1,4'-bipyridine]-2- Ketone 5a (120 mg, 0.291 mmol) was dissolved in isopropanol (2 mL), and N-chlorosuccinimide (43 mg, 0.321 mmol) was added. The reaction solution was stirred at 60°C for 4 hours. The reaction solution was concentrated to obtain a crude product, which was separated by silica gel column chromatography (eluent system A) to obtain the product 2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl )ethoxy)-6-methyl-2H-[1,4'-bipyridyl]-2-one 5b (110 mg), yield: 84%.
MS m/z(ESI):446.0[M+H]+.MS m/z(ESI):446.0[M+H] + .
第三步third step
将2',3,5'-三氯-4-((3,5-二氟吡啶-2-基)乙氧基)-6-甲基-2H-[1,4'-联吡啶]-2-酮5b(110mg，0.246mmol)，中间体5(115mg，0.616mmol)，1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(21mg，0.025mmol)和碳酸铯(160mg，0.493mmol)溶于1，4-二氧六环/水(V:V＝5:1,1mL)中，氮气保护下将反应加热至100℃搅拌3小时。向反应液加入饱和氯化钠(10mL)，水相用乙酸乙酯(10mL×3)萃取。有机相合并，干燥，浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到标题产物3,5'-二氯-4-((3,5-二氟吡啶-2-基)乙氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮5(103mg)，产率：75％。2',3,5'-Trichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2H-[1,4'-bipyridine]- 2-Kone 5b (110mg, 0.246mmol), intermediate 5 (115mg, 0.616mmol), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium dichloromethane complex (21mg, 0.025mmol ) and cesium carbonate (160 mg, 0.493 mmol) were dissolved in 1,4-dioxane/water (V:V=5:1, 1 mL), and the reaction was heated to 100° C. and stirred for 3 hours under nitrogen protection. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried and concentrated to give the crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the title product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)ethoxy)-2'- (2-(2-Hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 5 (103 mg), yield: 75% .
MS m/z(ESI):553.0[M+H]+.MS m/z(ESI):553.0[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.59(d,1H),8.26(s,1H),8.14(s,1H),8.07(m,1H),6.62(s,1H),6.09(s,1H),6.07(d,1H),1.96(s,3H),1.73(d,3H),1.54(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.92(s,1H),8.59(d,1H),8.26(s,1H),8.14(s,1H),8.07(m,1H),6.62( s,1H),6.09(s,1H),6.07(d,1H),1.96(s,3H),1.73(d,3H),1.54(s,6H).
实施例5的拆分 Splitting of Embodiment 5
(S)-3,5'-二氯-4-(((S)-3,5-二氟吡啶-2-基)乙氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮，(S)-3,5'-二氯-4-(((R)-3,5-二氟吡啶-2-基)乙氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮，(R)-3,5'-二氯-4-(((R)-3,5-二氟吡啶-2-基)乙氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3,5'-二氯-4-(((S)-3,5-二氟吡啶-2-基)乙氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3,5'-dichloro-4-(((S)-3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropane-2 -yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridine]-2-one, (S)-3,5'-dichloro-4-(((R) -3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-6-methyl-2H-[1 ,4'-bipyridyl]-2-one, (R)-3,5'-dichloro-4-(((R)-3,5-difluoropyridin-2-yl)ethoxy)-2 '-(2-(2-Hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one and (R)-3,5 '-Dichloro-4-(((S)-3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazole-4- Base)-6-methyl-2H-[1,4'-bipyridine]-2-one
实施例5(103mg,0.186mmol)通过手性拆分(AD柱)得到实施例5-1(20mg，R.T＝4.963min，产率：20％)、实施例5-2(18mg，R.T＝1.634min，产率：17％)，实施例5-3(21mg，R.T＝8.047min，产率：20％)，实施例5-4(18mg，R.T＝2.141min，产率：17％)。Example 5 (103mg, 0.186mmol) was obtained by chiral resolution (AD column) Example 5-1 (20mg, R.T = 4.963min, yield: 20%), Example 5-2 (18mg, R.T = 1.634 min, yield: 17%), Example 5-3 (21mg, R.T=8.047min, yield: 20%), Example 5-4 (18mg, R.T=2.141min, yield: 17%).
实施例5-1：MS m/z(ESI):553.0[M+H]+ Example 5-1: MS m/z (ESI): 553.0[M+H] +
实施例5-2：MS m/z(ESI):553.0[M+H]+ Example 5-2: MS m/z (ESI): 553.0 [M+H] +
实施例5-3：MS m/z(ESI):553.0[M+H]+ Example 5-3: MS m/z (ESI): 553.0 [M+H] +
实施例5-4：MS m/z(ESI):553.0[M+H]+ Example 5-4: MS m/z (ESI): 553.0 [M+H] +
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：

HPLC chiral analysis conditions:

实施例6Example 6
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-3-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyridine Azol-3-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
第一步first step
将6a(500mg,3.4mmol)，2-溴-2-甲基丙酸乙酯(862.6mg,4.42mmol)和碳酸钾(1.41g,10.21mmol)溶解于N,N-二甲基甲酰胺(20mL)中，反应加热至80℃搅拌16小时。反应液过滤，向滤液中加入饱和氯化铵(80mL)，水相用乙酸乙酯(30mL×3)萃取。有机相合并，干燥，浓缩得到粗产品产物2-(3-溴-1H-吡唑-1-基)-2-甲基丙酸乙酯6b(888mg)，产率：99.9％。不经进一步纯化，直接用于下一步反应中。6a (500 mg, 3.4 mmol), ethyl 2-bromo-2-methylpropionate (862.6 mg, 4.42 mmol) and potassium carbonate (1.41 g, 10.21 mmol) were dissolved in N,N-dimethylformamide ( 20 mL), the reaction was heated to 80 °C and stirred for 16 hours. The reaction solution was filtered, saturated ammonium chloride (80 mL) was added to the filtrate, and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried and concentrated to obtain the crude product ethyl 2-(3-bromo-1H-pyrazol-1-yl)-2-methylpropanoate 6b (888mg), yield: 99.9%. It was directly used in the next reaction without further purification.
MS m/z(ESI):261.1,263.1[M+H]+.MS m/z(ESI):261.1,263.1[M+H] + .
第二步 second step
将6b(730mg,2.8mmol)溶解于甲醇(10mL)中，0℃下向反应液中加入硼氢化钠(423mg，11.2mmol)。反应恢复至室温搅拌1小时。反应液浓缩，向残余物中加入饱和氯化铵(25mL)溶液，水相用乙酸乙酯(15mL×3)萃取。有机相合并，干燥，浓缩，残余物经反相HPLC(甲酸体系)制备得到产物2-(3-溴-1H-吡唑-1-基)-2-甲基丙烷-1-醇6c(390mg)，产率：63.7％。6b (730 mg, 2.8 mmol) was dissolved in methanol (10 mL), and sodium borohydride (423 mg, 11.2 mmol) was added to the reaction solution at 0°C. The reaction was returned to room temperature and stirred for 1 hour. The reaction solution was concentrated, a saturated ammonium chloride (25 mL) solution was added to the residue, and the aqueous phase was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried and concentrated, and the residue was prepared by reverse-phase HPLC (formic acid system) to obtain the product 2-(3-bromo-1H-pyrazol-1-yl)-2-methylpropan-1-ol 6c (390mg ), yield: 63.7%.
MS m/z(ESI):219.1,221.1[M+H]+.MS m/z(ESI):219.1,221.1[M+H] + .
第三步third step
氮气保护下，将6c(400mg,1.83mmol)，联硼酸频那醇酯(602.7mg,2.37mmol)，1,1-双(二苯基膦)二茂铁二氯化钯(133.6mg,0.18mmol)和醋酸钾(448mg,4.56mmol)溶解于无水1,4-二氧六环(10mL)中。反应加热至100℃搅拌16小时。反应液过滤，滤液浓缩，残余物经反相HPLC(甲酸体系)制备得到粗产品(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-3-基)硼酸6d(390mg，纯度约40％)，产率：46.4％。Under nitrogen protection, 6c (400mg, 1.83mmol), pinacol diborate (602.7mg, 2.37mmol), 1,1-bis(diphenylphosphine)ferrocenepalladium dichloride (133.6mg, 0.18 mmol) and potassium acetate (448 mg, 4.56 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The reaction was heated to 100°C and stirred for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was prepared by reverse phase HPLC (formic acid system) to obtain the crude product (1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-3-yl)boronic acid 6d (390 mg, about 40% purity), yield: 46.4%.
MS m/z(ESI):185.1[M+H]+.MS m/z(ESI):185.1[M+H] + .
第四步the fourth step
氮气保护下，将中间体1(40mg,0.1mmol)，6d(102.7mg,0.22mmol,纯度约40％)，1,1-双(二苯基膦)二茂铁二氯化钯(7.1mg,0.01mmol)和碳酸铯(94.8mg,0.29mmol)溶解于1,4-二氧六环(1.2mL)和水(0.1mL)混合溶剂中。反应加热至90℃搅拌0.5小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到标题产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-3-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮6(30mg)，产率：59.9％。Under nitrogen protection, intermediate 1 (40mg, 0.1mmol), 6d (102.7mg, 0.22mmol, about 40% purity), 1,1-bis(diphenylphosphine)ferrocenepalladium dichloride (7.1mg , 0.01mmol) and cesium carbonate (94.8mg, 0.29mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.2mL) and water (0.1mL). The reaction was heated to 90°C and stirred for 0.5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'- (1-(1-Hydroxy-2-methylpropan-2-yl)-1H-pyrazol-3-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]- 2-Kone 6 (30 mg), yield: 59.9%.
MS m/z(ESI):516.1[M+H]+.MS m/z(ESI):516.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.60(d,1H),8.15-8.05(m,1H),7.87(d,1H),7.77(s,1H),6.81(d,1H),6.79(s,1H),5.48(d,2H),4.97(t,1H),3.65-3.59(m,2H),2.00(s,3H),1.97(s,3H),1.50(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.64(s,1H),8.60(d,1H),8.15-8.05(m,1H),7.87(d,1H),7.77(s,1H), 6.81(d,1H),6.79(s,1H),5.48(d,2H),4.97(t,1H),3.65-3.59(m,2H),2.00(s,3H),1.97(s,3H) ,1.50(s,6H).
实施例6的拆分Splitting of Embodiment 6
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-3-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(1-(1-羟基-2-甲基丙烷-2-基)-1H-吡唑-3-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(1-(1-hydroxy-2-methylpropan-2-yl) -1H-pyrazol-3-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one and (R)-3-chloro-4-((3, 5-difluoropyridin-2-yl)methoxy)-2'-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-3-yl)-5', 6-Dimethyl-2H-[1,4'-bipyridyl]-2-one
将实施例6(30mg,0.06mmol)经手性拆分(AD柱)得到标题产物6-1(13.6mg，R.T＝6.367min)，产率：42.5％；6-2(15.0mg，R.T＝8.977min)，产率：46.9％。Example 6 (30mg, 0.06mmol) was subjected to chiral resolution (AD column) to obtain the title product 6-1 (13.6mg, R.T=6.367min), yield: 42.5%; 6-2 (15.0mg, R.T=8.977 min), yield: 46.9%.
实施例6-1：MS m/z(ESI):516.1[M+H]+；Embodiment 6-1: MS m/z (ESI): 516.1[M+H] + ;
实施例6-2：MS m/z(ESI):516.1[M+H]+.Example 6-2: MS m/z (ESI): 516.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例7Example 7
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)- 5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one

第一步first step
冰浴下将氘化锂铝(388mg，9.24mmol)分批加入到甲基3,5-二氟吡啶-2-羧酸酯(1.00g，5.78mmol)的四氢呋喃(20mL)溶液中。反应在室温下搅拌2小时。将反应使用冰块淬灭，反应液过滤。滤液浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物(3,5-二氟吡啶-2-基)甲烷-d2-醇7a(345mg)，产率：40.6％。Lithium aluminum deuteride (388 mg, 9.24 mmol) was added in portions to a solution of methyl 3,5-difluoropyridine-2-carboxylate (1.00 g, 5.78 mmol) in tetrahydrofuran (20 mL) under ice-cooling. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with ice cubes, and the reaction solution was filtered. The filtrate was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product (3,5-difluoropyridin-2-yl)methane-d2-ol 7a (345 mg), yield: 40.6%.
MS m/z(ESI):148.0[M+H]+.MS m/z(ESI):148.0[M+H] + .
第二步second step
搅拌下将二氯亚砜(839mg，7.06mmol)滴加到(3,5-二氟吡啶-2-基)甲烷-d2-醇7a(346mg，2.35mmol)的二氯甲烷(5mL)和N，N-二甲基甲酰胺(0.1mL)溶液中。反应在室温下搅拌3小时。将反应液使用乙酸乙酯(160mL)稀释，有机相用饱和碳酸氢钠和水洗涤。有机相浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物2-(氯甲基-d2)-3,5-二氟吡啶7b(150mg)，产率：38.5％。Thionyl chloride (839 mg, 7.06 mmol) was added dropwise to (3,5-difluoropyridin-2-yl)methane-d2-ol 7a (346 mg, 2.35 mmol) in dichloromethane (5 mL) and N with stirring. , in N-dimethylformamide (0.1 mL) solution. The reaction was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (160 mL), and the organic phase was washed with saturated sodium bicarbonate and water. The organic phase was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2-(chloromethyl-d2)-3,5-difluoropyridine 7b (150 mg), yield: 38.5%.
MS m/z(ESI):166.0[M+H]+.MS m/z(ESI):166.0[M+H] + .
第三步third step
将3-氯-1-(2-氯-5-甲基-4-吡啶基)-4-羟基-6-甲基-吡啶-2-酮(136mg,0.82mmol)，2-(氯甲基-d2)-3,5-二氟吡啶7b(180mg,1.09mmol)，碳酸钾(174mg,1.26mmol)和18-冠-6醚(167mg,0.63mmol)溶解于N,N-二甲基甲酰胺(3mL)中。反应加热至60℃搅拌16小时。向反应液中加入水(20mL),水相用乙酸乙酯(20mL×2)萃取。有机相合并，干燥，浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮7c(210mg)，产率：80.2％。3-Chloro-1-(2-chloro-5-methyl-4-pyridyl)-4-hydroxy-6-methyl-pyridin-2-one (136mg, 0.82mmol), 2-(chloromethyl -d2)-3,5-difluoropyridine 7b (180mg, 1.09mmol), potassium carbonate (174mg, 1.26mmol) and 18-crown-6 ether (167mg, 0.63mmol) were dissolved in N,N-dimethylformaldehyde amide (3 mL). The reaction was heated to 60°C and stirred for 16 hours. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methanol Oxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 7c (210 mg), yield: 80.2%.
MS m/z(ESI):414.0[M+H]+.MS m/z(ESI):414.0[M+H] + .
第四步the fourth step
将油浴预热到100℃。氮气保护下，将2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮7c(50mg，0.12mmol)，[2-(1-羟基-1-甲基-乙基)噻唑-4-基]硼酸(45mg,0.24mmol)，碳酸铯(78mg，0.24mmol)，和 1,1-双(二苯基膦)二荗铁二氯化钯(9mg，0.012mmol)溶解到1，4-二氧六环(3mL)中。反应在100℃下搅拌3小时。反应液过滤，滤液使用反相HPLC制备分离(甲酸体系)分离得到标题产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮7(38mg)，产率：60.6％。Preheat the oil bath to 100 °C. Under nitrogen protection, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1, 4'-bipyridyl]-2-one 7c (50mg, 0.12mmol), [2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]boronic acid (45mg, 0.24mmol), cesium carbonate (78 mg, 0.24 mmol), and 1,1-Bis(diphenylphosphine)ironium dichloride palladium (9 mg, 0.012 mmol) was dissolved in 1,4-dioxane (3 mL). The reaction was stirred at 100°C for 3 hours. The reaction solution was filtered, and the filtrate was separated by reverse phase HPLC (formic acid system) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-( 2-(2-Hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 7 (38 mg), yield : 60.6%.
MS m/z(ESI):521.1[M+H]+.MS m/z(ESI):521.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.10(ddd,1H),7.86(s,1H),6.80(d,1H),6.06(s,1H),2.03(s,3H),2.00–1.90(m,3H),1.56(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.18(s,1H),8.10(ddd,1H),7.86(s,1H),6.80( d,1H),6.06(s,1H),2.03(s,3H),2.00–1.90(m,3H),1.56(d,6H).
实施例7的拆分Splitting of Example 7
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazole-4 -yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoropyridine-2 -yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'- Bipyridyl]-2-one
实施例7(36mg,0.07mmol)通过手性拆分(OD柱)得到实施例7-1(15mg，R.T＝3.640min，产率：41.7％)和实施例7-2(13mg，R.T＝4.357min，产率：36.1％)，Example 7 (36mg, 0.07mmol) was obtained by chiral resolution (OD column) Example 7-1 (15mg, R.T=3.640min, yield: 41.7%) and Example 7-2 (13mg, R.T=4.357 min, yield: 36.1%),
实施例7-1：MS m/z(ESI):521.1[M+H]+；Embodiment 7-1: MS m/z (ESI): 521.1[M+H] + ;
实施例7-2：MS m/z(ESI):521.1[M+H]+.Example 7-2: MS m/z (ESI): 521.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：

HPLC chiral analysis conditions:

实施例8Example 8
3-氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)- 5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
第一步first step
将中间体3(350mg,1.23mmol)，2-(1-氯乙基)-3,5-二氟-吡啶(218mg,1.23mmol)，碳酸钾(509mg,3.68mmol)和18-冠-6醚(324mg,1.23mmol)溶解在N,N-二甲基甲酰胺(10mL)中搅拌。反应加热至60℃搅拌16小时。向反应液中加入乙酸乙酯(30mL)，有机相用水洗涤2次，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物2',3-二氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮8b(280mg)，产率：53.5％。Intermediate 3 (350mg, 1.23mmol), 2-(1-chloroethyl)-3,5-difluoro-pyridine (218mg, 1.23mmol), potassium carbonate (509mg, 3.68mmol) and 18-crown-6 Ether (324 mg, 1.23 mmol) was dissolved in N,N-dimethylformamide (10 mL) and stirred. The reaction was heated to 60°C and stirred for 16 hours. Ethyl acetate (30 mL) was added to the reaction solution, and the organic phase was washed twice with water, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-5' , 6-Dimethyl-2H-[1,4'-bipyridine]-2-one 8b (280 mg), yield: 53.5%.
MS m/z(ESI):426.0[M+H]+.MS m/z(ESI):426.0[M+H] + .
第二步second step
氮气保护下，将2',3-二氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮8b(190mg,0.446mmol)，[2-(1-羟基-1-甲基-乙基)噻唑-4-基]硼酸(167mg,0.892mmol)，1,1'-双二苯基膦二茂铁二氯化钯(33mg,0.045mmol)和碳酸铯(290mg,0.892mmol)溶解在1，4-二氧六环(2mL)中搅拌。反应用微波加热至100℃搅拌3小时。过滤反应液，滤饼用乙酸乙酯洗涤，滤液 用饱和氯化铵洗涤，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物3-氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮8(170mg)，产率：71.6％。Under nitrogen protection, 2',3-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-5',6-dimethyl-2H-[1, 4'-bipyridyl]-2-one 8b (190mg, 0.446mmol), [2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]boronic acid (167mg, 0.892mmol), 1, 1'-Bisdiphenylphosphinoferrocenepalladium dichloride (33 mg, 0.045 mmol) and cesium carbonate (290 mg, 0.892 mmol) were dissolved in 1,4-dioxane (2 mL) and stirred. The reaction was heated to 100° C. with microwave and stirred for 3 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate Wash with saturated ammonium chloride, dry and concentrate. The residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3-chloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-2'-(2- (2-Hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 8 (170mg), yield: 71.6 %.
MS m/z(ESI):533.1[M+H]+.MS m/z(ESI):533.1[M+H] + .
实施例8的拆分Splitting of Embodiment 8
(S)-3-氯-1-[2-[2-(1-羟基-1-甲基-乙基)噻唑-4-基]-5-甲基-4-吡啶基]-6-甲基-4-[(1S)-1-(3,5-二氟-2-吡啶基)乙氧基]吡啶-2-酮，(S)-3-氯-1-[2-[2-(1-羟基-1-甲基-乙基)噻唑-4-基]-5-甲基-4-吡啶基]-6-甲基-4-[(1R)-1-(3,5-二氟-2-吡啶基)乙氧基]吡啶-2-酮，(R)-3-氯-1-[2-[2-(1-羟基-1-甲基-乙基)噻唑-4-基]-5-甲基-4-吡啶基]-6-甲基-4-[(1S)-1-(3,5-二氟-2-吡啶基)乙氧基]吡啶-2-酮和(R)-3-氯-1-[2-[2-(1-羟基-1-甲基-乙基)噻唑-4-基]-5-甲基-4-吡啶基]-6-甲基-4-[(1R)-1-(3,5-二氟-2-吡啶基)乙氧基]吡啶-2-酮
(S)-3-Chloro-1-[2-[2-(1-hydroxyl-1-methyl-ethyl)thiazol-4-yl]-5-methyl-4-pyridyl]-6-methanol Base-4-[(1S)-1-(3,5-difluoro-2-pyridyl)ethoxy]pyridin-2-one, (S)-3-chloro-1-[2-[2- (1-Hydroxy-1-methyl-ethyl)thiazol-4-yl]-5-methyl-4-pyridyl]-6-methyl-4-[(1R)-1-(3,5- Difluoro-2-pyridyl)ethoxy]pyridin-2-one, (R)-3-chloro-1-[2-[2-(1-hydroxy-1-methyl-ethyl)thiazole-4 -yl]-5-methyl-4-pyridyl]-6-methyl-4-[(1S)-1-(3,5-difluoro-2-pyridyl)ethoxy]pyridine-2- Ketone and (R)-3-chloro-1-[2-[2-(1-hydroxy-1-methyl-ethyl)thiazol-4-yl]-5-methyl-4-pyridyl]-6 -Methyl-4-[(1R)-1-(3,5-difluoro-2-pyridyl)ethoxy]pyridin-2-one
实施例8(170mg)经手性拆分(AD柱)得到标题产物8-1(27.9mg，R.T＝3.91min)，产率：16.4％；8-2(18.0mg，R.T＝5.667min)，产率：10.6％；8-3(22.5mg，R.T＝6.460min)，产率：13.2％，8-4(26.5mg，R.T＝6.767min)，产率：15.6％。Example 8 (170mg) obtained the title product 8-1 (27.9mg, R.T=3.91min) through chiral resolution (AD column), yield: 16.4%; 8-2 (18.0mg, R.T=5.667min), produced Yield: 10.6%; 8-3 (22.5mg, R.T=6.460min), yield: 13.2%, 8-4 (26.5mg, R.T=6.767min), yield: 15.6%.
实施例8-1，MS m/z(ESI):533.1[M+H]+；Embodiment 8-1, MS m/z (ESI): 533.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.59(d,1H),8.16(s,1H),8.07(dd,1H),7.83(s,1H),6.59(s,1H),6.04(s,2H),2.01(s,3H),1.92(s,3H),1.73(d,3H),1.54(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.68(s,1H),8.59(d,1H),8.16(s,1H),8.07(dd,1H),7.83(s,1H),6.59( s,1H),6.04(s,2H),2.01(s,3H),1.92(s,3H),1.73(d,3H),1.54(s,6H).
实施例8-2，MS m/z(ESI):533.1[M+H]+；Embodiment 8-2, MS m/z (ESI): 533.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.60(d,1H),8.17(s,1H),8.07(dd,1H),7.84(s,1H),6.66(s,1H),6.06(d,2H),1.98(s,3H),1.94(s,3H),1.73(d,3H),1.55(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.68(s,1H),8.60(d,1H),8.17(s,1H),8.07(dd,1H),7.84(s,1H),6.66( s,1H),6.06(d,2H),1.98(s,3H),1.94(s,3H),1.73(d,3H),1.55(d,6H).
实施例8-3，MS m/z(ESI):533.1[M+H]+； Embodiment 8-3, MS m/z (ESI): 533.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.59(d,1H),8.16(s,1H),8.07(dd,1H),7.83(s,1H),6.59(s,1H),6.05(d,2H),2.01(s,3H),1.92(s,3H),1.73(d,3H),1.54(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.68(s,1H),8.59(d,1H),8.16(s,1H),8.07(dd,1H),7.83(s,1H),6.59( s,1H),6.05(d,2H),2.01(s,3H),1.92(s,3H),1.73(d,3H),1.54(s,6H).
实施例8-4，MS m/z(ESI):533.1[M+H]+；Embodiment 8-4, MS m/z (ESI): 533.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.60(d,1H),8.17(s,1H),8.07(dd,1H),7.84(s,1H),6.66(s,1H),6.06(d,2H),1.98(s,3H),1.94(s,3H),1.73(d,3H),1.55(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.68(s,1H),8.60(d,1H),8.17(s,1H),8.07(dd,1H),7.84(s,1H),6.66( s,1H),6.06(d,2H),1.98(s,3H),1.94(s,3H),1.73(d,3H),1.55(d,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例9Example 9
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(4-(2-羟基丙烷-2-基)噻唑-2-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one

第一步first step
将9a((5g,29.04mmol)，碳酸二叔丁酯(6.97g,31.94mmol)，三乙胺(2.94g,29.04mmol)和4-二甲氨基吡啶(1.06g,8.71mmol)溶解于二氯甲烷(35mL)和四氢呋喃(35mL)混合溶剂中。反应加热至60℃搅拌20小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物2-((叔丁氧基羰基)氨基)噻唑-4-羧酸乙酯9b(6.1g)，产率：77.2％。9a ((5g, 29.04mmol), di-tert-butyl carbonate (6.97g, 31.94mmol), triethylamine (2.94g, 29.04mmol) and 4-dimethylaminopyridine (1.06g, 8.71mmol) were dissolved in di Chloromethane (35mL) and tetrahydrofuran (35mL) in a mixed solvent. The reaction was heated to 60 ° C and stirred for 20 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2-((tert-butyl Oxycarbonyl)amino)thiazole-4-carboxylic acid ethyl ester 9b (6.1 g), yield: 77.2%.
MS m/z(ESI):273.1[M+H]+.MS m/z(ESI):273.1[M+H] + .
第二步second step
将9b(3g,11.02mmol)溶解于四氢呋喃(40mL)中。0℃下，搅拌下向反应液中滴加甲基溴化镁(3M,18.4mL)。反应恢复至室温搅拌1小时。0℃下向反应液中加入饱和氯化铵(50mL)溶液，水相用乙酸乙酯(35mL×2)萃取。有机相合并，干燥，浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物(4-(2-羟基丙烷-2-基)噻唑-2-基)氨基甲酸叔丁酯9c(2.0g)，产率：70.3％。9b (3 g, 11.02 mmol) was dissolved in tetrahydrofuran (40 mL). At 0°C, methylmagnesium bromide (3M, 18.4 mL) was added dropwise to the reaction solution with stirring. The reaction was returned to room temperature and stirred for 1 hour. A saturated ammonium chloride (50 mL) solution was added to the reaction solution at 0° C., and the aqueous phase was extracted with ethyl acetate (35 mL×2). The organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product (4-(2-hydroxypropan-2-yl)thiazol-2-yl)carbamate tert-butyl ester 9c (2.0 g), Yield: 70.3%.
MS m/z(ESI):259.1[M+H]+.MS m/z(ESI):259.1[M+H] + .
第三步third step
将9c(2g,7.74mmol)溶解于二氯甲烷(10mL)中，搅拌下向反应液中滴加三氟乙酸(7.45g,65.3mmol,5mL)。反应在室温下搅拌16小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物2-(2-氨基噻唑-4-基)丙烷-2-醇9d(675mg)，产率：55.1％。9c (2g, 7.74mmol) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (7.45g, 65.3mmol, 5mL) was added dropwise to the reaction solution with stirring. The reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 2-(2-aminothiazol-4-yl)propan-2-ol 9d (675mg), yield: 55.1%.
MS m/z(ESI):159.1[M+H]+.MS m/z(ESI):159.1[M+H] + .
第四步the fourth step
将亚硝酸叔丁酯(657.0mg,6.37mmol)和溴化铜(578.1mg,2.59mmol)溶解于乙腈(35mL)中。向反应液中加入9d(630mg,3.98mmol)。反应加热至80℃搅拌6小时。向反应液中加入水(50mL)和氨水(15mL)，水相用乙酸乙酯(30mL×2)萃取。有机相合并，干燥，浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到标题产物2-(2-溴噻唑-4-基)丙烷-2-醇9e(560mg)，产率：63.3％。 Dissolve tert-butyl nitrite (657.0 mg, 6.37 mmol) and copper bromide (578.1 mg, 2.59 mmol) in acetonitrile (35 mL). 9d (630mg, 3.98mmol) was added to the reaction solution. The reaction was heated to 80°C and stirred for 6 hours. Water (50 mL) and ammonia water (15 mL) were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the title product 2-(2-bromothiazol-4-yl)propan-2-ol 9e (560mg), the yield : 63.3%.
MS m/z(ESI):222.1,224.1[M+H]+.MS m/z(ESI):222.1,224.1[M+H] + .
第五步the fifth step
氮气保护下，将9e(24.0mg,0.11mmol)，中间体4(60mg,0.09mmol)和1,1-双(二苯基膦)二茂铁二氯化钯(6.6mg,0.009mmol)溶解于1,4-二氧六环(1mL)中。反应加热至120℃，搅拌5.5小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(4-(2-羟基丙烷-2-基)噻唑-2-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮9(25mg,)，产率：53.5％。Under nitrogen protection, 9e (24.0mg, 0.11mmol), intermediate 4 (60mg, 0.09mmol) and 1,1-bis(diphenylphosphine)ferrocenepalladium dichloride (6.6mg, 0.009mmol) were dissolved in 1,4-dioxane (1 mL). The reaction was heated to 120°C and stirred for 5.5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-( 4-(2-Hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 9 (25mg,), yield Rate: 53.5%.
MS m/z(ESI):519.1[M+H]+.MS m/z(ESI):519.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.61(d,1H),8.15-8.05(m,1H),8.01(s,1H),7.54(s,1H),6.81(s,1H),5.48(d,2H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.72(s,1H),8.61(d,1H),8.15-8.05(m,1H),8.01(s,1H),7.54(s,1H), 6.81(s,1H),5.48(d,2H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H).
实施例9的拆分Splitting of Example 9
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(4-(2-羟基丙烷-2-基)噻唑-2-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(4-(2-羟基丙烷-2-基)噻唑-2-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl )-5',6-Dimethyl-2H-[1,4'-bipyridyl]-2-one and (R)-3-chloro-4-((3,5-difluoropyridin-2-yl )methoxy)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]- 2-keto
将实施例9(50mg,0.096mmol)经手性拆分(OD柱)得到标题产物9-1(19.0mg，R.T＝4.630min)，产率：38.0％；9-2(18.2mg,，R.T＝6.027min)，产率：36.4％。Example 9 (50mg, 0.096mmol) was subjected to chiral resolution (OD column) to obtain the title product 9-1 (19.0mg, R.T=4.630min), yield: 38.0%; 9-2 (18.2mg, R.T= 6.027 min), yield: 36.4%.
实施例9-1：MS m/z(ESI):519.1[M+H]+；Embodiment 9-1: MS m/z (ESI): 519.1[M+H] + ;
实施例9-2：MS m/z(ESI):519.1[M+H]+.Example 9-2: MS m/z (ESI): 519.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例10Example 10
3-氯-6-环丙基-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5'-甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazole-4 -yl)-5'-methyl-2H-[1,4'-bipyridine]-2-one
第一步first step
将中间体6(110mg,0.27mmol)，N-氯代丁二酰亚胺(40.0mg,0.3mmol)溶解于异丙醇(2mL)中。反应加热至60℃搅拌16小时。向反应液中加入水(10mL)，搅拌30分钟，过滤得到产物2',3-二氯-6-环丙基-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-2H-[1,4'-联吡啶]-2-酮10a(104mg)，产率：87.1％。Intermediate 6 (110 mg, 0.27 mmol), N-chlorosuccinimide (40.0 mg, 0.3 mmol) was dissolved in isopropanol (2 mL). The reaction was heated to 60°C and stirred for 16 hours. Add water (10mL) to the reaction solution, stir for 30 minutes, and filter to obtain the product 2',3-dichloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy )-5'-methyl-2H-[1,4'-bipyridine]-2-one 10a (104 mg), yield: 87.1%.
MS m/z(ESI):438.1[M+H]+.MS m/z(ESI):438.1[M+H] + .
第二步second step
氮气保护下，将10a(80mg,0.18mmol)，中间体5(73.5mg,0.26mol，纯度：65％)，1,1-双(二苯基膦)二茂铁二氯化钯(13.4mg,0.02mol)和碳酸铯(119.0mg,0.37mmol)溶解于1,4-二氧六环(1.5mL)和水(0.5mL)混合溶剂中。反应加热至100℃搅拌2.5小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离 得到产物3-氯-6-环丙基-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5'-甲基-2H-[1,4'-联吡啶]-2-酮10(54mg)，产率：54.3％。Under nitrogen protection, 10a (80mg, 0.18mmol), intermediate 5 (73.5mg, 0.26mol, purity: 65%), 1,1-bis(diphenylphosphine)ferrocenepalladium dichloride (13.4mg , 0.02mol) and cesium carbonate (119.0mg, 0.37mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5mL) and water (0.5mL). The reaction was heated to 100°C and stirred for 2.5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) The product 3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl)thiazole was obtained -4-yl)-5'-methyl-2H-[1,4'-bipyridyl]-2-one 10 (54 mg), yield: 54.3%.
MS m/z(ESI):545.1[M+H]+.MS m/z(ESI):545.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.61(d,1H),8.16(s,1H),8.14-8.05(m,1H),7.90(s,1H),6.39(s,1H),6.05(s,1H),5.52(d,2H),2.06(s,3H),1.55(d,6H),1.37-1.21(m,1H),0.98-0.91(m,1H),0.89-0.81(m,1H),0.76-0.68(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ8.69(s,1H),8.61(d,1H),8.16(s,1H),8.14-8.05(m,1H),7.90(s,1H), 6.39(s,1H),6.05(s,1H),5.52(d,2H),2.06(s,3H),1.55(d,6H),1.37-1.21(m,1H),0.98-0.91(m, 1H),0.89-0.81(m,1H),0.76-0.68(m,2H).
实施例10的拆分Splitting of Example 10
(S)-3-氯-6-环丙基-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5'-甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-6-环丙基-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5'-甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropan-2-yl) )thiazol-4-yl)-5'-methyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-6-cyclopropyl-4-((3, 5-difluoropyridin-2-yl)methoxy)-2'-(2-(2-hydroxypropane-2-yl)thiazol-4-yl)-5'-methyl-2H-[1,4 '-bipyridyl]-2-one
将实施例10(54mg,0.099mmol)经手性拆分(OJ柱)得到标题产物10-1(24.0mg，R.T＝3.360min)，产率：44.4％；10-2(24.8mg，R.T＝3.907min)，产率：45.9％。Example 10 (54mg, 0.099mmol) was subjected to chiral resolution (OJ column) to obtain the title product 10-1 (24.0mg, R.T=3.360min), yield: 44.4%; 10-2 (24.8mg, R.T=3.907 min), yield: 45.9%.
实施例10-1：MS m/z(ESI):545.1[M+H]+；Embodiment 10-1: MS m/z (ESI): 545.1[M+H] + ;
实施例10-2：MS m/z(ESI):545.1[M+H]+.Example 10-2: MS m/z (ESI): 545.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：

HPLC chiral analysis conditions:

实施例11Example 11
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl )-5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
第一步first step
将1H-吡唑-3-甲酸甲酯(2g,15.9mmol)溶解在四氢呋喃(50mL)中冷却至0℃。搅拌下向反应液滴加甲基氯化镁(1M,47.58mL)。滴加完成后，反应升温至室温，继续搅拌2小时。向反应液加入乙酸乙酯(100mL)，有机相用水和饱和氯化铵洗涤，干燥，浓缩，得到产物2-(1H-吡唑-3-基)丙烷-2-醇11b(840mg)，产率：42％。1H-Pyrazole-3-carboxylic acid methyl ester (2 g, 15.9 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0°C. Methylmagnesium chloride (1M, 47.58 mL) was added dropwise to the reaction solution with stirring. After the addition was complete, the reaction was warmed to room temperature and stirring was continued for 2 hours. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with water and saturated ammonium chloride, dried, and concentrated to obtain the product 2-(1H-pyrazol-3-yl)propan-2-ol 11b (840 mg). Rate: 42%.
MS m/z(ESI):127.1[M+H]+.MS m/z(ESI):127.1[M+H] + .
1H NMR(400MHz,CDCl3)δ7.51(d,1H),6.64(s,2H),6.18(d,1H),1.62(s,6H). 1 H NMR (400MHz, CDCl 3 )δ7.51(d,1H),6.64(s,2H),6.18(d,1H),1.62(s,6H).
第二步second step
将2-溴-5-甲基-吡啶-4-胺11c(2.03g,10.86mmol)和2,2-二甲基-6-(2-羰基丙基)-4H-1,3-二噁英-4-酮(2g,10.86mmol)溶解于1，4-二氧六环(80mL)中搅拌。将反应置于预加热至90℃的反应器中搅拌3小时。向反应液中加入浓硫酸(1.8g,18.35mmol)，继续搅拌1小时。反应液冷却，移除上清液，向残余油状物加入水。混合物在室温下搅拌30分钟，过滤得到2'-溴-4-羟基-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮11d(1.7g)，产率：53％。2-Bromo-5-methyl-pyridin-4-amine 11c (2.03g, 10.86mmol) and 2,2-dimethyl-6-(2-carbonylpropyl)-4H-1,3-diox In-4-one (2 g, 10.86 mmol) was dissolved in 1,4-dioxane (80 mL) and stirred. The reaction was stirred for 3 hours in a reactor preheated to 90°C. Concentrated sulfuric acid (1.8 g, 18.35 mmol) was added to the reaction solution, and stirring was continued for 1 hour. The reaction solution was cooled, the supernatant was removed, and water was added to the residual oil. The mixture was stirred at room temperature for 30 minutes and filtered to give 2'-bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 11d (1.7 g), yielding Rate: 53%.
MS m/z(ESI):296.1[M+H]+. MS m/z(ESI):296.1[M+H] + .
第三步third step
将2'-溴-4-羟基-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮11d(1.7g,5.76mmol)溶解于异丙醇(40mL)和1，2-二氯乙烷(60mL)中加热至60℃搅拌。向反应液分批加入N-氯代丁二酰胺(923mg,6.91mmol)，继续搅拌2小时。反应液浓缩，向残余物加入异丙醇(20mL)，混合物加热至60℃搅拌0.5小时。反应液冷却，过滤得到1-(2-溴-5-甲基-4-吡啶基)-3-氯-4-羟基-6-甲基-吡啶-2-酮11e(1.71g)，产率：90.1％。2'-Bromo-4-hydroxy-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 11d (1.7 g, 5.76 mmol) was dissolved in isopropanol (40 mL) and 1,2-dichloroethane (60 mL) were heated to 60°C and stirred. N-chlorosuccinamide (923 mg, 6.91 mmol) was added in portions to the reaction solution, and stirring was continued for 2 hours. The reaction solution was concentrated, isopropanol (20 mL) was added to the residue, and the mixture was heated to 60° C. and stirred for 0.5 hours. The reaction solution was cooled and filtered to obtain 1-(2-bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxyl-6-methyl-pyridin-2-one 11e (1.71g), the yield : 90.1%.
MS m/z(ESI):330.9[M+H]+.MS m/z(ESI):330.9[M+H] + .
第四步the fourth step
将1-(2-溴-5-甲基-4-吡啶基)-3-氯-4-羟基-6-甲基-吡啶-2-酮11e(150mg,0.455mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(139mg,0.910mmol)溶解在N,N-二甲基甲酰胺(5mL)中搅拌。向反应液滴加2-(氯甲基)-3,5-二氟-吡啶(89mg,0.546mmol)，并加热至80℃搅拌2小时。向反应液中加入乙酸乙酯(20mL)，有机相用水，饱和氯化铵和饱和氯化钠洗涤，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系A)分离，得到2'-溴-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮11f(140mg)，产率：67.4％。1-(2-Bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one 11e (150mg, 0.455mmol) and 1,8-di Azabicyclo[5.4.0]undec-7-ene (139 mg, 0.910 mmol) was dissolved in N,N-dimethylformamide (5 mL) and stirred. 2-(Chloromethyl)-3,5-difluoro-pyridine (89 mg, 0.546 mmol) was added dropwise to the reaction solution, heated to 80°C and stirred for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution, and the organic phase was washed with water, saturated ammonium chloride and saturated sodium chloride, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5', 6-Dimethyl-2H-[1,4'-bipyridyl]-2-one 11f (140 mg), yield: 67.4%.
MS m/z(ESI):458.0[M+H]+.MS m/z(ESI):458.0[M+H] + .
第五步the fifth step
氮气保护下，将11b(55mg,0.438mmol)，2'-溴-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮11f(100mg,0.219mmol)，碘化亚铜(8mg,0.044mmol)，N,N'-二甲基-1,2-环己二胺(13mg,0.088mmol)和碳酸铯(143mg,0.438mmol)溶解在N,N-二甲基甲酰胺(5mL)中加热至100℃搅拌16小时。过滤反应液，滤液用反相柱分离，所得产品经反相HPLC制备分离(甲酸体系)得到标题产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮11(40mg)，产率：36％。Under nitrogen protection, 11b (55mg, 0.438mmol), 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl Base-2H-[1,4'-bipyridyl]-2-one 11f (100mg, 0.219mmol), cuprous iodide (8mg, 0.044mmol), N,N'-dimethyl-1,2-cyclo Hexamethylenediamine (13mg, 0.088mmol) and cesium carbonate (143mg, 0.438mmol) were dissolved in N,N-dimethylformamide (5mL) and heated to 100°C and stirred for 16 hours. The reaction solution was filtered, and the filtrate was separated by a reverse-phase column, and the resulting product was prepared and separated by reverse-phase HPLC (formic acid system) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy) -2'-(3-(2-Hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2 - Ketone 11 (40 mg), Yield: 36%.
MS m/z(ESI):501.8[M+H]+.MS m/z(ESI):501.8[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.54(s,1H),8.51(d,1H),8.10(t,1H),7.78(s,1H),6.80(s,1H),6.56(d,1H),5.48(s,2H),5.08(s,1H),2.00(d,6H),1.47(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.54(s,1H),8.51(d,1H),8.10(t,1H),7.78(s,1H),6.80( s,1H),6.56(d,1H),5.48(s,2H),5.08(s,1H),2.00(d,6H),1.47(s,6H).
实施例11的拆分Splitting of Example 11
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6'-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6'-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole -1-yl)-5',6'-dimethyl-2H-[1,4'-dipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoro Pyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl-2H- [1,4'-bipyridyl]-2-one
实施例11(9mg,0.018mmol)经手性拆分(AS柱)得到标题产物11-1(4.1mg，R.T＝3.287min)，产率：45.56％；11-2(4.3mg，R.T＝4.807min)，产率：47.78％。Example 11 (9mg, 0.018mmol) obtained the title product 11-1 (4.1mg, R.T=3.287min) through chiral resolution (AS column), yield: 45.56%; 11-2 (4.3mg, R.T=4.807min ), yield: 47.78%.
实施例11-1，MS m/z(ESI):501.8[M+H]+；Embodiment 11-1, MS m/z (ESI): 501.8[M+H] + ;
实施例11-2，MS m/z(ESI):501.8[M+H]+。Example 11-2, MS m/z (ESI): 501.8[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例12Example 12
2-(3-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-1-基)-2-甲基丙酰胺
2-(3-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4 '-bipyridyl]-2'-yl)-1H-pyrazol-1-yl)-2-methylpropionamide
第一步first step
将2-(3-溴-1H-吡唑-1-基)-2-甲基丙酸6b(1.6g,6.13mmol)溶解在乙醇(30mL)中。搅拌下向反应液滴加氢氧化钠水溶液(1M,6.13mL)。反应在25℃下搅拌3小时。反应液浓缩，向残余物加入水(10mL)和甲基叔丁基醚(10mL)。水相分离后，用盐酸(1M)调节pH至2。水相用乙酸乙酯(10mL×3)萃取，有机相合并，干燥，浓缩得到产物2-(3-溴-1H-吡唑-1-基)-2-甲基丙酸12a(1.4g，产率：98％。2-(3-Bromo-1H-pyrazol-1-yl)-2-methylpropanoic acid 6b (1.6 g, 6.13 mmol) was dissolved in ethanol (30 mL). Aqueous sodium hydroxide solution (1M, 6.13 mL) was added dropwise to the reaction solution with stirring. The reaction was stirred at 25°C for 3 hours. The reaction solution was concentrated, and water (10 mL) and methyl tert-butyl ether (10 mL) were added to the residue. After separation of the aqueous phase, the pH was adjusted to 2 with hydrochloric acid (1M). The aqueous phase was extracted with ethyl acetate (10 mL×3), and the organic phases were combined, dried, and concentrated to obtain the product 2-(3-bromo-1H-pyrazol-1-yl)-2-methylpropionic acid 12a (1.4 g, Yield: 98%.
MS m/z(ESI):233.0,235.0[M+H]+.MS m/z(ESI):233.0,235.0[M+H] + .
第二步second step
将2-(3-溴-1H-吡唑-1-基)-2-甲基丙酸12a(0.5g,2.15mmol)溶解在二氯甲烷(10mL)中。搅拌下向反应液滴加草酰氯(0.363mL,4.29mmol)。反应在25℃下搅拌2小时。反应液浓缩，向残余物加入四氢呋喃(5mL)溶解。搅拌下将所得溶液滴加到氨的甲醇溶液(7M,1.23mL)中。反应在25℃下搅拌2小时。浓缩反应液，残余物用乙酸乙酯(20mL)溶解，有机相用饱和氯化铵(10mL)洗涤，干燥，浓缩，得到产品2-(3-溴-1H-吡唑-1-基)-2-甲基丙酰胺12b(382mg)，产率：76.7％。2-(3-Bromo-1H-pyrazol-1-yl)-2-methylpropanoic acid 12a (0.5 g, 2.15 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (0.363 mL, 4.29 mmol) was added dropwise to the reaction with stirring. The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated, and tetrahydrofuran (5 mL) was added to the residue for dissolution. The resulting solution was added dropwise to ammonia in methanol (7M, 1.23 mL) with stirring. The reaction was stirred at 25°C for 2 hours. The reaction solution was concentrated, the residue was dissolved in ethyl acetate (20 mL), the organic phase was washed with saturated ammonium chloride (10 mL), dried, and concentrated to obtain the product 2-(3-bromo-1H-pyrazol-1-yl)- 2-Methylpropanamide 12b (382 mg), yield: 76.7%.
MS m/z(ESI):232.0,234.0[M+H]+.MS m/z(ESI):232.0,234.0[M+H] + .
第三步third step
氮气保护下，将中间体4(100mg,0.150mmol)，12b(70mg,0.3mmol)和二(三苯基膦)二氯化钯(11mg,0.015mmol)溶解在1，4-二氧六环(3mL)中。反应用微波加热至130℃搅拌2小时。过滤反应液，滤液浓缩。残余物用硅 胶柱色谱法(洗脱剂体系A)分离，得到产物2-(3-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-1-基)-2-甲基丙酰胺12(26mg)，产率：32.8％。Under nitrogen protection, intermediate 4 (100mg, 0.150mmol), 12b (70mg, 0.3mmol) and bis(triphenylphosphine)palladium dichloride (11mg, 0.015mmol) were dissolved in 1,4-dioxane (3 mL). The reaction was heated to 130° C. with microwave and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated. Silica for the residue Gel column chromatography (eluent system A) separation, the product 2-(3-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6 -Dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-1H-pyrazol-1-yl)-2-methylpropanamide 12 (26 mg), yield : 32.8%.
MS m/z(ESI):529.1[M+H]+.MS m/z(ESI):529.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.60(d,1H),8.15–8.02(m,1H),7.93(d,1H),7.78(s,1H),7.19(s,1H),6.94(s,1H),6.87(d,1H),6.79(s,1H),5.47(s,2H),2.01(s,3H),1.97(s,3H),1.75(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.66(s,1H),8.60(d,1H),8.15–8.02(m,1H),7.93(d,1H),7.78(s,1H), 7.19(s,1H),6.94(s,1H),6.87(d,1H),6.79(s,1H),5.47(s,2H),2.01(s,3H),1.97(s,3H),1.75 (s,6H).
实施例12的拆分Splitting of Example 12
(S)-2-(3-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-1-基)-2-甲基丙酰胺和(R)-2-(3-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-1-基)-2-甲基丙酰胺
(S)-2-(3-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H- [1,4'-bipyridyl]-2'-yl)-1H-pyrazol-1-yl)-2-methylpropanamide and (R)-2-(3-(3-chloro-4-( (3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H -pyrazol-1-yl)-2-methylpropanamide
实施例12(26mg)经手性拆分(AS柱)得到标题产物12-1(6.8mg，R.T＝4.98min)，产率：26.15％；12-2(6.8mg，R.T＝8.113min)，产率：26.15％。Example 12 (26mg) obtained the title product 12-1 (6.8mg, R.T=4.98min) through chiral resolution (AS column), yield: 26.15%; 12-2 (6.8mg, R.T=8.113min), produced Rate: 26.15%.
实施例12-1，MS m/z(ESI):529.1[M+H]+；Embodiment 12-1, MS m/z (ESI): 529.1[M+H] + ;
实施例12-2，MS m/z(ESI):529.1[M+H]+。Example 12-2, MS m/z (ESI): 529.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

HPLC chiral analysis method:

实施例13Example 13
2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2)'-基)噻唑-2-基)-2-甲基丙腈
2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1, 4'-bipyridyl]-2)'-yl)thiazol-2-yl)-2-methylpropionitrile
第一步first step
将2-氰基-2-甲基-丙酸甲酯13a(2g,15.73mmol)溶于氨水(7M,20mL)，30℃搅拌16小时。将反应液减压浓缩后即得化合物2-氰基-2-甲基丙酰胺13b(1.76g)，产率：100％。2-Cyano-2-methyl-propionic acid methyl ester 13a (2 g, 15.73 mmol) was dissolved in ammonia water (7 M, 20 mL), and stirred at 30°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain compound 2-cyano-2-methylpropionamide 13b (1.76 g), yield: 100%.
1H NMR(400MHz,DMSO-d6)δ7.64(s,1H),7.42(d,1H),1.49(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ7.64(s,1H),7.42(d,1H),1.49(s,6H).
第二步second step
氮气保护下，将2-氰基-2-甲基丙酰胺13b(0.1g,0.892mmol)和劳森试剂(198mg,0.490mmol)溶于四氢呋喃(5mL)。反应回流搅拌3小时。反应液用乙酸乙酯(25mL)稀释，饱和食盐水洗涤，干燥，浓缩后用制备型硅胶色谱板纯化(洗脱体系B)得产物2-氰基-2-甲基丙硫酰胺13c(0.097g)，产率：85％。Under nitrogen protection, 2-cyano-2-methylpropanamide 13b (0.1 g, 0.892 mmol) and Lawson's reagent (198 mg, 0.490 mmol) were dissolved in tetrahydrofuran (5 mL). The reaction was stirred at reflux for 3 hours. The reaction solution was diluted with ethyl acetate (25 mL), washed with saturated brine, dried, concentrated and purified by preparative silica gel chromatography (elution system B) to obtain the product 2-cyano-2-methylpropanesulfamide 13c (0.097 g), yield: 85%.
MS m/z(ESI):129.0[M+H]+.MS m/z(ESI):129.0[M+H] + .
第三步 third step
将2-氰基-2-甲基丙硫酰胺13c(0.5g,3.90mmol)，溴代乙醛缩二乙醇(845mg,4.29mmol)和对甲苯磺酸(67mg,0.39mmol)溶于乙醇(6mL)和水(0.6mL)，于封管中加热至100℃搅拌20小时。反应液浓缩后得黑色残留物用硅胶柱层析(洗脱体系B)得化合物2-甲基-2-(噻唑-2-基)丙腈13d(94mg)，产率：16％。2-cyano-2-methylpropansulfamide 13c (0.5g, 3.90mmol), bromoacetaldehyde diethyl acetal (845mg, 4.29mmol) and p-toluenesulfonic acid (67mg, 0.39mmol) were dissolved in ethanol ( 6 mL) and water (0.6 mL), heated to 100°C in a sealed tube and stirred for 20 hours. After the reaction solution was concentrated, a black residue was obtained. Silica gel column chromatography (elution system B) gave compound 2-methyl-2-(thiazol-2-yl)propionitrile 13d (94 mg), yield: 16%.
MS m/z(ESI):153.1[M+H]+.MS m/z(ESI):153.1[M+H] + .
1H NMR(400MHz,CDCl3)δ7.78(d,1H),7.35(d,1H),1.88(s,6H). 1 H NMR (400MHz, CDCl 3 )δ7.78(d,1H),7.35(d,1H),1.88(s,6H).
第四步the fourth step
将2-甲基-2-(噻唑-2-基)丙腈13d(0.45g,2.96mmol)溶于N,N-二甲基甲酰胺(5mL)。搅拌下加入N-溴代丁二酰亚胺(1.16g,6.50mmol)，反应在30℃下搅拌20小时。反应液用乙酸乙酯(35mL)稀释，饱和食盐水洗，干燥，浓缩后用硅胶柱层析(洗脱体系B)得产物2-(5-溴噻唑-2-基)-2-甲基丙腈13e(312mg)，产率：46％。2-Methyl-2-(thiazol-2-yl)propionitrile 13d (0.45 g, 2.96 mmol) was dissolved in N,N-dimethylformamide (5 mL). N-bromosuccinimide (1.16 g, 6.50 mmol) was added with stirring and the reaction was stirred at 30°C for 20 hours. The reaction solution was diluted with ethyl acetate (35 mL), washed with saturated brine, dried, concentrated and then subjected to silica gel column chromatography (elution system B) to obtain the product 2-(5-bromothiazol-2-yl)-2-methylpropane Nitrile 13e (312 mg), Yield: 46%.
MS m/z(ESI):230.8,232.8[M+H]+.MS m/z(ESI):230.8,232.8[M+H] + .
1H NMR(400MHz,CDCl3)δ7.65(s,1H),1.83(s,6H). 1 H NMR (400MHz, CDCl 3 )δ7.65(s,1H),1.83(s,6H).
第五步the fifth step
将2-(5-溴噻唑-2-基)-2-甲基丙腈13d(0.312g,1.35mmol)溶于无水四氢呋喃(6mL)，氮气置换保护，干冰浴冷却至-78℃，通过针筒缓慢加入二异丙基氨基锂(2M,1.35mL)，加毕，保持-78℃搅拌反应3小时。反应液用饱和氯化铵溶液淬灭，搅拌5分钟后用乙酸乙酯稀释(40mL)，饱和食盐水洗，干燥，浓缩残留物用硅胶柱层析(洗脱体系B)得产物2-(4-溴噻唑-2-基)-2-甲基丙腈13f(0.147g)，产率47％。2-(5-Bromothiazol-2-yl)-2-methylpropionitrile 13d (0.312g, 1.35mmol) was dissolved in anhydrous tetrahydrofuran (6mL), protected by nitrogen replacement, cooled to -78°C in a dry ice bath, passed Slowly add lithium diisopropylamide (2M, 1.35mL) into the syringe, after the addition is complete, keep stirring at -78°C for 3 hours. The reaction solution was quenched with saturated ammonium chloride solution, stirred for 5 minutes, diluted with ethyl acetate (40mL), washed with saturated brine, dried, and the concentrated residue was subjected to silica gel column chromatography (elution system B) to obtain the product 2-(4 -Bromothiazol-2-yl)-2-methylpropionitrile 13f (0.147 g), 47% yield.
MS m/z(ESI):230.8,232.8[M+H]+.MS m/z(ESI):230.8,232.8[M+H] + .
1H NMR(400MHz,CDCl3)δ7.24(s,1H),1.86(s,6H). 1 H NMR (400MHz, CDCl 3 )δ7.24(s,1H),1.86(s,6H).
第六步step six
氮气保护下，将3-氯-4-[(3,5-二氟-2-吡啶基)甲氧基]-6-甲基-1-(5-甲基-2-三丁基甲锡烷基-4-吡啶基)吡啶-2-酮中间体4(80mg,0.120mmol)，2-(4-溴噻唑-2-基)-2-甲基丙腈13f(33mg,0.144mmol)和双三苯基膦二氯化钯(17mg,0.024mmol)溶于二氧六环(1.5mL)。反应用微波加热至130℃搅拌2小时。反应液用乙酸乙酯(25mL)稀释，经硅藻土过滤，浓缩，残留物用制备型硅胶色谱板纯化(洗脱体系A)后得标题产物2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2)'-基)噻唑-2-基)-2-甲基丙腈13(30mg)，产率：47％。Under nitrogen protection, 3-chloro-4-[(3,5-difluoro-2-pyridyl)methoxy]-6-methyl-1-(5-methyl-2-tributylstannyl -4-pyridyl)pyridin-2-one intermediate 4 (80mg, 0.120mmol), 2-(4-bromothiazol-2-yl)-2-methylpropionitrile 13f (33mg, 0.144mmol) and bistri Phenylphosphinepalladium dichloride (17mg, 0.024mmol) was dissolved in dioxane (1.5mL). The reaction was heated to 130° C. with microwave and stirred for 2 hours. The reaction solution was diluted with ethyl acetate (25 mL), filtered through celite, concentrated, and the residue was purified by preparative silica gel chromatography (elution system A) to obtain the title product 2-(4-(3-chloro-4- ((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridine]-2)'-yl )thiazol-2-yl)-2-methylpropionitrile 13 (30 mg), yield: 47%.
MS m/z(ESI):528.0[M+H]+.MS m/z(ESI):528.0[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.60(s,1H),8.39(s,1H),8.10(t,1H),7.92(s,1H),6.81(s,1H),5.48(s,2H),2.04(s,3H),1.98(s,3H),1.87(s,6H). 1 H NMR (400MHz, DMSO-d 6 )δ8.74(s,1H),8.60(s,1H),8.39(s,1H),8.10(t,1H),7.92(s,1H),6.81( s,1H),5.48(s,2H),2.04(s,3H),1.98(s,3H),1.87(s,6H).
实施例13的拆分 Splitting of Example 13
(S)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2)'-基)噻唑-2-基)-2-甲基丙腈和(R)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2)'-基)噻唑-2-基)-2-甲基丙腈
(S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H -[1,4'-bipyridine]-2)'-yl)thiazol-2-yl)-2-methylpropionitrile and (R)-2-(4-(3-chloro-4-((3 ,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridine]-2)'-yl)thiazole- 2-yl)-2-methylpropionitrile
实施例13(30mg，0.057mmol)经手性拆分(OD柱)得到标题产物13-1(7mg，R.T＝4.223min)，产率：23％；13-2(7mg，R.T＝5.453min)，产率：23％。Example 13 (30mg, 0.057mmol) was subjected to chiral resolution (OD column) to obtain the title product 13-1 (7mg, R.T=4.223min), yield: 23%; 13-2 (7mg, R.T=5.453min), Yield: 23%.
实施例13-1，MS m/z(ESI):527.8[M+H]+.Example 13-1, MS m/z (ESI): 527.8[M+H] + .
实施例13-2，MS m/z(ESI):527.8[M+H]+.Example 13-2, MS m/z (ESI): 527.8[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例14Example 14
2-(((3-氯-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-4-基)氧代)甲基)-3,5-二氟苯甲腈
2-(((3-chloro-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2-carbonyl-2H-[1, 4'-bipyridyl]-4-yl)oxo)methyl)-3,5-difluorobenzonitrile
第一步first step
室温下将2-氨基-4,6-二氟苯甲酸14a(5g，28.9mmol)和碳酸钾(5.98g，43.3mmol)溶于N,N-二甲基甲酰胺(50mL)中。搅拌下向反应液缓慢滴加碘甲烷(4.92g，34.7mmol)。反应液于25℃下搅拌2小时。向反应液中加入水(180mL)，继续搅拌1小时。反应液过滤得到标题产物2-氨基-4,6-二氟苯甲酸甲酯14b(3.9g)，产品不经纯化直接用于下一步反应。2-Amino-4,6-difluorobenzoic acid 14a (5 g, 28.9 mmol) and potassium carbonate (5.98 g, 43.3 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature. Methane iodide (4.92 g, 34.7 mmol) was slowly added dropwise to the reaction solution with stirring. The reaction solution was stirred at 25°C for 2 hours. Water (180 mL) was added to the reaction solution, and stirring was continued for 1 hour. The reaction solution was filtered to obtain the title product 2-amino-4,6-difluorobenzoic acid methyl ester 14b (3.9 g), which was directly used in the next reaction without purification.
MS m/z(ESI):188.0[M+H]+.MS m/z(ESI):188.0[M+H] + .
第二步second step
将2-氨基-4,6-二氟苯甲酸甲酯14b(1g，5.34mmol)溶于20％的硫酸溶液(30mL)中，冷却至0℃。依次滴加亚硝酸钠(442mg，6.41mmol)水溶液(4mL)和碘化钾(1.78g，10.7mmol)水溶液(4mL)。反应液于25℃下搅拌4小时。向反应液加入饱和亚硫酸钠(20mL)，水相用乙酸乙酯(30mL×3)萃取。有机相合并，干燥，浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到产物2,4-二氟-6-碘苯甲酸甲酯14c(1.1g)，产率：70％。Methyl 2-amino-4,6-difluorobenzoate 14b (1 g, 5.34 mmol) was dissolved in 20% sulfuric acid solution (30 mL), cooled to 0°C. Sodium nitrite (442 mg, 6.41 mmol) aqueous solution (4 mL) and potassium iodide (1.78 g, 10.7 mmol) aqueous solution (4 mL) were added dropwise in sequence. The reaction solution was stirred at 25°C for 4 hours. Saturated sodium sulfite (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried and concentrated to give the crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 2,4-difluoro-6-iodobenzoic acid methyl ester 14c (1.1 g), yield: 70%.
MS m/z(ESI):298.9[M+H]+.MS m/z(ESI):298.9[M+H] + .
第三步third step
将2,4-二氟-6-碘苯甲酸甲酯14c(2g,6.71mmol)和氰化亚铜(1.26g，13.4mmol)溶于N,N-二甲基甲酰胺(10mL)中，反应用微波加热至120℃下搅拌1小时。向反应液加入乙酸乙酯(10mL)，过滤，加入水(30mL)，滤液用乙酸 乙酯(10mL×3)萃取。有机相合并，干燥，浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到产物2-氰基-4,6-二氟苯甲酸甲酯14d(740mg)，产率：56％。Methyl 2,4-difluoro-6-iodobenzoate 14c (2 g, 6.71 mmol) and cuprous cyanide (1.26 g, 13.4 mmol) were dissolved in N,N-dimethylformamide (10 mL), The reaction was heated to 120° C. with microwave and stirred for 1 hour. Ethyl acetate (10mL) was added to the reaction solution, filtered, water (30mL) was added, and the filtrate was washed with acetic acid Ethyl ester (10 mL×3) was extracted. The organic phases were combined, dried and concentrated to give the crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 2-cyano-4,6-difluorobenzoic acid methyl ester 14d (740 mg), yield: 56%.
MS m/z(ESI):198.0[M+H]+.MS m/z(ESI):198.0[M+H] + .
第四步the fourth step
将2-氰基-4,6-二氟苯甲酸甲酯14d(700mg，3.55mmol)和无水氯化钙(394mg，3.55mmol)溶于乙醇(10mL)和四氢呋喃(10mL)中，搅拌下分批加入硼氢化钠(296mg，7.81mmol)。反应液于25℃下搅拌16小时。反应液浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到标题产物3,5-二氟-2-(羟甲基)苯甲腈14e(340mg，无色液体)，产率：57％。Methyl 2-cyano-4,6-difluorobenzoate 14d (700 mg, 3.55 mmol) and anhydrous calcium chloride (394 mg, 3.55 mmol) were dissolved in ethanol (10 mL) and tetrahydrofuran (10 mL), and stirred Sodium borohydride (296 mg, 7.81 mmol) was added portionwise. The reaction solution was stirred at 25°C for 16 hours. The reaction solution was concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the title product 3,5-difluoro-2-(hydroxymethyl)benzonitrile 14e (340 mg, colorless liquid), yield: 57%.
MS m/z(ESI):170.0[M+H]+.MS m/z(ESI):170.0[M+H] + .
第五步the fifth step
将中间体3(200mg，0.701mmol)溶于无水二氯甲烷中(2mL)中，加入三乙胺(142mg，1.40mmol)搅拌均匀。反应液于0℃下加入三氟甲磺酸酐(297mg，1.05mmol)，并于25℃下继续搅拌2小时。反应液浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到产物2',3-二氯-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-4-基三氟甲磺酸14f(150mg)，产率：51％。Intermediate 3 (200mg, 0.701mmol) was dissolved in anhydrous dichloromethane (2mL), triethylamine (142mg, 1.40mmol) was added and stirred evenly. Trifluoromethanesulfonic anhydride (297mg, 1.05mmol) was added to the reaction solution at 0°C, and stirring was continued at 25°C for 2 hours. The reaction solution was concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to obtain the product 2',3-dichloro-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]- 4-yltrifluoromethanesulfonic acid 14f (150 mg), yield: 51%.
MS m/z(ESI):416.9[M+H]+.MS m/z(ESI):416.9[M+H] + .
第六步step six
将2',3-二氯-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-4-基三氟甲磺酸14f(120mg，0.288mmol)、3,5-二氟-2-(羟甲基)苯甲腈14e(73mg，0.431mmol)和碳酸铯(187mg，0.575mmol)溶于N,N-二甲基甲酰胺(2mL)中。反应液加热至70℃搅拌4小时。向反应液中加入饱和氯化钠(50mL)，水相用乙酸乙酯(50mL×3)萃取，有机相合并，干燥，浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到产物2-(((2',3-二氯-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-4-基)氧代)甲基)-3,5-二氟苯甲腈14g(74mg)，产率：58％。2',3-dichloro-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yltrifluoromethanesulfonic acid 14f (120mg, 0.288mmol), 3,5-Difluoro-2-(hydroxymethyl)benzonitrile 14e (73 mg, 0.431 mmol) and cesium carbonate (187 mg, 0.575 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction solution was heated to 70°C and stirred for 4 hours. Saturated sodium chloride (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the product 2-(((2',3-dichloro-5',6-dimethyl-2-carbonyl-2H-[1,4' -bipyridyl]-4-yl)oxo)methyl)-3,5-difluorobenzonitrile 14 g (74 mg), yield: 58%.
MS m/z(ESI):436.0[M+H]+.MS m/z(ESI):436.0[M+H] + .
第七步step seven
将2-(((2',3-二氯-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-4-基)氧代)甲基)-3,5-二氟苯甲腈14g(65mg，0.149mmol)，中间体5(70mg，0.373mmol)，1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(12mg，0.015mmol)和碳酸铯(97mg，0.298mmol)溶于1，4-二氧六环/水(v:v＝5:1,1mL)中，氮气保护下将反应加热至100℃搅拌3小时。向反应液加入饱和氯化钠(10mL)，水相用乙酸乙酯(10mL×3)萃取。有机相合并，干燥，浓缩得粗品。粗品用硅胶柱色谱法(洗脱剂体系B)分离，得到标题产物2-(((3-氯-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6- 二甲基-2-羰基-2H-[1,4'-联吡啶]-4-基)氧代)甲基)-3,5-二氟苯甲腈14(40mg)，产率：49％。2-(((2',3-dichloro-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxo)methyl)- 3,5-difluorobenzonitrile 14g (65mg, 0.149mmol), intermediate 5 (70mg, 0.373mmol), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium dichloromethane complex (12mg, 0.015mmol) and cesium carbonate (97mg, 0.298mmol) were dissolved in 1,4-dioxane/water (v:v=5:1, 1mL), and the reaction was heated to 100°C under nitrogen protection Stir for 3 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried and concentrated to give the crude product. The crude product was separated by silica gel column chromatography (eluent system B) to give the title product 2-(((3-chloro-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)- 5',6- Dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxo)methyl)-3,5-difluorobenzonitrile 14 (40 mg), yield: 49% .
MS m/z(ESI):543.1[M+H]+.MS m/z(ESI):543.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.18(s,1H),7.99(d,1H),7.97–7.90(m,1H),7.89(s,1H),6.87(s,1H),6.05(s,1H),5.43(s,2H),2.04(s,3H),2.01(s,3H),1.55(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.18(s,1H),7.99(d,1H),7.97–7.90(m,1H),7.89(s,1H), 6.87(s,1H),6.05(s,1H),5.43(s,2H),2.04(s,3H),2.01(s,3H),1.55(d,6H).
实施例14的拆分Splitting of Example 14
(S)-2-(((3-氯-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-4-基)氧代)甲基)-3,5-二氟苯甲腈和(R)-2-(((3-氯-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-4-基)氧代)甲基)-3,5-二氟苯甲腈
(S)-2-(((3-chloro-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2-carbonyl-2H -[1,4'-bipyridyl]-4-yl)oxo)methyl)-3,5-difluorobenzonitrile and (R)-2-(((3-chloro-2'-(2 -(2-Hydroxypropan-2-yl)thiazol-4-yl)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-4-yl)oxo) Methyl)-3,5-difluorobenzonitrile
实施例14(40mg,0.074mmol)通过手性拆分得到实施例14-1(10.3mg，R.T＝5.847min，产率：26％)和实施例14-2(8.5mg，R.T＝7.160min，产率：21％)，Example 14 (40mg, 0.074mmol) was obtained by chiral resolution Example 14-1 (10.3mg, R.T = 5.847min, yield: 26%) and Example 14-2 (8.5mg, R.T = 7.160min, Yield: 21%),
实施例14-1：MS m/z(ESI):543.1[M+H]+；Example 14-1: MS m/z (ESI): 543.1[M+H] + ;
实施例14-2：MS m/z(ESI):543.1[M+H]+.Example 14-2: MS m/z (ESI): 543.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：

HPLC chiral analysis conditions:

实施例34Example 34
2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N,2-二甲基丙酰胺
2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1, 4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide
第一步first step
氮气保护下，将氢化钠(1.98g,49.4mmol,纯度：60％)溶于四氢呋喃(55mL)。冰浴下，搅拌下缓慢滴加丙二酸二乙酯(7.91g,49.4mmol)。反应缓慢升至室温，加入2,4-二溴噻唑(10.0g,41.2mmol)，加热至70℃搅拌16小时。将反应液用乙酸乙酯稀释后，分别用饱和氯化铵和饱和食盐水洗，有机相干燥，浓缩。残留物用硅胶柱层析(洗脱体系B)得产物2-(4-溴噻唑-2-基)丙二酸二乙酯34b(6.04g)，产率：46％。Under nitrogen protection, sodium hydride (1.98 g, 49.4 mmol, purity: 60%) was dissolved in tetrahydrofuran (55 mL). Under ice bath, diethyl malonate (7.91 g, 49.4 mmol) was slowly added dropwise with stirring. The reaction was slowly raised to room temperature, 2,4-dibromothiazole (10.0 g, 41.2 mmol) was added, heated to 70°C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine, and the organic phase was dried and concentrated. The residue was subjected to silica gel column chromatography (elution system B) to obtain the product 2-(4-bromothiazol-2-yl)diethyl malonate 34b (6.04 g), yield: 46%.
MS m/z(ESI):321.8[M+H]+.MS m/z(ESI):321.8[M+H] + .
第二步second step
将2-(4-溴噻唑-2-基)丙二酸二乙酯34b(6.0g,18.6mmol)溶于二甲亚砜(30mL)，加入氯化钠(2.18g,37.2mmol)和纯水(671mg,37.2mmol)，反应加热至130℃搅拌1小时。反应液用乙酸乙酯稀释，饱和氯化铵和饱和食盐水洗涤，有机相干燥，浓缩后得产物2-(4-溴噻唑-2-基)乙酸乙酯34c(4.5g)，产率：96％。Diethyl 2-(4-bromothiazol-2-yl)malonate 34b (6.0 g, 18.6 mmol) was dissolved in dimethylsulfoxide (30 mL), sodium chloride (2.18 g, 37.2 mmol) and pure Water (671mg, 37.2mmol), the reaction was heated to 130°C and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine, the organic phase was dried and concentrated to give the product 2-(4-bromothiazol-2-yl) ethyl acetate 34c (4.5g), the yield: 96%.
MS m/z(ESI):250.0[M+H]+. MS m/z(ESI):250.0[M+H] + .
第三步third step
氮气保护下，冰浴下将氢化钠(2.40g,60.0mmol,纯度：60％)溶解于四氢呋喃(20mL)中搅拌10分钟。向反应液中缓慢加入2-(4-溴噻唑-2-基)乙酸乙酯34c(5.0g,20.0mmol)，继续冰浴搅拌0.5小时。向反应液加入碘甲烷(11.3g,80.0mmol)，升至室温反应16小时。反应液用乙酸乙酯稀释后用饱和食盐水洗涤，水相用乙酸乙酯萃取，有机相合并后用饱和食盐水洗涤、干燥、浓缩。残余物用硅胶柱层析用硅胶柱层析(洗脱体系B)得产物2-(4-溴噻唑-2-基)-2-甲基丙酸乙酯34d(3.15g)，产率：57％。Under nitrogen protection, sodium hydride (2.40 g, 60.0 mmol, purity: 60%) was dissolved in tetrahydrofuran (20 mL) under ice-cooling and stirred for 10 minutes. Ethyl 2-(4-bromothiazol-2-yl)acetate 34c (5.0 g, 20.0 mmol) was slowly added to the reaction liquid, and the stirring in ice bath was continued for 0.5 hours. Iodomethane (11.3 g, 80.0 mmol) was added to the reaction liquid, and the reaction was raised to room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed with saturated brine, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried and concentrated. The residue was subjected to silica gel column chromatography (elution system B) to obtain the product 2-(4-bromothiazol-2-yl)-2-methylpropanoic acid ethyl ester 34d (3.15g), the yield: 57%.
MS m/z(ESI):278.0[M+H]+.MS m/z(ESI):278.0[M+H] + .
第四步the fourth step
将2-(4-溴噻唑-2-基)-2-甲基丙酸乙酯34d(3.15g,11.3mmol)溶于氨水(20mL)，置于耐压密封管中加热至80℃搅拌16小时。反应液减压浓缩得化合物2-(4-溴噻唑-2-基)-2-甲基丙酰胺34e(2.8g)，产物无需纯化直接用于下步反应。Dissolve ethyl 2-(4-bromothiazol-2-yl)-2-methylpropionate 34d (3.15g, 11.3mmol) in aqueous ammonia (20mL), heat to 80°C in a pressure-resistant sealed tube and stir for 16 Hour. The reaction solution was concentrated under reduced pressure to obtain compound 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (2.8 g), which was directly used in the next reaction without purification.
MS m/z(ESI):248.9[M+H]+.MS m/z(ESI):248.9[M+H] + .
第五步the fifth step
氮气保护下，将氢化钠(302mg,7.55mmol,纯度：60％)溶解于四氢呋喃(2mL)中。搅拌下向反应液滴加2-(4-溴噻唑-2-基)-2-甲基丙酰胺34e(1.88g,7.55mmol)的四氢呋喃溶液(2mL)。反应加热至30℃搅拌1小时，随后升温至70℃缓慢滴加碘甲烷(1.07g,7.55mmol)，在该温度下继续反应0.5小时。反应液用饱和氯化铵溶液淬灭，浓缩后粗品用硅胶柱层析(洗脱体系B)得产物2-(4-溴噻唑-2-基)-N,2-二甲基丙酰胺34f(225mg)，产率：11％。Under nitrogen protection, sodium hydride (302 mg, 7.55 mmol, purity: 60%) was dissolved in tetrahydrofuran (2 mL). A tetrahydrofuran solution (2 mL) of 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (1.88 g, 7.55 mmol) was added dropwise to the reaction solution with stirring. The reaction was heated to 30°C and stirred for 1 hour, then warmed to 70°C and methyl iodide (1.07 g, 7.55 mmol) was slowly added dropwise, and the reaction was continued at this temperature for 0.5 hour. The reaction solution was quenched with saturated ammonium chloride solution, concentrated and the crude product was subjected to silica gel column chromatography (elution system B) to obtain the product 2-(4-bromothiazol-2-yl)-N,2-dimethylpropanamide 34f (225 mg), Yield: 11%.
MS m/z(ESI):262.9[M+H]+.MS m/z(ESI):262.9[M+H] + .
第六步step six
将中间体4(90mg,0.135mmol)，2-(4-溴噻唑-2-基)-N,2-二甲基丙酰胺34f(36mg,0.135mmol)和四三苯基膦钯(23mg,0.020mmol)溶于二氧六环(2mL)中，氮气保护下，于105℃下搅拌16小时。反应液浓缩后经制备型HPLC纯化(甲酸体系)得标题产物2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N,2-二甲基丙酰胺34(60mg)，产率：71％。Intermediate 4 (90 mg, 0.135 mmol), 2-(4-bromothiazol-2-yl)-N,2-dimethylpropanamide 34f (36 mg, 0.135 mmol) and tetrakistriphenylphosphine palladium (23 mg, 0.020 mmol) was dissolved in dioxane (2 mL), and stirred at 105° C. for 16 hours under nitrogen protection. After the reaction solution was concentrated, it was purified by preparative HPLC (formic acid system) to obtain the title product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5', 6-Dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide 34 (60 mg), yielding Rate: 71%.
MS m/z(ESI):560.0[M+H]+.MS m/z(ESI):560.0[M+H] + .
1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.40(s,1H),8.17(s,1H),7.89(s,1H),7.31(dd,1H),6.57(s,1H),6.42(s,1H),5.42(s,2H),2.77(s,3H),2.15(s,3H),2.02(s,3H),1.74(s,6H). 1 H NMR (400MHz, CDCl 3 )δ8.67(s,1H),8.40(s,1H),8.17(s,1H),7.89(s,1H),7.31(dd,1H),6.57(s, 1H), 6.42(s,1H), 5.42(s,2H), 2.77(s,3H), 2.15(s,3H), 2.02(s,3H), 1.74(s,6H).
实施例34的拆分Splitting of Example 34
(S)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N,2-二甲基丙酰胺和(R)-2-(4-(3-氯-4-((3,5-二 氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N,2-二甲基丙酰胺
(S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H -[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide and (R)-2-(4-(3-chloro-4-( (3,5-two Fluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)- N,2-Dimethylpropanamide
实施例34(60mg，0.107mmol)经手性拆分(OD柱)得到34-1(13mg，R.T＝3.417min)，产率：22％；34-2(13mg，R.T＝3.880min)，产率：22％。Example 34 (60mg, 0.107mmol) was subjected to chiral resolution (OD column) to obtain 34-1 (13mg, R.T=3.417min), yield: 22%; 34-2 (13mg, R.T=3.880min), yield :twenty two%.
实施例34-1：MS m/z(ESI):559.8[M+H]+；Example 34-1: MS m/z (ESI): 559.8[M+H] + ;
实施例34-2：MS m/z(ESI):559.8[M+H]+；Example 34-2: MS m/z (ESI): 559.8[M+H] + ;
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例35Example 35
2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺
2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1, 4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropionamide
第一步first step
氮气保护下，将中间体4(135mg,0.202mmol)，2-(4-溴噻唑-2-基)-2-甲基丙酰胺34e(50mg,0.202mmol)和四三苯基膦钯(35mg,0.030mmol)溶于二氧六环(2mL)。反应加热至105℃搅拌16小时。反应液经硅藻土过滤后减压浓缩，所得残留物用制备型硅胶色谱板纯化(洗脱体系A)得标题产物2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺35(60mg)，产率：55％。Under nitrogen protection, intermediate 4 (135 mg, 0.202 mmol), 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (50 mg, 0.202 mmol) and tetrakistriphenylphosphine palladium (35 mg , 0.030mmol) was dissolved in dioxane (2mL). The reaction was heated to 105°C and stirred for 16 hours. The reaction solution was filtered through diatomaceous earth and then concentrated under reduced pressure. The resulting residue was purified by preparative silica gel chromatography (elution system A) to obtain the title product 2-(4-(3-chloro-4-((3,5-di Fluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)- 2-Methylpropanamide 35 (60 mg), yield: 55%.
MS m/z(ESI):545.8[M+H]+.MS m/z(ESI):545.8[M+H] + .
1H NMR(400MHz,CD3OD)δ8.67(s,1H),8.46(d,1H),8.16(s,1H),8.02(s,1H),7.78–7.67(m,1H),6.82(s,1H),5.51(d,2H),2.13(s,3H),2.08(s,3H),1.73(s,6H). 1 H NMR (400MHz, CD 3 OD) δ8.67(s,1H),8.46(d,1H),8.16(s,1H),8.02(s,1H),7.78–7.67(m,1H),6.82 (s,1H),5.51(d,2H),2.13(s,3H),2.08(s,3H),1.73(s,6H).
实施例35的拆分Splitting of Example 35
(S)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺和(R)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺
(S)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H -[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropionamide and (R)-2-(4-(3-chloro-4-((3, 5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazole-2- base)-2-methylpropanamide
实施例35(60mg，0.110mmol)经手性拆分(OD柱)得到35-1(18mg，R.T＝4.387min)，产率：30％；35-2(18mg，R.T＝5.447min)，产率：30％。Example 35 (60mg, 0.110mmol) was subjected to chiral resolution (OD column) to obtain 35-1 (18mg, R.T=4.387min), yield: 30%; 35-2 (18mg, R.T=5.447min), yield : 30%.
实施例35-1：MS m/z(ESI):546.1[M+H]+；Example 35-1: MS m/z (ESI): 546.1[M+H] + ;
1H NMR(400MHz,CD3OD)δ8.67(s,1H),8.46(d,1H),8.16(s,1H),8.02(s,1H),7.78–7.67(m,1H),6.82(s,1H),5.51(d,2H),2.13(s,3H),2.08(s,3H),1.73(s,6H). 1 H NMR (400MHz, CD 3 OD) δ8.67(s,1H),8.46(d,1H),8.16(s,1H),8.02(s,1H),7.78–7.67(m,1H),6.82 (s,1H),5.51(d,2H),2.13(s,3H),2.08(s,3H),1.73(s,6H).
实施例35-2：MS m/z(ESI):546.1[M+H]+；Example 35-2: MS m/z (ESI): 546.1[M+H] + ;
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例36Example 36
2-(4-(3-氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺

2-(4-(3-chloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-5',6-dimethyl-2-oxo-2H-[ 1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropionamide

第一步first step
氮气保护下，将2-(4-溴噻唑-2-基)-2-甲基丙酰胺34e(105mg,0.423mmol)，3-氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-5',6-二甲基-2'-(三丁基锡)-2H-[1,4'-联吡啶]-2-酮36a(240mg,0.353mmol，其合成方法参考中间体4的合成)和双三苯基膦二氯化钯(25mg,0.035mmol)溶解于1，4-二氧六环(5mL)中，反应加热至106℃，搅拌14小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到产物2-(4-(3-氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺36(65.6mg)，产率：33.2％。Under nitrogen protection, 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (105mg, 0.423mmol), 3-chloro-4-(1-(3,5-difluoropyridine- 2-yl)ethoxy)-5',6-dimethyl-2'-(tributyltin)-2H-[1,4'-bipyridyl]-2-one 36a (240 mg, 0.353 mmol, synthesized from The method refers to the synthesis of intermediate 4) and bistriphenylphosphine palladium dichloride (25mg, 0.035mmol) were dissolved in 1,4-dioxane (5mL), and the reaction was heated to 106°C and stirred for 14 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 2-(4-(3-chloro-4-(1-(3,5-difluoropyridin-2-yl) ethyl) Oxy)-5',6-dimethyl-2-oxo-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropionamide 36( 65.6 mg), yield: 33.2%.
MS m/z(ESI):560.1[M+H]+；MS m/z(ESI):560.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.60(d,1H),8.23(d,1H),8.09-8.04(m,1H),7.93(d,1H),7.27-7.15(m,2H),6.67-6.60(m,1H),6.09-6.03(m,1H),2.02-1.99(m,3H),1.95-1.93(m,3H),1.74-1.72(m,3H),1.63-1.61(m,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.69(s,1H),8.60(d,1H),8.23(d,1H),8.09-8.04(m,1H),7.93(d,1H), 7.27-7.15(m,2H),6.67-6.60(m,1H),6.09-6.03(m,1H),2.02-1.99(m,3H),1.95-1.93(m,3H),1.74-1.72(m ,3H),1.63-1.61(m,6H).
实施例37Example 37
(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺
(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxyl-2H-[1, 4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropionamide
参照实施例35的合成方法，合成得到目标产物(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺37。Referring to the synthesis method of Example 35, the target product (4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl yl-2-oxyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropanamide 37.
MS m/z(ESI):548.1[M+H]+. MS m/z(ESI):548.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28(s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H).
实施例37的拆分Splitting of Example 37
(R)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺和(S)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺(R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxyl -2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropionamide and (S)-2-(4-(3-chloro-4-(( 3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxyl-2H-[1,4'-bipyridyl]-2'-yl) Thiazol-2-yl)-2-methylpropanamide
实施例37(30mg，0.055mmol)经手性拆分(OD柱)得到标题产物37-1(12mg，R.T＝3.352min)，产率：40.0％；37-2(11mg，R.T＝5.430min)，产率：36.7％。Example 37 (30mg, 0.055mmol) was subjected to chiral resolution (OD column) to obtain the title product 37-1 (12mg, R.T=3.352min), yield: 40.0%; 37-2 (11mg, R.T=5.430min), Yield: 36.7%.
实施例37-1，MS m/z(ESI):548.1[M+H]+；Embodiment 37-1, MS m/z (ESI): 548.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28(s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H).
实施例37-2，MS m/z(ESI):548.1[M+H]+；Embodiment 37-2, MS m/z (ESI): 548.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28(s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.24(s,1H),8.10(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.62(s,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：

HPLC chiral analysis conditions:

实施例38Example 38
2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-6-(甲基-d3)-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺
2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2-oxo -2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropionamide
参照实施例35的合成方法，合成得到目标产物2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-6-(甲基-d3)-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙胺38。Referring to the synthesis method of Example 35, the target product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6 was synthesized -(Methyl-d3)-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropylamine 38.
MS m/z(ESI):549.1[M+H]+.MS m/z(ESI):549.1[M+H] + .
实施例38的拆分Splitting of Example 38
(R)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-6-(甲基-d3)-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺和(S)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-甲基-6-(甲基-d3)-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺
(R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)- 2-oxo-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropanamide and (S)-2-(4-(3-chloro- 4-((3,5-difluoropyridin-2-yl)methoxy)-5'-methyl-6-(methyl-d3)-2-oxo-2H-[1,4'-bis Pyridine]-2'-yl)thiazol-2-yl)-2-methylpropionamide
实施例38(32mg，0.058mmol)经手性拆分(OD柱)得到标题产物38-1(11mg，R.T＝4.362min)，产率：34.3％；38-2(12mg，R.T＝5.423min)，产率：37.5％。Example 38 (32mg, 0.058mmol) was subjected to chiral resolution (OD column) to obtain the title product 38-1 (11mg, R.T=4.362min), yield: 34.3%; 38-2 (12mg, R.T=5.423min), Yield: 37.5%.
实施例38-1，MS m/z(ESI):549.1[M+H]+；Example 38-1, MS m/z (ESI): 549.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.61(d,1H),8.24(s,1H),8.11(m,1H),7.95(s,1H),7.28(s,1H),7.17(s,1H),6.91(s,1H),5.49(s,2H),2.01(s,3H),1.64(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.71(s,1H),8.61(d,1H),8.24(s,1H),8.11(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.91(s,1H),5.49(s,2H),2.01(s,3H),1.64(s,6H).
实施例38-2，MS m/z(ESI):549.1[M+H]+； Embodiment 38-2, MS m/z (ESI): 549.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.61(d,1H),8.24(s,1H),8.11(m,1H),7.95(s,1H),7.28(s,1H),7.17(s,1H),6.91(s,1H),5.49(s,2H),2.01(s,3H),1.64(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.71(s,1H),8.61(d,1H),8.24(s,1H),8.11(m,1H),7.95(s,1H),7.28( s,1H),7.17(s,1H),6.91(s,1H),5.49(s,2H),2.01(s,3H),1.64(s,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例41Example 41
2-(4-(3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺2-(4-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2-carbonyl-2H-[1,4 '-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropionamide
第一步first step
氮气保护下，将2-(4-溴噻唑-2-基)-2-甲基丙酰胺34e(116mg，0.45mmol)，联硼酸频那醇酯(137.2mg，0.54mmol)，三(二亚苄基丙酮)二钯(20.6mg，0.02mmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(25.8mg，0.05mmol)和醋酸钾(88.4mg，0.9mmol)溶解于无水1，4-二氧六环(5mL)中。反应加热至110℃搅拌2小时。冷却至室温，反应液过滤，滤液浓缩，残余物经反相HPLC(甲酸体系)制备得到产物(2-(1-氨基-2-甲基-1-羰基丙烷-2-基)噻唑-4-基)硼酸41a(62mg)，产率：64％。Under nitrogen protection, 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (116mg, 0.45mmol), pinacol diboronate (137.2mg, 0.54mmol), tris(diethylene Benzylacetone) dipalladium (20.6mg, 0.02mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (25.8mg, 0.05mmol) and potassium acetate (88.4mg, 0.9 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL). The reaction was heated to 110°C and stirred for 2 hours. Cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated, and the residue was prepared by reverse phase HPLC (formic acid system) to obtain the product (2-(1-amino-2-methyl-1-carbonylpropane-2-yl)thiazole-4- base) boronic acid 41a (62 mg), yield: 64%.
MS m/z(ESI):215.0[M+H]+.MS m/z(ESI):215.0[M+H] + .
第二步second step
氮气保护下，将41a(50mg，0.116mmol)，4d(30mg，0.139mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(9mg，0.012mmol)和碳酸铯(75mg，0.231mmol)溶于二氧六环(1mL)和水(0.1mL)的混合液中。反应加热至100℃搅拌3小时。向反应液加入乙酸乙酯(10mL)，经硅藻土过滤后，滤液浓缩。残留物用制备型硅胶色谱板纯化(洗脱体系A)得产物2-(4-(3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-6-甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺41(25mg)，产率：38％Under nitrogen protection, 41a (50mg, 0.116mmol), 4d (30mg, 0.139mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (9mg, 0.012mmol) and cesium carbonate ( 75mg, 0.231mmol) was dissolved in a mixture of dioxane (1mL) and water (0.1mL). The reaction was heated to 100°C and stirred for 3 hours. Ethyl acetate (10 mL) was added to the reaction solution, and after filtration through celite, the filtrate was concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to give the product 2-(4-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy) )-6-methyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropanamide 41 (25 mg), yield: 38 %
MS m/z(ESI):566.0[M+1]+.MS m/z(ESI):566.0[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.61(d,1H),8.33(s,1H),8.25(s,1H),8.10(d,1H),7.29(s,1H),7.19(s,1H),6.84(s,1H),5.50(d,2H),2.02(s,3H),1.63(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.94(s,1H),8.61(d,1H),8.33(s,1H),8.25(s,1H),8.10(d,1H),7.29( s,1H),7.19(s,1H),6.84(s,1H),5.50(d,2H),2.02(s,3H),1.63(s,6H).
实施例42Example 42
2-(4-(3,5'-二氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-6-甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺
2-(4-(3,5'-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-6-methyl-2-carbonyl-2H-[1 ,4'-bipyridyl]-2'-yl)thiazol-2-yl)-2-methylpropionamide
参照实施例41的合成方法，合成得到目标产物2-(4-(3,5'-二氯-4-(1-(3,5-二氟吡啶-2-基)乙氧基)-6-甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-2-甲基丙酰胺42。Referring to the synthesis method of Example 41, the target product 2-(4-(3,5'-dichloro-4-(1-(3,5-difluoropyridin-2-yl)ethoxy)-6 was synthesized -Methyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-2-methylpropanamide 42.
MS m/z(ESI):580.0[M+1]+. MS m/z(ESI):580.0[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.60(d,1H),8.32(d,1H),8.23(d,1H),8.06(t,1H),7.29(s,1H),7.19(s,1H),6.71(s,1H),6.08(d,1H),1.98(d,3H),1.73(d,3H),1.62(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.93(s,1H),8.60(d,1H),8.32(d,1H),8.23(d,1H),8.06(t,1H),7.29( s,1H),7.19(s,1H),6.71(s,1H),6.08(d,1H),1.98(d,3H),1.73(d,3H),1.62(d,6H).
实施例45Example 45
2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5'，6-二甲基-2-氧基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N，2-二甲基丙酰胺
2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxyl-2H-[ 1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide
参照实施例34的合成方法，合成得到目标产物2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5'，6-二甲基-2-氧基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N，2-二甲基丙酰胺45。Referring to the synthesis method of Example 34, the target product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6- Dimethyl-2-oxy-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide 45.
MS m/z(ESI):562.1[M+H]+.MS m/z(ESI):562.1[M+H] + .
实施例45的拆分Splitting of Example 45
(R)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5'，6-二甲基-2-氧基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N，2-二甲基丙酰胺和(S)-2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5'，6-二甲基-2-氧基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N，2-二甲基丙酰胺
(R)-2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxyl -2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-N,2-dimethylpropanamide and (S)-2-(4-(3-chloro-4 -((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-oxyl-2H-[1,4'-bipyridine]-2' -yl)thiazol-2-yl)-N,2-dimethylpropanamide
实施例45(30mg，0.053mmol)经手性拆分(OD柱)得到标题产物45-1(12mg，R.T＝3.397min)，产率：40.0％；45-2(11mg，R.T＝3.860min)，产率：36.7％。Example 45 (30mg, 0.053mmol) was subjected to chiral resolution (OD column) to obtain the title product 45-1 (12mg, R.T=3.397min), yield: 40.0%; 45-2 (11mg, R.T=3.860min), Yield: 36.7%.
实施例45-1，MS m/z(ESI):562.1[M+H]+；Embodiment 45-1, MS m/z (ESI): 562.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.61(s,1H),8.24(s,1H),8.10(m,1H),7.92(s,1H),7.66(m,1H),6.81(s,1H),2.60(d,3H),2.03(s,3H),1.98(s,3H),1.63(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.71(s,1H),8.61(s,1H),8.24(s,1H),8.10(m,1H),7.92(s,1H),7.66( m,1H),6.81(s,1H),2.60(d,3H),2.03(s,3H),1.98(s,3H),1.63(s,6H).
实施例45-2，MS m/z(ESI):562.1[M+H]+； Embodiment 45-2, MS m/z (ESI): 562.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.61(s,1H),8.24(s,1H),8.10(m,1H),7.92(s,1H),7.66(m,1H),6.81(s,1H),2.60(d,3H),2.03(s,3H),1.98(s,3H),1.63(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.71(s,1H),8.61(s,1H),8.24(s,1H),8.10(m,1H),7.92(s,1H),7.66( m,1H),6.81(s,1H),2.60(d,3H),2.03(s,3H),1.98(s,3H),1.63(s,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例46Example 46
2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N,N,2-三甲基丙酰胺

2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-oxo-2H-[1, 4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,N,2-trimethylpropanamide

第一步first step
氮气保护下，冰浴下将氢化钠(302mg,7.55mmol,60％纯度)溶解于四氢呋喃(2mL)中搅拌。向反应液滴加2-(4-溴噻唑-2-基)-2-甲基丙酰胺34e(1.88g,7.55mmol)的四氢呋喃溶液(2mL)，反应加热至30℃搅拌1小时，然后升温至70℃缓慢滴加碘甲烷(1.07g,7.55mmol)，继续搅拌0.5小时。反应液用饱和氯化铵溶液淬灭，浓缩后用硅胶柱色谱(洗脱体系B)分离得标题产物2-(4-溴噻唑-2-基)-N,N,2-三甲基丙酰胺46a(489mg，淡黄色固体)，收率：23％。Under nitrogen protection, sodium hydride (302mg, 7.55mmol, 60% purity) was dissolved in tetrahydrofuran (2mL) and stirred under ice-cooling. Add 2-(4-bromothiazol-2-yl)-2-methylpropanamide 34e (1.88g, 7.55mmol) in tetrahydrofuran (2mL) dropwise to the reaction solution, heat the reaction to 30°C and stir for 1 hour, then heat up Slowly add iodomethane (1.07g, 7.55mmol) dropwise to 70°C and continue stirring for 0.5 hours. The reaction solution was quenched with saturated ammonium chloride solution, concentrated and separated by silica gel column chromatography (elution system B) to obtain the title product 2-(4-bromothiazol-2-yl)-N,N,2-trimethylpropane Amide 46a (489 mg, pale yellow solid), yield: 23%.
MS m/z(ESI):277.0[M+H]+.MS m/z(ESI):277.0[M+H] + .
第二步second step
参照实施例34第六步的合成方法，合成得到目标产物2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-N,N,2-三甲基丙酰胺46。Referring to the synthesis method in the sixth step of Example 34, the target product 2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6 -Dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)-N,N,2-trimethylpropanamide 46.
MS m/z(ESI):573.8[M+H]+.MS m/z(ESI):573.8[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.60(d,1H),8.30(s,1H),8.13–8.05(m,1H),7.85(s,1H),6.80(s,1H),5.48(s,2H),2.71(d,6H),2.03(s,3H),1.97(s,3H),1.62(s,6H). 1 H NMR (400MHz,DMSO-d6)δ8.71(s,1H),8.60(d,1H),8.30(s,1H),8.13–8.05(m,1H),7.85(s,1H),6.80 (s,1H),5.48(s,2H),2.71(d,6H),2.03(s,3H),1.97(s,3H),1.62(s,6H).
实施例47Example 47
3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮

3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazole-4 -yl)-6-methyl-2H-[1,4'-bipyridine]-2-one

第一步first step
氮气保护下，将2',3,5'-三氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-6-甲基-2H-[1,4'-联吡啶]-2-酮47a(100mg,0.230mmol，参考实施例4中4d的合成方法)，中间体5(86mg,0.460mmol)，1,1'-双二苯基膦二茂铁二氯化钯(17mg,0.023mmol)和碳酸铯(150mg,0.46mmol)溶解于1，4-二氧六环(1.5mL)和水(0.5mL)中，反应加热至100℃搅拌2.5小时。反应液浓缩，残余物用硅胶柱色谱(洗脱剂体系B)分离得到产物3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮47(65mg)，产率：52.2％yield。Under nitrogen protection, 2',3,5'-trichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-6-methyl-2H-[1,4 '-bipyridyl]-2-one 47a (100mg, 0.230mmol, refer to the synthesis method of 4d in Example 4), intermediate 5 (86mg, 0.460mmol), 1,1'-bisdiphenylphosphinoferrocene Palladium dichloride (17mg, 0.023mmol) and cesium carbonate (150mg, 0.46mmol) were dissolved in 1,4-dioxane (1.5mL) and water (0.5mL), and the reaction was heated to 100°C and stirred for 2.5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2) -2'-(2-(2-Hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 47 (65mg), yield Rate: 52.2% yield.
MS m/z(ESI):541.1[M+H]+；MS m/z(ESI):541.1[M+H] + ;
实施例47的拆分Splitting of Example 47
(S)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl) )thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridine]-2-one and (R)-3,5'-dichloro-4-((3,5-di Fluoropyridin-2-yl)methoxy-d2)-2'-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'- Bipyridyl]-2-one
实施例47(65mg,0.12mmol)经手性拆分(OD柱)得到标题产物47-1(20.8mg，R.T＝3.333min)，产率：32.0％；47-2(21.6mg，R.T＝4.167min)，产率：33.2％。Example 47 (65mg, 0.12mmol) obtained the title product 47-1 (20.8mg, R.T=3.333min) through chiral resolution (OD column), yield: 32.0%; 47-2 (21.6mg, R.T=4.167min ), yield: 33.2%.
实施例47-1，MS m/z(ESI):541.1[M+H]+；Embodiment 47-1, MS m/z (ESI): 541.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.13-8.07(m,1H),6.83(d,1H),6.10(s,1H),2.01(s,3H),1.56(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.94(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.13-8.07(m,1H), 6.83(d,1H),6.10(s,1H),2.01(s,3H),1.56(s,6H).
实施例47-2，MS m/z(ESI):541.1[M+H]+；Embodiment 47-2, MS m/z (ESI): 541.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.13-8.07(m,1H),6.83(d,1H),6.10(s,1H),2.01(s,3H),1.56(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.94(s,1H),8.60(d,1H),8.27(s,1H),8.16(s,1H),8.13-8.07(m,1H), 6.83(d,1H),6.10(s,1H),2.01(s,3H),1.56(s,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例48Example 48
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6'-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole-1 -yl)-5',6'-dimethyl-2H-[1,4'-bipyridyl]-2-one
第一步first step
将1-(2-溴-5-甲基-4-吡啶基)-3-氯-4-羟基-6-甲基-吡啶-2-酮11e(550g,1.67mmol)，2-(氯甲基-d2)-3,5-二氟吡啶7b(387mg,2.34mmol)，碳酸钾(577mg,4.17mmol)和18-冠-6醚(662mg,2.50mmol)溶解于N,N-二甲基甲酰胺(25mL)中加热至70℃搅拌3小时。向反应液中加入乙酸乙酯(50mL)，有机相用水和饱和氯化钠洗涤，干燥，浓缩。残余物用硅胶色谱柱纯化(洗脱体系A)得到2'-溴-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮48a(540mg)，产率：70.6％。1-(2-Bromo-5-methyl-4-pyridyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one 11e (550g, 1.67mmol), 2-(chloromethyl Base-d2)-3,5-difluoropyridine 7b (387mg, 2.34mmol), potassium carbonate (577mg, 4.17mmol) and 18-crown-6 ether (662mg, 2.50mmol) were dissolved in N,N-dimethyl Formamide (25 mL) was heated to 70°C and stirred for 3 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the organic phase was washed with water and saturated sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (elution system A) to give 2'-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6 -Dimethyl-2H-[1,4'-bipyridyl]-2-one 48a (540 mg), yield: 70.6%.
MS m/z(ESI):458.0[M+H]+.MS m/z(ESI):458.0[M+H] + .
第二步second step
氮气保护下，将2'-溴-3-氯-4-((3,5-二氟-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮48a(210mg,0.458mmol)，2-(1H-吡唑-3-基)丙烷-2-醇11b(87mg,0.687mmol)，N1,N2-二甲基环己烷-1,2-二胺(26mg,0.183mmol)，碘化亚铜(17mg,0.092mmol)和碳酸铯(298mg,0.916mmol)溶解在1,4-二氧六环(5mL)中。反应加热至100℃搅拌8小时。向反应液中加入乙酸乙酯(25mL)，有机相用水和饱和氯化钠洗涤，干燥，浓缩。残余物用硅胶色谱柱纯化(洗脱体系A)得标题产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6'-二甲基-2H-[1,4'-联吡啶]-2-酮48(75mg)，产率：32.5％。Under nitrogen protection, 2'-bromo-3-chloro-4-((3,5-difluoro-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1, 4'-bipyridyl]-2-one 48a (210mg, 0.458mmol), 2-(1H-pyrazol-3-yl) propan-2-ol 11b (87mg, 0.687mmol), N1,N2-dimethyl Cyclohexane-1,2-diamine (26 mg, 0.183 mmol), cuprous iodide (17 mg, 0.092 mmol) and cesium carbonate (298 mg, 0.916 mmol) were dissolved in 1,4-dioxane (5 mL) . The reaction was heated to 100°C and stirred for 8 hours. Ethyl acetate (25 mL) was added to the reaction solution, and the organic phase was washed with water and saturated sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (elution system A) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-( 2-Hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl-2H-[1,4'-bipyridyl]-2-one 48 (75mg), Yield: 32.5%.
MS m/z(ESI):504.1[M+H]+.MS m/z(ESI):504.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.54(s,1H),8.51(d,1H),8.10(t,1H),7.78(s,1H),6.80(s,1H),6.56(d,1H),5.09(s,1H),2.00(d,6H),1.48(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.54(s,1H),8.51(d,1H),8.10(t,1H),7.78(s,1H),6.80( s,1H),6.56(d,1H),5.09(s,1H),2.00(d,6H),1.48(s,6H).
实施例48的拆分Splitting of Example 48
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6'-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6'-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-1H- Pyrazol-1-yl)-5',6'-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5- Difluoropyridin-2-yl)methoxy-d2)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6'-dimethyl Base-2H-[1,4'-bipyridyl]-2-one
实施例48(140mg,0.278mmol)经手性拆分(AS柱)得到标题产物48-1(54mg，R.T＝3.28min)，产率：38.57％；48-2(52mg，R.T＝4.757min)，产率：34.14％。 Example 48 (140mg, 0.278mmol) was subjected to chiral resolution (AS column) to obtain the title product 48-1 (54mg, RT=3.28min), yield: 38.57%; 48-2 (52mg, RT=4.757min), Yield: 34.14%.
实施例48-1，MS m/z(ESI):504.1[M+H]+；Embodiment 48-1, MS m/z (ESI): 504.1[M+H] + ;
实施例48-2，MS m/z(ESI):504.1[M+H]+。Example 48-2, MS m/z (ESI): 504.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例49Example 49
3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole -1-yl)-6-methyl-2H-[1,4'-bipyridine]-2-one
第一步 first step
将2',5'-二氯-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮4b(10g,36.89mmol)溶解在二氯乙烷(600mL)和异丙醇(400mL)的混合液中，加热到60℃搅拌。向反应液中分批加N-氯代丁二酰胺(6.2g，46.11mmol)，反应在60℃下继续搅拌2小时。反应液浓缩，残余物用反相柱(甲酸体系)分离得到2',3,5'-三氯-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮49a(5.1g)，产率：45.3％。Dissolve 2',5'-dichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 4b (10 g, 36.89 mmol) in dichloroethane (600 mL) and isopropanol (400 mL), heated to 60°C and stirred. N-chlorosuccinamide (6.2 g, 46.11 mmol) was added in portions to the reaction solution, and the reaction was stirred at 60° C. for 2 hours. The reaction solution was concentrated, and the residue was separated by a reverse-phase column (formic acid system) to obtain 2',3,5'-trichloro-4-hydroxy-6-methyl-2H-[1,4'-bipyridine]-2- Ketone 49a (5.1 g), yield: 45.3%.
MS m/z(ESI):306.8[M+H]+.MS m/z(ESI):306.8[M+H] + .
1H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.80(s,1H),7.98(s,1H),6.19(d,1H),1.90(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.72(s,1H),8.80(s,1H),7.98(s,1H),6.19(d,1H),1.90(s,3H).
第二步second step
将49a(300mg,0,982mmol)，2-(1H-吡唑-3-基)丙烷-2-醇11b(186mg,1.47mmol)和碳酸铯(640mg,1.96mmol)溶于二甲亚砜(4mL)中。反应加热至110℃搅拌16小时。反应液用反相柱(甲酸体系)纯化得产物3,5'-二氯-4-羟基-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮49b(263mg)，产率：68％。49a (300 mg, 0,982 mmol), 2-(1H-pyrazol-3-yl)propan-2-ol 11b (186 mg, 1.47 mmol) and cesium carbonate (640 mg, 1.96 mmol) were dissolved in dimethylsulfoxide (4 mL )middle. The reaction was heated to 110°C and stirred for 16 hours. The reaction solution was purified by a reverse-phase column (formic acid system) to obtain the product 3,5'-dichloro-4-hydroxy-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl )-6-methyl-2H-[1,4'-bipyridine]-2-one 49b (263 mg), yield: 68%.
MS m/z(ESI):395.0[M+H]+.MS m/z(ESI):395.0[M+H] + .
第三步third step
将3,5'-二氯-4-羟基-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮49b(70mg,0.177mmol)，2-(氯甲基)-3,5-二氟-吡啶(58mg,0.354mmol)和碳酸钾(73mg,0.531mmol)溶于N,N-二甲基甲酰胺(1.5mL)中。反应加热至70℃搅拌3小时。反应液用乙酸乙酯稀释后，有机相用饱和食盐水洗涤，干燥，浓缩，残余物用制备型硅胶色谱板纯化(洗脱体系A)得标题产物3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮49(75mg)，产率：81％。3,5'-dichloro-4-hydroxyl-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1, 4'-bipyridyl]-2-one 49b (70mg, 0.177mmol), 2-(chloromethyl)-3,5-difluoro-pyridine (58mg, 0.354mmol) and potassium carbonate (73mg, 0.531mmol) were dissolved In N,N-dimethylformamide (1.5 mL). The reaction was heated to 70°C and stirred for 3 hours. After the reaction solution was diluted with ethyl acetate, the organic phase was washed with saturated brine, dried and concentrated, and the residue was purified by preparative silica gel chromatography (elution system A) to obtain the title product 3,5'-dichloro-4-( (3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl- 2H-[1,4'-bipyridyl]-2-one 49 (75 mg), yield: 81%.
MS m/z(ESI):522.1[M+H]+.MS m/z(ESI):522.1[M+H] + .
实施例49的拆分Splitting of Example 49
(S)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮(S)-3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)- 1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridine]-2-one and (R)-3,5'-dichloro-4-((3,5 -Difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1 ,4'-bipyridyl]-2-one
实施例49(75mg，0.144mmol)经手性拆分(OJ柱)得到49-1(28mg，R.T＝3.650min)产率：37％；49-2(28mg，R.T＝8.937min)，产率：37％。Example 49 (75mg, 0.144mmol) was obtained by chiral resolution (OJ column) to obtain 49-1 (28mg, R.T=3.650min) yield: 37%; 49-2 (28mg, R.T=8.937min), yield: 37%.
实施例49-1：MS m/z(ESI):522.1[M+H]+；Example 49-1: MS m/z (ESI): 522.1[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.45(d,1H),8.40(d,1H),7.92(s,1H),7.36–7.27(m,1H),6.42(d,1H),6.40(s,1H),5.42(s,2H),2.08(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.55(s, 1H), 8.45(d, 1H), 8.40(d, 1H), 7.92(s, 1H), 7.36–7.27(m, 1H), 6.42( d,1H),6.40(s,1H),5.42(s,2H),2.08(s,3H),1.59(d,6H).
实施例49-2：MS m/z(ESI):522.1[M+H]+；Example 49-2: MS m/z (ESI): 522.1[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.45(d,1H),8.40(d,1H),7.92(s,1H),7.37–7.28(m,1H),6.47–6.41(m,1H),6.40(s,1H),5.40(d,2H),2.08(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.55(s,1H),8.45(d,1H),8.40(d,1H),7.92(s,1H),7.37–7.28(m,1H),6.47– 6.41(m,1H),6.40(s,1H),5.40(d,2H),2.08(s,3H),1.59(d,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例50Example 50
3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H -pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one
参照实施例49的合成方法，合成得到目标产物3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮50。Referring to the synthesis method of Example 49, the target product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3- (2-Hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 50.
MS m/z(ESI):524.1[M+H]+.MS m/z(ESI):524.1[M+H] + .
实施例50的拆分Splitting of Example 50
(S)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙-2-基)-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropane-2- Base)-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridine]-2-one and (R)-3,5'-dichloro-4-(( 3,5-Difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-6-methanol Base-2H-[1,4'-bipyridyl]-2-one
实施例50(65mg，0.124mmol)经手性拆分(OJ柱)得到50-1(25mg，R.T＝3.633min)产率：38％；50-2(25mg，R.T＝9.053min)，产率：38％。Example 50 (65mg, 0.124mmol) was obtained by chiral resolution (OJ column) to obtain 50-1 (25mg, R.T=3.633min) yield: 38%; 50-2 (25mg, R.T=9.053min), yield: 38%.
实施例50-1：MS m/z(ESI):524.1[M+H]+；Example 50-1: MS m/z (ESI): 524.1[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.45(d,1H),8.40(d,1H),7.92(s,1H),7.36–7.29(m,1H),6.42(d,1H),6.40(s,1H),2.08(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.55(s,1H),8.45(d,1H),8.40(d,1H),7.92(s,1H),7.36–7.29(m,1H),6.42( d,1H),6.40(s,1H),2.08(s,3H),1.59(d,6H).
实施例50-2：MS m/z(ESI):524.1[M+H]+；Example 50-2: MS m/z (ESI): 524.1[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.54(s,1H),8.43(d,1H),8.40(s,1H),7.92(s,1H),7.31(dd,1H),6.42(d,1H),6.40(s,1H),2.08(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.54(s,1H),8.43(d,1H),8.40(s,1H),7.92(s,1H),7.31(dd,1H),6.42(d, 1H), 6.40(s,1H), 2.08(s,3H), 1.59(d,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

HPLC chiral analysis method:

实施例51Example 51
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-(2-羟基丙烷-2-基)噻唑-2-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)- 5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
参照实施例9的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-(2-羟基丙烷-2-基)噻唑-2-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮51。Referring to the synthetic method of Example 9, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-(2-hydroxypropane) was synthesized -2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 51.
MS m/z(ESI):521.1[M+H]+；MS m/z(ESI):521.1[M+H] + ;
实施例51的拆分Splitting of Example 51
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-(2-羟基丙烷-2-基)噻唑-2-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-(2-羟基丙烷-2-基)噻唑-2-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-(2-hydroxypropan-2-yl)thiazole-2 -yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoropyridine-2 -yl)methoxy-d2)-2'-(4-(2-hydroxypropan-2-yl)thiazol-2-yl)-5',6-dimethyl-2H-[1,4'- Bipyridyl]-2-one
实施例51(58mg,0.111mmol)经手性拆分(OD柱)得到标题产物51-1(21mg，R.T＝4.653min)，产率：36.2％；51-2(22.4mg，R.T＝6.000min)，产率：38.6％。Example 51 (58 mg, 0.111 mmol) was subjected to chiral resolution (OD column) to obtain the title product 51-1 (21 mg, R.T = 4.653 min), yield: 36.2%; 51-2 (22.4 mg, R. T = 6.000 min) , Yield: 38.6%.
实施例51-1，MS m/z(ESI):521.1[M+H]+；Embodiment 51-1, MS m/z (ESI): 521.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.60(d,1H),8.13-8.08(m,1H),8.01(s,1H),7.54(s,1H),6.81(d,1H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.72(s,1H),8.60(d,1H),8.13-8.08(m,1H),8.01(s,1H),7.54(s,1H), 6.81(d,1H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H).
实施例51-2，MS m/z(ESI):521.1[M+H]+； Embodiment 51-2, MS m/z (ESI): 521.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.60(d,1H),8.13-8.08(m,1H),8.01(s,1H),7.54(s,1H),6.81(d,1H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.72(s,1H),8.60(d,1H),8.13-8.08(m,1H),8.01(s,1H),7.54(s,1H), 6.81(d,1H),5.22(s,1H),2.05(s,3H),1.99(s,3H),1.50(s,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例52Example 52
5-氯-6-((3,5-二氟吡啶-2-基)甲氧基)-3-(2-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5-甲基吡啶-4-基)-2-甲基嘧啶-4(3H)-酮

5-Chloro-6-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)- 5-methylpyridin-4-yl)-2-methylpyrimidin-4(3H)-one

第一步first step
氮气保护下，将2-氯-4-碘-5-甲基吡啶52a(2.5g，9.86mmol)，盐酸乙脒(1.86g，19.7mmol)，碘化亚铜(188mg，0.986mmol)和碳酸铯(9.64g，29.6mmol)溶于N,N-二甲基甲酰胺(15mL)中。反应加热至100℃搅拌16小时。向反应液加入乙腈(40mL)，经硅藻土过滤后，滤液浓缩。残留物用制备型硅胶色谱板纯化(洗脱体系A)得产物N-(2-氯-5-甲基吡啶-4-基)乙酰脒52b(650mg)，产率：36％Under nitrogen protection, 2-chloro-4-iodo-5-methylpyridine 52a (2.5g, 9.86mmol), acetamidine hydrochloride (1.86g, 19.7mmol), cuprous iodide (188mg, 0.986mmol) and carbonic acid Cesium (9.64 g, 29.6 mmol) was dissolved in N,N-dimethylformamide (15 mL). The reaction was heated to 100°C and stirred for 16 hours. Acetonitrile (40 mL) was added to the reaction solution, and after filtration through celite, the filtrate was concentrated. The residue was purified by preparative silica gel chromatography (elution system A) to obtain the product N-(2-chloro-5-methylpyridin-4-yl)acetamidine 52b (650mg), yield: 36%
MS m/z(ESI):184.0[M+1]+.MS m/z(ESI):184.0[M+1] + .
第二步second step
将52b(300mg，1.63mmol)、二(2,4,6-三氯苯基)丙二酸酯(832mg，1.8mmol)溶于四氢呋喃(8mL)中。反应液加热至90℃搅拌8小时。反应液浓缩，残余物用硅胶柱色谱(洗脱剂体系A)分离，得到产物3-(2-氯-5-甲基吡啶-4-基)-6-羟基-2-甲基嘧啶-4(3H)-酮52c(180mg)，产率：44％。52b (300 mg, 1.63 mmol), bis(2,4,6-trichlorophenyl)malonate (832 mg, 1.8 mmol) were dissolved in tetrahydrofuran (8 mL). The reaction solution was heated to 90°C and stirred for 8 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 3-(2-chloro-5-methylpyridin-4-yl)-6-hydroxyl-2-methylpyrimidine-4 (3H)-Kone 52c (180 mg), Yield: 44%.
MS m/z(ESI):252.0[M+1]+.MS m/z(ESI):252.0[M+1] + .
第三步third step
将52c(180mg，0.715mmol)，2-(氯甲基)-3,5-二氟吡啶(175mg，1.07mmol)，碳酸钾(247mg，1.79mmol)和18-冠-6醚(189mg，0.715mmol)溶解在N,N-二甲基甲酰胺(4mL)中。反应加热至70℃搅拌3小时。向反应液中加入乙酸乙酯(10mL)，有机相用水洗涤3次，干燥，浓缩。残余物用硅胶柱色谱(洗脱剂体系B)分离得到产物3-(2-氯-5-甲基吡啶-4-基)-6-((3,5-二氟吡啶-2-基)甲氧基)-2-甲基嘧啶-4(3H)-酮52d(190mg)，产率：70％。52c (180mg, 0.715mmol), 2-(chloromethyl)-3,5-difluoropyridine (175mg, 1.07mmol), potassium carbonate (247mg, 1.79mmol) and 18-crown-6 ether (189mg, 0.715 mmol) was dissolved in N,N-dimethylformamide (4 mL). The reaction was heated to 70°C and stirred for 3 hours. Ethyl acetate (10 mL) was added to the reaction solution, and the organic phase was washed with water three times, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to obtain the product 3-(2-chloro-5-methylpyridin-4-yl)-6-((3,5-difluoropyridin-2-yl) Methoxy)-2-methylpyrimidin-4(3H)-one 52d (190 mg), yield: 70%.
MS m/z(ESI):379.0[M+H]+.MS m/z(ESI):379.0[M+H] + .
第四步the fourth step
将52d(100mg,0.264mmol)和N-氯代丁二酰亚胺(39mg,0.29mmol)溶解于异丙醇(3mL)中，反应加热至60℃搅拌6小时。冷却至室温，反应液浓 缩，残余物用硅胶柱色谱(洗脱剂体系A)分离得到产物5-氯-3-(2-氯-5-甲基吡啶-4-基)-6-((3,5-二氟吡啶-2-基)甲氧基)-2-甲基嘧啶-4(3H)-酮52e(80mg)，产率：73％。52d (100 mg, 0.264 mmol) and N-chlorosuccinimide (39 mg, 0.29 mmol) were dissolved in isopropanol (3 mL), and the reaction was heated to 60° C. and stirred for 6 hours. Cool to room temperature, the reaction solution is concentrated and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 5-chloro-3-(2-chloro-5-methylpyridin-4-yl)-6-((3,5-difluoro Pyridin-2-yl)methoxy)-2-methylpyrimidin-4(3H)-one 52e (80 mg), yield: 73%.
MS m/z(ESI):413.0[M+H]+.MS m/z(ESI):413.0[M+H] + .
第五步the fifth step
氮气保护下，将52e(80mg，0.194mmol)，中间体5(91mg，0.484mmol)，1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(16mg，0.019mmol)和碳酸铯(126mg，0.387mmol)溶于1，4-二氧六环/水(V:V＝10:1,1mL)中，将反应加热至100℃搅拌3小时。向反应液加入饱和氯化钠(10mL)，水相用乙酸乙酯(10mL×3)萃取。有机相合并，干燥，浓缩。残余物用硅胶柱色谱(洗脱剂体系B)分离，得到标题产物5-氯-6-((3,5-二氟吡啶-2-基)甲氧基)-3-(2-(2-(2-羟基丙烷-2-基)噻唑-4-基)-5-甲基吡啶-4-基)-2-甲基嘧啶-4(3H)-酮52(70mg)，产率：70％。Under nitrogen protection, 52e (80mg, 0.194mmol), intermediate 5 (91mg, 0.484mmol), 1,1-bis(diphenylphosphine)ferrocenedichloropalladium dichloromethane complex (16mg, 0.019 mmol) and cesium carbonate (126 mg, 0.387 mmol) were dissolved in 1,4-dioxane/water (V:V=10:1, 1 mL), and the reaction was heated to 100°C and stirred for 3 hours. Saturated sodium chloride (10 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give the title product 5-chloro-6-((3,5-difluoropyridin-2-yl)methoxy)-3-(2-(2 -(2-Hydroxypropan-2-yl)thiazol-4-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4(3H)-one 52 (70 mg), yield: 70 %.
MS m/z(ESI):520.0[M+1]+.MS m/z(ESI):520.0[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.58(d,1H),8.17(s,1H),8.09(s,1H),8.07–8.02(m,1H),6.07(s,1H),5.61(m,2H),2.12(s,3H),2.08(s,3H),1.56(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.71(s,1H),8.58(d,1H),8.17(s,1H),8.09(s,1H),8.07–8.02(m,1H), 6.07(s,1H),5.61(m,2H),2.12(s,3H),2.08(s,3H),1.56(d,6H).
实施例53Example 53
3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-4-methyl -1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridine]-2-one
第一步first step
氮气保护下，将4-甲基-1H-吡唑-3-甲酸乙酯53a(2.5g,16.2mmol)溶于四氢呋喃(25mL)中。冰浴下，搅拌下向反应液中滴加甲基溴化镁(3M,16.2mL)。反 应升温至室温后继续搅拌1小时。反应液用饱和氯化铵淬灭后，减压浓缩至一半体积，乙酸乙酯萃取，水层用乙酸乙酯再萃取一次。有机相合并，用饱和食盐水洗涤，干燥，浓缩，得产物2-(4-甲基-1H-吡唑-3-基)丙-2-醇53b(1.89g)，产物无需纯化，直接用于下步反应。Under nitrogen protection, ethyl 4-methyl-1H-pyrazole-3-carboxylate 53a (2.5 g, 16.2 mmol) was dissolved in tetrahydrofuran (25 mL). Under ice cooling, methylmagnesium bromide (3M, 16.2 mL) was added dropwise to the reaction solution with stirring. opposite Stirring was continued for 1 hour after warming to room temperature. The reaction solution was quenched with saturated ammonium chloride, concentrated under reduced pressure to half volume, extracted with ethyl acetate, and the aqueous layer was extracted once more with ethyl acetate. The organic phases were combined, washed with saturated brine, dried, and concentrated to obtain the product 2-(4-methyl-1H-pyrazol-3-yl)propan-2-ol 53b (1.89g), which was directly used without purification react in the next step.
MS m/z(ESI):141.1[M+H]+.MS m/z(ESI):141.1[M+H] + .
第二步second step
将49a(500mg,1.64mmol)，2-(4-甲基-1H-吡唑-3-基)丙-2-醇53b(344mg,2.45mmol)和碳酸铯(1.07g,3.27mmol)溶于二甲亚砜(7mL)中，加热至110℃搅拌14小时。反应液经反相HPLC(甲酸体系)纯化得产物3,5'-二氯-4-羟基-2'-(3-(2-羟基丙-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮53c(460mg)，产率：69％。49a (500 mg, 1.64 mmol), 2-(4-methyl-1H-pyrazol-3-yl)propan-2-ol 53b (344 mg, 2.45 mmol) and cesium carbonate (1.07 g, 3.27 mmol) were dissolved in Dimethylsulfoxide (7 mL), heated to 110°C and stirred for 14 hours. The reaction solution was purified by reverse-phase HPLC (formic acid system) to obtain the product 3,5'-dichloro-4-hydroxy-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyridine Azol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 53c (460 mg), yield: 69%.
MS m/z(ESI):409.1[M+H]+.MS m/z(ESI):409.1[M+H] + .
第三步third step
将,5'-二氯-4-羟基-2'-(3-(2-羟基丙-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮53c(80mg,0.196mmol)，2-(氯甲基)-3,5-二氟-吡啶(64mg,0.391mmol)，碳酸钾(81mg,0.586mmol)和18-冠醚-6(77mg,0.293mmol)溶于N,N-二甲基甲酰胺(1.5mL)中。反应加热至70℃搅拌3小时。反应液经反相HPLC(甲酸体系)纯化得标题产物3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮53(70mg)，产率：67％。Will,5'-dichloro-4-hydroxy-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H -[1,4'-bipyridine]-2-one 53c (80mg, 0.196mmol), 2-(chloromethyl)-3,5-difluoro-pyridine (64mg, 0.391mmol), potassium carbonate (81mg, 0.586mmol) and 18-crown-6 (77mg, 0.293mmol) were dissolved in N,N-dimethylformamide (1.5mL). The reaction was heated to 70°C and stirred for 3 hours. The reaction solution was purified by reverse-phase HPLC (formic acid system) to obtain the title product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-( 2-Hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 53 (70 mg), Yield: 67%.
MS m/z(ESI):537.1[M+H]+.MS m/z(ESI):537.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.40(d,1H),8.23(s,1H),7.86(s,1H),7.36–7.28(m,1H),6.40(s,1H),5.41(s,2H),2.22(s,3H),2.07(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 ) δ8.51(s, 1H), 8.40(d, 1H), 8.23(s, 1H), 7.86(s, 1H), 7.36–7.28(m, 1H), 6.40( s,1H),5.41(s,2H),2.22(s,3H),2.07(s,3H),1.59(d,6H).
实施例53的拆分Splitting of Example 53
(S)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)- 4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one and (R)-3,5'-dichloro-4- ((3,5-difluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl) -6-Methyl-2H-[1,4'-bipyridyl]-2-one
实施例53(65mg，0.121mmol)经手性拆分(OD柱)得到53-1(30mg，R.T＝3.160min)产率：46％；53-2(30mg，R.T＝5.810min)，产率：46％。Example 53 (65mg, 0.121mmol) was obtained by chiral resolution (OD column) to obtain 53-1 (30mg, R.T=3.160min) yield: 46%; 53-2 (30mg, R.T=5.810min), yield: 46%.
实施例53-1：MS m/z(ESI):537.1[M+H]+；Example 53-1: MS m/z (ESI): 537.1[M+H] + ;
实施例53-2：MS m/z(ESI):537.1[M+H]+；Example 53-2: MS m/z (ESI): 537.1[M+H] + ;
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例54Example 54
3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
3,5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-4 -Methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one
参照实施例53的合成方法，合成得到目标产物3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮54。Referring to the synthesis method of Example 53, the target product 3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3- (2-Hydroxypropan-2-yl)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 54.
MS m/z(ESI):538.1[M+H]+.MS m/z(ESI):538.1[M+H] + .
实施例54的拆分Splitting of Example 54
(S)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-4-甲基-1H-吡唑-1-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropane-2- Base)-4-methyl-1H-pyrazol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one and (R)-3,5'-dichloro -4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyridine Azol-1-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one
实施例54(80mg，0.148mmol)经手性拆分(OD柱)得到54-1(31mg，R.T＝3.160min)，产率：39％；54-2(30mg，R.T＝5.823min)，产率：38％。Example 54 (80mg, 0.148mmol) was subjected to chiral resolution (OD column) to obtain 54-1 (31mg, R.T=3.160min), yield: 39%; 54-2 (30mg, R.T=5.823min), yield : 38%.
实施例54-1：MS m/z(ESI):538.1[M+H]+；Example 54-1: MS m/z (ESI): 538.1[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.40(d,1H),8.23(d,1H),7.84(s,1H),7.32(ddd,1H),6.40(d,1H),2.22(s,3H),2.07(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.51(s,1H),8.40(d,1H),8.23(d,1H),7.84(s,1H),7.32(ddd,1H),6.40(d, 1H), 2.22(s,3H), 2.07(s,3H), 1.59(d,6H).
实施例54-2：MS m/z(ESI):538.1[M+H]+；Example 54-2: MS m/z (ESI): 538.1[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.40(s,1H),8.23(s,1H),7.85(s,1H),7.32(t,1H),6.40(s,1H),2.22(s,3H),2.07(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.51(s,1H),8.40(s,1H),8.23(s,1H),7.85(s,1H),7.32(t,1H),6.40(s, 1H), 2.22(s,3H), 2.07(s,3H), 1.59(d,6H).
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例55Example 55
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-氟-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-fluoro-2'-(2-(2-hydroxypropan-2-yl)thiazole-4- Base)-6-methyl-2H-[1,4'-bipyridine]-2-one
第一步first step
将2-氯-5-氟-吡啶-4-胺55a(500mg,3.41mmol)和2,2-二甲基-6-(2-羰基丙基)-4H-1,3-二噁英-4-酮(1.26g,6.82mmol)溶解在1，4-二氧六环(5mL)中的反应液放置于预热至95℃的油浴中搅拌2小时。向反应液中加入浓硫酸(569mg,5.80mmol,0.309mL)，反应继续在95℃下搅拌1小时。反应液冷却，移除上层有机相。向下层油状物加入水，超声震荡后析出固体，过滤后得到2'-氯-5'- 氟-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮55b(0.38g)，产物不经纯化直接用于下一步反应。2-Chloro-5-fluoro-pyridin-4-amine 55a (500 mg, 3.41 mmol) and 2,2-dimethyl-6-(2-carbonylpropyl)-4H-1,3-dioxin- The reaction solution in which 4-ketone (1.26 g, 6.82 mmol) was dissolved in 1,4-dioxane (5 mL) was placed in an oil bath preheated to 95°C and stirred for 2 hours. Concentrated sulfuric acid (569mg, 5.80mmol, 0.309mL) was added to the reaction solution, and the reaction was continued to stir at 95°C for 1 hour. The reaction solution was cooled, and the upper organic phase was removed. Add water to the oil in the lower layer, precipitate a solid after ultrasonic vibration, and obtain 2'-chloro-5'- Fluoro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 55b (0.38g), the product was directly used in the next reaction without purification.
MS m/z(ESI):255.0[M+1]+.MS m/z(ESI):255.0[M+1] + .
第二步second step
将2'-氯-5'-氟-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮55b(0.38g,1.49mmol)溶解在异丙醇(4mL)和1,2-二氯乙烷(6mL)的混合液中加热至60℃搅拌10分钟。搅拌下向反应液中分批加入N-氯代丁二酰胺(239.12mg,1.79mmol)，反应在60℃下搅拌1小时。浓缩反应液，向残余物中加入异丙醇(4mL)，超声下析出固体后，加热至50℃搅拌1小时。冷却反应液至室温，过滤反应液得到2',3-二氯-5'-氟-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮55c(420mg)，产物不经纯化直接用于下一步反应。2'-Chloro-5'-fluoro-4-hydroxy-6-methyl-2H-[1,4'-bipyridyl]-2-one 55b (0.38g, 1.49mmol) was dissolved in isopropanol (4mL ) and 1,2-dichloroethane (6 mL) were heated to 60°C and stirred for 10 minutes. N-chlorosuccinamide (239.12mg, 1.79mmol) was added in batches to the reaction solution with stirring, and the reaction was stirred at 60°C for 1 hour. The reaction solution was concentrated, and isopropanol (4 mL) was added to the residue. After the solid was precipitated under ultrasound, the mixture was heated to 50° C. and stirred for 1 hour. Cool the reaction solution to room temperature, filter the reaction solution to obtain 2',3-dichloro-5'-fluoro-4-hydroxy-6-methyl-2H-[1,4'-bipyridine]-2-one 55c (420mg ), the product was directly used in the next reaction without purification.
MS m/z(ESI):299.2[M+1]+.MS m/z(ESI):299.2[M+1] + .
第三步third step
将2',3-二氯-5'-氟-4-羟基-6-甲基-2H-[1,4'-联吡啶]-2-酮55c(150mg,0.519mmol)，碳酸钾(179mg,1.30mmol)和18-冠-6醚(206mg,0.778mmol)溶解在N,N-二甲基甲酰胺(10mL)中加热至70℃搅拌10分钟。向反应液中滴加2-(氯甲基)-3,5-二氟吡啶(119mg,0.726mmol)，并在70℃下搅拌3小时。向反应液中加入乙酸乙酯(50mL)，有机相用水(10mL×2)和饱和氯化铵(10mL)洗涤，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系B)分离得到2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-氟-6-甲基-2H-[1,4'-联吡啶]-2-酮55d(150mg)，产率：69.46％。2',3-dichloro-5'-fluoro-4-hydroxy-6-methyl-2H-[1,4'-bipyridine]-2-one 55c (150mg, 0.519mmol), potassium carbonate (179mg , 1.30mmol) and 18-crown-6 ether (206mg, 0.778mmol) were dissolved in N,N-dimethylformamide (10mL) and heated to 70°C and stirred for 10 minutes. 2-(Chloromethyl)-3,5-difluoropyridine (119 mg, 0.726 mmol) was added dropwise to the reaction solution, followed by stirring at 70°C for 3 hours. Ethyl acetate (50 mL) was added to the reaction solution, and the organic phase was washed with water (10 mL×2) and saturated ammonium chloride (10 mL), dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to give 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-fluoro- 6-Methyl-2H-[1,4'-bipyridyl]-2-one 55d (150 mg), yield: 69.46%.
MS m/z(ESI):416.0[M+1]+.MS m/z(ESI):416.0[M+1] + .
第四步the fourth step
氮气保护下，将2',3-二氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-氟-6-甲基-2H-[1,4'-联吡啶]-2-酮55d(70mg,0.168mmol)，中间体5(47mg,0.252mmol)，1,1-双(二苯基膦)1,1'-双二苯基膦二茂铁二氯化钯(12mg,17mmol)和碳酸铯(110mg,0.336mmol)溶解在1,4-二氧六环(1mL)中，加热至100℃搅拌2小时。过滤反应液，滤饼用乙酸乙酯洗涤，滤液浓缩。残余物用硅胶柱色谱法(洗脱剂体系A)分离得到3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'-氟-2'-(2-(2-羟基丙烷-2-基)噻唑-4-基)-6-甲基-2H-[1,4'-联吡啶]-2-酮55(60mg)产率：68.22％。Under nitrogen protection, 2',3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-fluoro-6-methyl-2H-[1,4 '-bipyridyl]-2-one 55d (70mg, 0.168mmol), intermediate 5 (47mg, 0.252mmol), 1,1-bis(diphenylphosphine) 1,1'-bisdiphenylphosphine Iron palladium dichloride (12mg, 17mmol) and cesium carbonate (110mg, 0.336mmol) were dissolved in 1,4-dioxane (1mL), heated to 100°C and stirred for 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5'-fluoro-2'-( 2-(2-Hydroxypropan-2-yl)thiazol-4-yl)-6-methyl-2H-[1,4'-bipyridyl]-2-one 55 (60 mg) Yield: 68.22%.
MS m/z(ESI):523.1[M+1]+.MS m/z(ESI):523.1[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.60(d,1H),8.18(s,1H),8.16(d,1H),8.13–8.06(m,1H),6.82(s,1H),6.08(s,1H),5.51(s,2H),2.08(s,3H),1.56(d,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.89(s,1H),8.60(d,1H),8.18(s,1H),8.16(d,1H),8.13–8.06(m,1H), 6.82(s,1H),6.08(s,1H),5.51(s,2H),2.08(s,3H),1.56(d,6H).
实施例56 Example 56
N-(2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)丙烷-2-基)乙酰胺
N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H -[1,4'-bipyridine]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide
第一步first step
将2-(4-溴噻唑-2-基)丙烷-2-醇5C(440mg,1.98mmol)和乙腈(488mg,11.89mmol)溶解于醋酸(952mg,15.85mmol)中搅拌，0℃下向以上反应液中滴加浓硫酸(1.75g,17.83mmol)，反应升温至20℃搅拌16小时。冷却到0℃下向反应液中加入饱和碳酸氢钠溶液(40mL)，水相用乙酸乙酯(25mL×3)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到N-(2-(4-溴噻唑-2-基)丙烷-2-基)乙酰胺56a(434mg)，产率：83.25％。Dissolve 2-(4-bromothiazol-2-yl)propan-2-ol 5C (440mg, 1.98mmol) and acetonitrile (488mg, 11.89mmol) in acetic acid (952mg, 15.85mmol) and stir at 0°C Concentrated sulfuric acid (1.75 g, 17.83 mmol) was added dropwise to the reaction solution, and the reaction temperature was raised to 20° C. and stirred for 16 hours. After cooling to 0°C, saturated sodium bicarbonate solution (40 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (25 mL×3), the organic phases were combined, dried, concentrated, and the residue was subjected to silica gel column chromatography (eluted System B) N-(2-(4-bromothiazol-2-yl)propan-2-yl)acetamide 56a (434 mg) was isolated, yield: 83.25%.
MS m/z(ESI):263.0[M+H]+；MS m/z(ESI):263.0[M+H] + ;
第二步second step
氮气保护下，将N-(2-(4-溴噻唑-2-基)丙烷-2-基)乙酰胺56a(100mg,0.38mmol)，联硼酸频那醇酯(106mg,0.418mmol)，三(二亚苄基丙酮)二钯(17mg,0.019mmol)，2-二环己基膦-2’,4’,6’-三异丙基联苯(22mg,0.046mmol)和醋酸钾(112mg,1.14mmol)溶解于1，4-二氧六环(2mL)中，反应加热至100℃，搅拌1小时。反应液过滤，滤液浓缩得到粗产物(2-(2-乙酰氨基丙烷-2-基)噻唑-4-基)硼酸56b(83mg)，不经进一步纯化，直接用于下一步反应中。Under nitrogen protection, N-(2-(4-bromothiazol-2-yl)propan-2-yl)acetamide 56a (100mg, 0.38mmol), pinacol diborate (106mg, 0.418mmol), three (Dibenzylideneacetone) dipalladium (17mg, 0.019mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (22mg, 0.046mmol) and potassium acetate (112mg, 1.14 mmol) was dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100° C. and stirred for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product (2-(2-acetylaminopropan-2-yl)thiazol-4-yl)boronic acid 56b (83 mg), which was directly used in the next reaction without further purification.
MS m/z(ESI):229.1[M+H]+；MS m/z(ESI):229.1[M+H] + ;
第三步third step
氮气保护下，将(2-(2-乙酰氨基丙烷-2-基)噻唑-4-基)硼酸56b(83mg,0.362mmol)，48a(100mg,0.241mmol)，1,1-双(二苯基膦)二茂铁二氯化钯(18 mg,0.024mmol)和碳酸铯(157mg,0.483mmol)溶解于1，4-二氧六环(1.5mL)和水(0.5mL)的混合溶剂中，反应加热至100℃搅拌1.5小时。反应液浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到N-(2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)丙烷-2-基)乙酰胺56(103mg)，产率：75.91％。Under nitrogen protection, (2-(2-acetylaminopropan-2-yl)thiazol-4-yl)boronic acid 56b (83mg, 0.362mmol), 48a (100mg, 0.241mmol), 1,1-bis(diphenyl Phosphine) ferrocene palladium dichloride (18 mg, 0.024mmol) and cesium carbonate (157mg, 0.483mmol) were dissolved in a mixed solvent of 1,4-dioxane (1.5mL) and water (0.5mL), and the reaction was heated to 100°C and stirred for 1.5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy) Base-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide 56 (103 mg), yield: 75.91%.
MS m/z(ESI):562.2[M+H]+；MS m/z(ESI):562.2[M+H] + ;
实施例56的拆分Splitting of Example 56
(S)-N-(2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)丙烷-2-基)乙酰胺和(R)-N-(2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)丙烷-2-基)乙酰胺(S)-N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2 -carbonyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide and (R)-N-(2-(4-(3- Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]- 2'-yl)thiazol-2-yl)propan-2-yl)acetamide
实施例56(103mg,0.183mmol)经手性拆分(AD柱)得到标题产物56-1(44.3mg，R.T＝4.643min)，产率：43.01％；56-2(42.4mg，R.T＝5.823min)，产率：41.17％。Example 56 (103mg, 0.183mmol) was subjected to chiral resolution (AD column) to obtain the title product 56-1 (44.3mg, R.T=4.643min), yield: 43.01%; 56-2 (42.4mg, R.T=5.823min ), yield: 41.17%.
实施例56-1，MS m/z(ESI):562.1[M+H]+；Embodiment 56-1, MS m/z (ESI): 562.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.14-8.07(m,1H),7.85(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.14-8.07(m,1H), 7.85(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63(s,3H).
实施例56-2，MS m/z(ESI):562.1[M+H]+；Embodiment 56-2, MS m/z (ESI): 562.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.14-8.07(m,1H),7.85(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.14-8.07(m,1H), 7.85(s,1H),6.81(s,1H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例57Example 57
3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-4-((3-甲氧苄基)氧代)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-4-((3-methoxybenzyl)oxo)-5',6 -Dimethyl-2H-[1,4'-bipyridyl]-2-one
第一步first step
氮气保护下，将11e(800mg，2.43mmol)，2-(1H-吡唑-3-基)丙烷-2-醇(459mg，3.64mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(69mg，0.49mmol)，碳酸铯(1.18g，3.64mmol)，和碘化亚铜(46mg，0.24mmol)溶解到二氧六环(5mL)中，加热至100℃搅拌3小时。将反应液过滤，滤液用甲酸调节pH值到3，反应液浓缩，残余物用Prep-HPLC色谱法(甲酸体系)分离得到标题产物3-氯-4-羟基-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮57a(580mg)，产率：63.8％。Under nitrogen protection, 11e (800mg, 2.43mmol), 2-(1H-pyrazol-3-yl)propan-2-ol (459mg, 3.64mmol), (1S,2S)-N1,N2-dimethyl Cyclohexane-1,2-diamine (69 mg, 0.49 mmol), cesium carbonate (1.18 g, 3.64 mmol), and cuprous iodide (46 mg, 0.24 mmol) were dissolved in dioxane (5 mL) and heated Stir at 100°C for 3 hours. The reaction solution was filtered, the filtrate was adjusted to pH 3 with formic acid, the reaction solution was concentrated, and the residue was separated by Prep-HPLC chromatography (formic acid system) to obtain the title product 3-chloro-4-hydroxyl-2'-(3-(2 -Hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 57a (580 mg), yield : 63.8%.
MS m/z(ESI):375.2[M+H]+.MS m/z(ESI):375.2[M+H] + .
第二步second step
将3-氯-4-羟基-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮57a(50mg，0.13mmol)，1-(氯甲基)-3-甲氧基苯(42mg，0.27 mmol)，18-冠醚-6(35mg，0.13mmol)，碳酸钾(27mg，0.20mmol)溶解到N,N-二甲基甲酰胺(2mL)中。反应加热至60℃搅拌16小时。将反应液浓缩，残余物用Prep-HPLC色谱法(洗脱剂体系A)分离得到标题产物3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-4-((3-甲氧基苄基)氧代)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮57(20mg)，产率：30.3％。3-chloro-4-hydroxyl-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1, 4'-bipyridyl]-2-one 57a (50mg, 0.13mmol), 1-(chloromethyl)-3-methoxybenzene (42mg, 0.27 mmol), 18-crown-6 (35 mg, 0.13 mmol), potassium carbonate (27 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL). The reaction was heated to 60°C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by Prep-HPLC chromatography (eluent system A) to obtain the title product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole- 1-yl)-4-((3-methoxybenzyl)oxo)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 57 (20mg), Yield: 30.3%.
MS m/z(ESI):495.2[M+H]+.MS m/z(ESI):495.2[M+H] + .
1H NMR(400MHz,CDCl3)δ8.48(d,1H),8.40(s,1H),7.77(s,1H),7.34(t,1H),7.00(m,2H),6.91(dd,1H),6.39(d,1H),6.14(s,1H),5.27(s,2H),3.85(s,3H),2.10(s,3H),2.00(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.48(d,1H),8.40(s,1H),7.77(s,1H),7.34(t,1H),7.00(m,2H),6.91(dd, 1H),6.39(d,1H),6.14(s,1H),5.27(s,2H),3.85(s,3H),2.10(s,3H),2.00(s,3H),1.59(d,6H ).
实施例58Example 58
3-氯-4-((2,4-二氟苄基)氧代)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((2,4-difluorobenzyl)oxo)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-4-((2,4-二氟苄基)氧代)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮58。Referring to the synthesis method of Example 57, the target product 3-chloro-4-((2,4-difluorobenzyl) oxo)-2'-(3-(2-hydroxypropan-2-yl)- 1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 58.
MS m/z(ESI):501.1[M+H]+.MS m/z(ESI):501.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.50(s,1H),8.42(s,1H),7.79(s,1H),7.58(t,1H),6.99(t,1H),6.90(m,1H),6.40(d,1H),6.20(s,1H),5.28(s,2H),2.11(s,3H),2.04(s,3H),1.60(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.50(s,1H),8.42(s,1H),7.79(s,1H),7.58(t,1H),6.99(t,1H),6.90(m, 1H), 6.40(d,1H), 6.20(s,1H), 5.28(s,2H), 2.11(s,3H), 2.04(s,3H), 1.60(d,6H).
实施例59Example 59
3-氯-4-((3,5-二氯吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-dichloropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl )-5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-4-((3,5-二氯吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮59。Referring to the synthesis method of Example 57, the target product 3-chloro-4-((3,5-dichloropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropane-2 -yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 59.
MS m/z(ESI):534.1[M+H]+.MS m/z(ESI):534.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.50(m,2H),8.41(s,1H),7.80(m,2H),6.41(s,1H),6.31(s,1H),5.46(s,2H),2.11(s,3H),2.03(s,3H),1.60(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.50(m,2H),8.41(s,1H),7.80(m,2H),6.41(s,1H),6.31(s,1H),5.46(s, 2H), 2.11(s,3H), 2.03(s,3H), 1.60(d,6H).
实施例60Example 60
3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((3-(三氟甲基)苯甲基)氧代)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((3-(trifluoromethyl Base) benzyl) oxo) -2H-[1,4'-bipyridyl] -2-one
参照实施例57的合成方法，合成得到目标产物3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((3-(三氟甲基)苯甲基)氧代)-2H-[1,4'-联吡啶]-2-酮60。Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized yl-4-((3-(trifluoromethyl)benzyl)oxo)-2H-[1,4'-bipyridyl]-2-one 60.
MS m/z(ESI):533.1[M+1]+.MS m/z(ESI):533.1[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.51(d,1H),7.88(s,1H),7.81(d,1H),7.77(s,2H),7.72(d,1H),6.75(s,1H),6.56(d,1H),5.48(s,2H),5.07(s,1H),2.00(s,6H),1.47(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.54(s,1H),8.51(d,1H),7.88(s,1H),7.81(d,1H),7.77(s,2H),7.72( d,1H),6.75(s,1H),6.56(d,1H),5.48(s,2H),5.07(s,1H),2.00(s,6H),1.47(s,6H).
实施例61Example 61
3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((1-甲基-1H-吡唑-3-基)甲氧基)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((1-methyl-1H -pyrazol-3-yl)methoxy)-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((1-甲基-1H-吡唑-3-基)甲氧基)-2H-[1,4'-联吡啶]-2-酮61。Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized Base-4-((1-methyl-1H-pyrazol-3-yl)methoxy)-2H-[1,4'-bipyridyl]-2-one 61.
MS m/z(ESI):469.2[M+H]+. MS m/z(ESI):469.2[M+H] + .
1H NMR(400MHz,CDCl3)δ8.43(d,2H),7.74(s,1H),7.39(s,1H),6.38(m,3H),5.30(s,2H),3.94(s,3H),2.09(s,3H),2.01(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.43(d,2H),7.74(s,1H),7.39(s,1H),6.38(m,3H),5.30(s,2H),3.94(s, 3H), 2.09(s,3H), 2.01(s,3H), 1.59(d,6H).
实施例62Example 62
3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((2,4,5-三氟苄基)氧代)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,5- Trifluorobenzyl)oxo)-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((2,4,5-三氟苄基)氧代)-2H-[1,4'-联吡啶]-2-酮62。Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized yl-4-((2,4,5-trifluorobenzyl)oxo)-2H-[1,4'-bipyridyl]-2-one 62.
MS m/z(ESI):519.1[M+H]+.MS m/z(ESI):519.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.44(d,2H),7.76(s,1H),7.47(d,1H),7.01(d,1H),6.39(s,1H),6.16(s,1H),5.25(s,2H),2.11(s,3H),2.04(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.44(d,2H),7.76(s,1H),7.47(d,1H),7.01(d,1H),6.39(s,1H),6.16(s, 1H), 5.25(s, 2H), 2.11(s, 3H), 2.04(s, 3H), 1.59(d, 6H).
实施例63Example 63
3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((2,3,4-三氟苄基)氧代)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,3,4- Trifluorobenzyl)oxo)-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((2,3,4-三氟苄基)氧代)-2H-[1,4'-联吡啶]-2-酮63。Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized yl-4-((2,3,4-trifluorobenzyl)oxo)-2H-[1,4'-bipyridyl]-2-one 63.
MS m/z(ESI):519.1[M+H]+.MS m/z(ESI):519.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.44(d,2H),7.75(s,1H),7.35(d,1H),7.08(d,1H),6.39(s,1H),6.18(s,1H),5.29(s,2H),2.10(s,3H),2.04(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.44(d,2H),7.75(s,1H),7.35(d,1H),7.08(d,1H),6.39(s,1H),6.18(s, 1H), 5.29(s, 2H), 2.10(s, 3H), 2.04(s, 3H), 1.59(d, 6H).
实施例64Example 64
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-4-甲基-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl- 1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例48的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-4-甲基-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮64。Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxyl Propan-2-yl)-4-methyl-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 64.
MS m/z(ESI):518.1[M+H]+.MS m/z(ESI):518.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.40(d,1H),8.37(s,1H),8.25(s,1H),7.68(s,1H),7.35–7.29(m,1H),6.39(s,1H),2.21(s,3H),2.08(s,3H),2.03(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.40(d,1H),8.37(s,1H),8.25(s,1H),7.68(s,1H),7.35–7.29(m,1H),6.39( s,1H),2.21(s,3H),2.08(s,3H),2.03(s,3H),1.59(d,6H).
实施例64的拆分Splitting of Example 64
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-4-甲基-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-4-甲基-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-4 -Methyl-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one and (R)-3-chloro-4-( (3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-4-methyl-1H-pyrazole-1- base)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
实施例64(25mg，0.048mmol)经手性拆分(OD柱)得到64-1(11mg，R.T＝3.107min)，产率：44％；64-2(12mg，R.T＝4.890min)，产率：48％。Example 64 (25mg, 0.048mmol) was resolved by chiral resolution (OD column) to obtain 64-1 (11mg, R.T=3.107min), yield: 44%; 64-2 (12mg, R.T=4.890min), yield : 48%.
实施例64-1：MS m/z(ESI):518.1[M+H]+；Embodiment 64-1: MS m/z (ESI): 518.1 [M+H] + ;
实施例64-2：MS m/z(ESI):518.1[M+H]+；Embodiment 64-2: MS m/z (ESI): 518.1[M+H] + ;
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例66Example 66
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(3-羟基戊烷-3-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentan-3-yl)-1H-pyrazole- 1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例48的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(3-羟基戊烷-3-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮66。Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentyl) was synthesized Alk-3-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 66.
MS m/z(ESI):532.2[M+H]+.MS m/z(ESI):532.2[M+H] + .
实施例66的拆分Splitting of Example 66
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(3-羟基戊烷-3-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(3-羟基戊烷-3-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentan-3-yl)-1H -pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5- Difluoropyridin-2-yl)methoxy-d2)-2'-(3-(3-hydroxypentane-3-yl)-1H-pyrazol-1-yl)-5',6-dimethyl Base-2H-[1,4'-bipyridyl]-2-one
实施例66(80mg，0.027mmol)经手性拆分(OD柱)得到66-1(36mg，R.T＝6.273min)，产率：45％；66-2(32mg，R.T＝7.830min)，产率：40％。Example 66 (80mg, 0.027mmol) was subjected to chiral resolution (OD column) to obtain 66-1 (36mg, R.T=6.273min), yield: 45%; 66-2 (32mg, R.T=7.830min), yield : 40%.
实施例66-1：MS m/z(ESI):532.2[M+H]+；Embodiment 66-1: MS m/z (ESI): 532.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.40(s,2H),7.76(s,1H),7.32(t,1H),6.40(s,1H),6.27(s,1H),2.07(d,6H),1.79(m,4H),0.81(m,6H). 1 H NMR (400MHz, CDCl 3 )δ8.51(s,1H),8.40(s,2H),7.76(s,1H),7.32(t,1H),6.40(s,1H),6.27(s, 1H),2.07(d,6H),1.79(m,4H),0.81(m,6H).
实施例66-2：MS m/z(ESI):532.2[M+H]+；Embodiment 66-2: MS m/z (ESI): 532.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.40(s,2H),7.76(s,1H),7.32(t,1H),6.40(s,1H),6.27(s,1H),2.07(d,6H),1.79(m,4H),0.81(m,6H). 1 H NMR (400MHz, CDCl 3 )δ8.51(s,1H),8.40(s,2H),7.76(s,1H),7.32(t,1H),6.40(s,1H),6.27(s, 1H),2.07(d,6H),1.79(m,4H),0.81(m,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例67Example 67
3-氯-4-((5-氯-3-氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole-1- base)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-4-((5-氯-3-氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮67。Referring to the synthetic method of Example 57, the target product 3-chloro-4-((5-chloro-3-fluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropane- 2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 67.
MS m/z(ESI):518.1[M+H]+.MS m/z(ESI):518.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.46(s,3H),7.74(s,1H),7.57(d,1H),6.36(s,2H),5.41(s,2H),2.10(s,3H),2.03(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.46(s,3H),7.74(s,1H),7.57(d,1H),6.36(s,2H),5.41(s,2H),2.10(s, 3H), 2.03(s,3H), 1.59(d,6H).
实施例68Example 68
3-氯-4-((3-氯-5-氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole-1- base)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-4-((3-氯-5-氟吡啶-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮68。Referring to the synthesis method of Example 57, the target product 3-chloro-4-((3-chloro-5-fluoropyridin-2-yl)methoxy)-2'-(3-(2-hydroxypropane- 2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 68.
MS m/z(ESI):518.1[M+H]+.MS m/z(ESI):518.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.41(m,3H),7.75(s,1H),7.59(dd,1H),6.39(d,1H),6.33(s,1H),5.46(s,2H),2.10(s,3H),2.02(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.41(m,3H),7.75(s,1H),7.59(dd,1H),6.39(d,1H),6.33(s,1H),5.46(s, 2H), 2.10(s,3H), 2.02(s,3H), 1.59(d,6H).
实施例69Example 69
3-氯-4-((5-氟嘧啶-4-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((5-fluoropyrimidin-4-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5 ',6-Dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-4-((5-氟嘧啶-4-基)甲氧 基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮69。Referring to the synthetic method of Example 57, the target product 3-chloro-4-((5-fluoropyrimidin-4-yl)methoxy base)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine] -2-keto69.
MS m/z(ESI):485.1[M+H]+；MS m/z(ESI):485.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ9.12(d,1H),8.98(d,1H),8.54(s,1H),8.51(d,1H),7.77(s,1H),6.72(s,1H),6.56(d,1H),5.63(d,2H),5.07(s,1H),2.00(s,3H),1.96(s,3H),1.48(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ9.12(d,1H),8.98(d,1H),8.54(s,1H),8.51(d,1H),7.77(s,1H),6.72( s,1H),6.56(d,1H),5.63(d,2H),5.07(s,1H),2.00(s,3H),1.96(s,3H),1.48(s,6H).
实施例70Example 70
3-氯-4-((4-氯-2-氟苄基)氧代)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-chloro-4-((4-chloro-2-fluorobenzyl)oxo)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5 ',6-Dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-4-((4-氯-2-氟苄基)氧代)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮70。Referring to the synthesis method of Example 57, the target product 3-chloro-4-((4-chloro-2-fluorobenzyl) oxo)-2'-(3-(2-hydroxypropan-2-yl) was synthesized -1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 70.
MS m/z(ESI):517.1[M+H]+.MS m/z(ESI):517.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.46(d,1H),8.40(s,1H),7.75(s,1H),7.55(t,1H),7.25(d,1H),7.17(d,1H),6.39(d,1H),6.17(s,1H),5.29(s,2H),2.10(s,3H),2.03(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.46(d,1H),8.40(s,1H),7.75(s,1H),7.55(t,1H),7.25(d,1H),7.17(d, 1H), 6.39(d,1H), 6.17(s,1H), 5.29(s,2H), 2.10(s,3H), 2.03(s,3H), 1.59(d,6H).
实施例71Example 71
3-氯-4-((2-氯-4-氟苄基)氧代)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-chloro-4-((2-chloro-4-fluorobenzyl)oxo)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5 ',6-Dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-4-((2-氯-4-氟苄基)氧代)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮71。Referring to the synthesis method of Example 57, the target product 3-chloro-4-((2-chloro-4-fluorobenzyl) oxo)-2'-(3-(2-hydroxypropane-2-yl) was synthesized -1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 71.
MS m/z(ESI):517.1[M+H]+.MS m/z(ESI):517.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.47(d,1H),8.41(s,1H),7.76(s,1H),7.65(m,1H),7.20(dd,1H),7.11(d,1H),6.39(d,1H),6.16(s,1H),5.31(s,2H),2.11(s,3H), 2.03(s,3H),1.59(d,6H) 1 H NMR (400MHz, CDCl 3 )δ8.47(d,1H),8.41(s,1H),7.76(s,1H),7.65(m,1H),7.20(dd,1H),7.11(d, 1H),6.39(d,1H),6.16(s,1H),5.31(s,2H),2.11(s,3H), 2.03(s,3H),1.59(d,6H)
实施例72Example 72
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2’-(3-(2-甲氧基丙烷-2-基)-1H-吡唑-1-基)-5’,6-二甲基-2H-[1,4'-联吡啶]-2-酮3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-methoxypropan-2-yl)-1H-pyridine Azol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
第一步first step
冰浴下将1H-吡唑-3-甲酸甲酯(2g,15.9mmol)和碳酸钾(4.39g,31.8mmol)溶解在N,N-二甲基甲酰胺(20mL)中搅拌，滴加2-(三甲基硅烷基)乙氧甲基氯(3.96g,23.8mmol)，反应升温至室温搅拌2小时。将反应液倒入水(100mL)中，水相用甲基叔丁基醚萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-甲酸甲酯72a(1.6g)，产率：39.4％。Dissolve 1H-pyrazole-3-carboxylic acid methyl ester (2g, 15.9mmol) and potassium carbonate (4.39g, 31.8mmol) in N,N-dimethylformamide (20mL) under ice-cooling, and add dropwise 2 -(Trimethylsilyl)ethoxymethyl chloride (3.96g, 23.8mmol), the reaction was warmed up to room temperature and stirred for 2 hours. The reaction solution was poured into water (100 mL), and the aqueous phase was extracted with methyl tert-butyl ether (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 1-((2-(trimethyl Silyl)ethoxy)methyl)-1H-pyrazole-3-carboxylic acid methyl ester 72a (1.6 g), yield: 39.4%.
MS m/z(ESI):257.1[M+H]+.MS m/z(ESI):257.1[M+H] + .
第二步second step
将72a(1.6g，6.24mmol)溶解在无水四氢呋喃(15mL)中搅拌，冰浴下向反应液滴加甲基溴化镁四氢呋喃溶液(3M，6.2mL，18.6mmol)。反应在室温下搅拌2小时，将反应液倒入饱和氯化铵溶液(100mL)中，水相用甲基叔丁基醚萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50 mL)洗涤，干燥，浓缩，得到2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-基)丙烷-2-醇72b(1.6g)，产物不经纯化直接用于下步反应。72a (1.6g, 6.24mmol) was dissolved in anhydrous tetrahydrofuran (15mL) and stirred, and methylmagnesium bromide tetrahydrofuran solution (3M, 6.2mL, 18.6mmol) was added dropwise to the reaction solution under ice cooling. The reaction was stirred at room temperature for 2 hours, the reaction solution was poured into saturated ammonium chloride solution (100 mL), and the aqueous phase was extracted with methyl tert-butyl ether (50 mL×2). The organic phases were combined, followed by water (50mL) and saturated sodium chloride solution (50 mL) was washed, dried, and concentrated to give 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propan-2-ol 72b ( 1.6 g), the product was directly used in the next step without purification.
MS m/z(ESI):257.1[M+H]+.MS m/z(ESI):257.1[M+H] + .
第三步third step
将72b(700mg，2.72mmol)溶解在无水四氢呋喃(10mL)中搅拌，冰浴下加入氢化钠(218mg，5.45mmol,含量60％)。反应在室温下搅拌0.5小时后加入碘甲烷(774mg，5.45mmol)。反应在室温下搅拌1.5小时，将反应液倒入冰水(50mL)中，水相用乙酸乙酯萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，得到3-(2-甲氧基丙烷-2-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑72c(720mg)，产物不经纯化直接用于下步反应。72b (700 mg, 2.72 mmol) was dissolved in anhydrous THF (10 mL) and stirred, and sodium hydride (218 mg, 5.45 mmol, content 60%) was added under ice cooling. The reaction was stirred at room temperature for 0.5 h before the addition of iodomethane (774 mg, 5.45 mmol). The reaction was stirred at room temperature for 1.5 hours, the reaction solution was poured into ice water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, and concentrated to give 3-(2-methoxypropan-2-yl)-1-((2-(trimethyl Silyl)ethoxy)methyl)-1H-pyrazole 72c (720 mg), the product was directly used in the next reaction without purification.
MS m/z(ESI):271.2[M+H]+.MS m/z(ESI):271.2[M+H] + .
第四步the fourth step
将72c(720mg，2.66mmol)溶解在四丁基氟化胺的四氢呋喃溶液(1M，20mL，20mmol)中，反应加热至65℃搅拌16小时。将反应液冷却至室温，倒入水(100mL)中，水相用二氯甲烷萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得3-(1-甲氧基-1-甲基-乙基)-1H-吡唑72d(170mg)，产率：45.7％。72c (720 mg, 2.66 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (1M, 20 mL, 20 mmol), and the reaction was heated to 65° C. and stirred for 16 hours. The reaction solution was cooled to room temperature, poured into water (100 mL), and the aqueous phase was extracted with dichloromethane (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 3-(1-methoxy-1 -Methyl-ethyl)-1H-pyrazole 72d (170 mg), yield: 45.7%.
MS m/z(ESI):281.2[M+H]+.MS m/z(ESI):281.2[M+H] + .
第五步the fifth step
将48a(80mg,0.174mmol)溶解在1,4-二氧六环(2mL)中，加入72d(37mg，0.262mmol)，反-N,N'-二甲基1,2-环己烷二胺(12mg，0.087mmol)，碳酸铯(114mg,0.349mmol)和碘化亚铜(50mg,0.262mmol)，反应在氮气保护下加热至100℃搅拌2小时。将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，浓缩，残余物用反相色谱法以洗脱剂体系C纯化，得3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-甲氧基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮(40mg)72，产率：44.3％。48a (80 mg, 0.174 mmol) was dissolved in 1,4-dioxane (2 mL), and 72d (37 mg, 0.262 mmol), trans-N,N'-dimethyl 1,2-cyclohexane di Amine (12mg, 0.087mmol), cesium carbonate (114mg, 0.349mmol) and cuprous iodide (50mg, 0.262mmol), the reaction was heated to 100°C under nitrogen protection and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30mL) and saturated sodium chloride solution (30mL), dried, concentrated, and the residue was purified by reverse phase chromatography with eluent system C to obtain 3-chloro-4-((3, 5-Difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-methoxypropan-2-yl)-1H-pyrazol-1-yl)-5', 6-Dimethyl-2H-[1,4'-bipyridyl]-2-one (40 mg) 72, Yield: 44.3%.
MS m/z(ESI):518.1[M+H]+.MS m/z(ESI):518.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.59(d,1H),8.56(s,1H),8.13-8.08(m,1H),7.82(s,1H),6.81(s,1H),6.55(d,1H),3.01(s,3H),2.01(s,3H),2.00(s,3H),1.51(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.61(d,1H),8.59(d,1H),8.56(s,1H),8.13-8.08(m,1H),7.82(s,1H), 6.81(s,1H),6.55(d,1H),3.01(s,3H),2.01(s,3H),2.00(s,3H),1.51(s,6H).
实施例72的拆分 Splitting of Example 72
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-甲氧基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-甲氧基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-methoxypropan-2-yl) -1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one and (R)-3-chloro-4-((3, 5-Difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-methoxypropan-2-yl)-1H-pyrazol-1-yl)-5', 6-Dimethyl-2H-[1,4'-bipyridyl]-2-one
实施例72(45mg，0.087mmol)经手性拆分(OD柱)得到72-1(8.9mg，R.T＝3.463min)，产率：19％；72-2(9.8mg，R.T＝4.063min)，产率：22％。Example 72 (45mg, 0.087mmol) was obtained by chiral resolution (OD column) to obtain 72-1 (8.9mg, R.T=3.463min), yield: 19%; 72-2 (9.8mg, R.T=4.063min), Yield: 22%.
实施例72-1：MS m/z(ESI):518.1[M+H]+；Embodiment 72-1: MS m/z (ESI): 518.1[M+H] + ;
实施例72-2：MS m/z(ESI):518.1[M+H]+；Embodiment 72-2: MS m/z (ESI): 518.1[M+H] + ;
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例73Example 73
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl- 2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
第一步first step
冰浴下，将4-氟-1H-吡唑-3-甲酸甲酯(600mg，4.16mmol)溶解在无水四氢呋喃(20mL)中，搅拌下向反应液中滴加甲基溴化镁的四氢呋喃溶液(3M，6.9mL，20.7mmol)，反应在室温下搅拌3小时。搅拌下将反应液缓慢倒入饱和氯化铵溶液(50mL)中，水相用乙酸乙酯萃取(50mL×3)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，得到2-(4-氟-1H-吡唑-3-基)丙烷-2-醇73a(600mg)，产物不经纯化直接用于下步反应。Under ice-cooling, dissolve methyl 4-fluoro-1H-pyrazole-3-carboxylate (600mg, 4.16mmol) in anhydrous tetrahydrofuran (20mL), and add methylmagnesium bromide in tetrahydrofuran dropwise to the reaction solution while stirring solution (3M, 6.9 mL, 20.7 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction solution was slowly poured into saturated ammonium chloride solution (50 mL) with stirring, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried and concentrated to give 2-(4-fluoro-1H-pyrazol-3-yl)propan-2-ol 73a (600 mg) , the product was directly used in the next reaction without purification.
MS m/z(ESI):145.1[M+H]+.MS m/z(ESI):145.1[M+H] + .
第二步second step
将73a(600mg)溶解在乙腈(15mL)中搅拌，0℃下向反应液中滴加浓硫酸(5mL)，反应升温至室温搅拌3小时。将反应液缓慢倒入饱和碳酸氢钠溶液(100mL)中，水相用乙酸乙酯萃取(50mL×3)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到N-(2-(4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺73b(510mg)，产率：86.8％。73a (600 mg) was dissolved in acetonitrile (15 mL) and stirred. Concentrated sulfuric acid (5 mL) was added dropwise to the reaction solution at 0° C., and the reaction was warmed to room temperature and stirred for 3 hours. The reaction solution was slowly poured into saturated sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro- 1H-pyrazol-3-yl)propan-2-yl)acetamide 73b (510 mg), yield: 86.8%.
MS m/z(ESI):186.1[M+H]+.MS m/z(ESI):186.1[M+H] + .
第三步third step
氮气保护下将48a(80mg,0.174mmol)溶解在1,4-二氧六环(2mL)中，然后依次加入73b(48mg,0.261mmol)，(反)-二甲基-1,2-环己二胺(12mg,0.087mmol)，碳酸铯(170mg,0.523mmol)和碘化亚铜(66mg,0.349mmol)，反应加热至100℃搅拌2小时。将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液 (30mL)洗涤，干燥，浓缩，残余物用反相色谱法以洗脱剂体系C纯化，得到N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺73(75mg)，产率：76.1％。Under nitrogen protection, 48a (80mg, 0.174mmol) was dissolved in 1,4-dioxane (2mL), and then 73b (48mg, 0.261mmol), (trans)-dimethyl-1,2-cyclo Hexamethylenediamine (12mg, 0.087mmol), cesium carbonate (170mg, 0.523mmol) and cuprous iodide (66mg, 0.349mmol), the reaction was heated to 100°C and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, followed by water (30mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by reverse phase chromatography with eluent system C to give N-(2-(1-(3-chloro-4-((3,5-difluoropyridine- 2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyridine Azol-3-yl)propan-2-yl)acetamide 73 (75 mg), yield: 76.1%.
MS m/z(ESI):563.2[M+H]+.MS m/z(ESI):563.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.56(d,1H),8.54(s,1H),8.11-8.06(m,2H),7.78(s,1H),6.80(s,1H),2.01(s,3H),1.99(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.56(d,1H),8.54(s,1H),8.11-8.06(m,2H),7.78(s,1H), 6.80(s,1H),2.01(s,3H),1.99(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H).
实施例73的拆分Splitting of Example 73
(S)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl- 2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N- (2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H- [1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例73(40mg，0.071mmol)经手性拆分(OD柱)得到73-1(18.3mg，Example 73 (40mg, 0.071mmol) obtained 73-1 (18.3mg,
R.T＝3.020min)，产率：45％；73-2(17.3mg，R.T＝3.960min)，产率：43％。R.T=3.020min), yield: 45%; 73-2 (17.3mg, R.T=3.960min), yield: 43%.
实施例73-1：MS m/z(ESI):563.2[M+H]+；Embodiment 73-1: MS m/z (ESI): 563.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.56(d,1H),8.54(s,1H),8.12-8.06(m,2H),7.78(s,1H),6.80(s,1H),2.00(s,3H),1.99(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.56(d,1H),8.54(s,1H),8.12-8.06(m,2H),7.78(s,1H), 6.80(s,1H),2.00(s,3H),1.99(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H).
实施例73-2：MS m/z(ESI):563.2[M+H]+；Example 73-2: MS m/z (ESI): 563.2[M+H] + ;
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

HPLC chiral analysis method:

实施例75Example 75
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(2-(2-羰基吡咯烷-1-基)丙烷-2-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(2-(2-carbonylpyrrole Alkyl-1-yl)propan-2-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one
第一步first step
将2-(1-苄基-1H-吡唑-3-基)丙烷-2-醇75a(400mg，1.85mmol)，4-氯丁腈(4.79g，46.24mmol)溶解到三氟乙酸(5mL)和氯仿(5mL)中，反应在30℃下搅拌48小时。反应液浓缩，残余物用Prep-HPLC色谱柱法(甲酸体系)分离得到标题产物N-(2-(1-苄基-1H-吡唑-3-基)丙烷-2-基)-4-氯丁酰胺75b(200mg)，产率：33.8％。2-(1-Benzyl-1H-pyrazol-3-yl)propan-2-ol 75a (400 mg, 1.85 mmol), 4-chlorobutyronitrile (4.79 g, 46.24 mmol) were dissolved in trifluoroacetic acid (5 mL ) and chloroform (5 mL), the reaction was stirred at 30°C for 48 hours. The reaction solution was concentrated, and the residue was separated by Prep-HPLC column method (formic acid system) to obtain the title product N-(2-(1-benzyl-1H-pyrazol-3-yl)propan-2-yl)-4- Chlorobutanamide 75b (200 mg), yield: 33.8%.
MS m/z(ESI):320.2[M+H]+.MS m/z(ESI):320.2[M+H] + .
第二步second step
将氢化钠(125mg,3.13mmol,含量60％)于冰浴下加入到N-[1-(1-苄基吡唑-3-基)-1-甲基-乙基]-4-氯丁酰胺75b(500mg，1.56mmol)的四氢呋喃(10mL)溶液中。反应在22℃下搅拌3小时。将反应液使用甲醇淬灭，浓缩，使用Prep-HPLC 色谱柱法(甲酸体系)分离得到标题产物1-[1-(1-苄基吡唑-3-基)-1-甲基-乙基]吡咯烷-2-酮75c(310mg)，产率：70.0％。Sodium hydride (125mg, 3.13mmol, content 60%) was added to N-[1-(1-benzylpyrazol-3-yl)-1-methyl-ethyl]-4-chlorobutyl under ice-cooling Amide 75b (500 mg, 1.56 mmol) in tetrahydrofuran (10 mL). The reaction was stirred at 22°C for 3 hours. The reaction solution was quenched with methanol, concentrated, and used Prep-HPLC The title product 1-[1-(1-benzylpyrazol-3-yl)-1-methyl-ethyl]pyrrolidin-2-one 75c (310 mg) was obtained by separation by chromatographic column method (formic acid system). The yield was : 70.0%.
MS m/z(ESI):284.2[M+H]+.MS m/z(ESI):284.2[M+H] + .
第三步third step
将1-[1-(1-苄基吡唑-3-基)-1-甲基-乙基]吡咯烷-2-酮75c(300mg，1.06mmol)和Pd/C(300mg,含量Pd量5％，含水量55％)的四氢呋喃(10mL)和乙酸(2mL)的悬浊液，用氢气置换。在氢气环境中25℃搅拌16小时。将反应液过滤除去钯碳，滤液浓缩，使用Prep-HPLC色谱柱法(甲酸体系)分离得到标题产物1-[1-甲基-1-(1H-吡唑-3-基)乙基]吡咯烷-2-酮75d(160mg)，产率：78.2％。1-[1-(1-Benzylpyrazol-3-yl)-1-methyl-ethyl]pyrrolidin-2-one 75c (300mg, 1.06mmol) and Pd/C (300mg, content Pd amount 5%, with a water content of 55%) in tetrahydrofuran (10 mL) and acetic acid (2 mL), and replaced with hydrogen. Stir at 25°C for 16 hours under hydrogen atmosphere. The reaction solution was filtered to remove palladium carbon, the filtrate was concentrated, and the title product 1-[1-methyl-1-(1H-pyrazol-3-yl)ethyl]pyrrole was obtained by separation using Prep-HPLC column method (formic acid system) Alkan-2-one 75d (160 mg), Yield: 78.2%.
MS m/z(ESI):194.1[M+H]+.MS m/z(ESI):194.1[M+H] + .
第四步the fourth step
将产物1-[1-甲基-1-(1H-吡唑-3-基)乙基]吡咯烷-2-酮75d(63mg，0.33mmol)，48a(100mg，0.22mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(12mg，0.09mmol)，碳酸铯(106mg 0.33mmol)，和碘化亚铜(17mg，0.09mmol)溶解到二氧六环(2mL)中。反应在100℃下搅拌3小时。将反应液浓缩，使用正相硅胶柱色谱法(洗脱剂体系A)分离得到标题产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(2-(2-羰基吡咯烷-1-基)丙烷-2-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮75(86mg)，产率：69.1％。The product 1-[1-methyl-1-(1H-pyrazol-3-yl)ethyl]pyrrolidin-2-one 75d (63 mg, 0.33 mmol), 48a (100 mg, 0.22 mmol), (1S, 2S)-N1,N2-Dimethylcyclohexane-1,2-diamine (12mg, 0.09mmol), cesium carbonate (106mg 0.33mmol), and cuprous iodide (17mg, 0.09mmol) were dissolved in dioxygen Hexacyclic (2mL). The reaction was stirred at 100°C for 3 hours. The reaction solution was concentrated and separated using normal phase silica gel column chromatography (eluent system A) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)- 5',6-Dimethyl-2'-(3-(2-(2-carbonylpyrrolidin-1-yl)propan-2-yl)-1H-pyrazol-1-yl)-2H-[1 ,4'-bipyridyl]-2-one 75 (86 mg), yield: 69.1%.
MS m/z(ESI):571.2[M+H]+.MS m/z(ESI):571.2[M+H] + .
实施例75的拆分Splitting of Example 75
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(2-(2-羰基吡咯烷-1-基)丙烷-2-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(2-(2-羰基吡咯烷-1-基)丙烷-2-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(2-( 2-Carbonylpyrrolidin-1-yl)propan-2-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one and (R)-3-chloro -4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(2-(2-carbonylpyrrolidine-1 -yl)propan-2-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one
实施例75(75mg，0.131mmol)经手性拆分(OD柱)得到75-1(30mg，R.T＝4.527min)，产率：40％；75-2(35mg，R.T＝5.733min)，产率：46％。Example 75 (75mg, 0.131mmol) was subjected to chiral resolution (OD column) to obtain 75-1 (30mg, R.T=4.527min), yield: 40%; 75-2 (35mg, R.T=5.733min), yield : 46%.
实施例75-1：MS m/z(ESI):571.2[M+H]+；Embodiment 75-1: MS m/z (ESI): 571.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.40(m,3H),7.71(s,1H),7.33(m,1H),6.40(d,2H),3.42(dt,2H),2.37(d,2H),2.06(d,6H),1.95(d,2H),1.79(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.40(m,3H),7.71(s,1H),7.33(m,1H),6.40(d,2H),3.42(dt,2H),2.37(d, 2H), 2.06(d,6H), 1.95(d,2H), 1.79(d,6H).
实施例75-2：MS m/z(ESI):571.2[M+H]+；Embodiment 75-2: MS m/z (ESI): 571.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.40(m,3H),7.71(s,1H),7.33(m,1H),6.40(d, 2H),3.42(dt,2H),2.37(d,2H),2.06(d,6H),1.95(d,2H),1.79(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.40(m,3H),7.71(s,1H),7.33(m,1H),6.40(d, 2H), 3.42(d,2H), 2.37(d,2H), 2.06(d,6H), 1.95(d,2H), 1.79(d,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例76Example 76
2'-(3-(1-乙酰基-3-甲基氮杂环丁烷-3-基)-1H-吡唑-1-基)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
2'-(3-(1-acetyl-3-methylazetidin-3-yl)-1H-pyrazol-1-yl)-3-chloro-4-((3,5-di Fluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
第一步first step
将2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(4.24g，11.15mmol)，加入到1-叔丁氧羰基-3-甲基-氮杂环丁烷-3-甲酸76a(2.00g，9.29mmol)，N-甲氧基甲胺盐酸盐(997mg，10.22mmol)和三乙胺(2.82g，27.88mmol)的二氯甲烷溶液(50mL)中，反应液于25℃搅拌3小时。反应结束后，将反应液过滤除去固体杂质，滤液浓缩，残余物用正相硅胶柱色谱法(洗脱剂体系A)分离得到标题产物3-[甲氧基(甲基)氨基甲酰基]-3-甲基-氮杂环丁烷-1-甲酸叔丁酯76b(2.10g)，产率：87.5％。2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.24g, 11.15mmol), was added to 1-tert-butoxycarbonyl- 3-Methyl-azetidine-3-carboxylic acid 76a (2.00 g, 9.29 mmol), N-methoxymethylamine hydrochloride (997 mg, 10.22 mmol) and triethylamine (2.82 g, 27.88 mmol) In dichloromethane solution (50 mL), the reaction solution was stirred at 25°C for 3 hours. After the reaction, the reaction solution was filtered to remove solid impurities, the filtrate was concentrated, and the residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product 3-[methoxy(methyl)carbamoyl]- 3-Methyl-azetidine-1-carboxylic acid tert-butyl ester 76b (2.10 g), yield: 87.5%.
MS m/z(ESI):259.2[M+H]+.MS m/z(ESI):259.2[M+H] + .
第二步second step
0℃下将甲基溴化镁(4.24g，11.15mmol)于冰浴下滴加到到3-[甲氧基(甲基)氨基甲酰基]-3-甲基-氮杂环丁烷-1-甲酸叔丁酯76b(2.38g，9.21mmol)的四氢呋喃(50mL)溶液中。滴加完毕，反应液升温到25℃搅拌2小时。反应结束后，将反应液使用甲醇和水淬灭，形成白色固体，过滤除去固体杂质，滤液浓缩，残余物用正相硅胶柱色谱法(洗脱剂体系A)分离得到标题产物3-乙酰基-3-甲基氮杂环丁烷-1-甲酸叔丁酯76c(1.90g)，产率：96.7％。Methylmagnesium bromide (4.24g, 11.15mmol) was added dropwise to 3-[methoxy(methyl)carbamoyl]-3-methyl-azetidine- tert-Butyl 1-carboxylate 76b (2.38 g, 9.21 mmol) in tetrahydrofuran (50 mL). After the dropwise addition was completed, the temperature of the reaction solution was raised to 25° C. and stirred for 2 hours. After the reaction, the reaction solution was quenched with methanol and water to form a white solid, which was filtered to remove solid impurities, the filtrate was concentrated, and the residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product 3-acetyl - tert-butyl 3-methylazetidine-1-carboxylate 76c (1.90 g), yield: 96.7%.
MS m/z(ESI):427.1[2M+H]+.MS m/z(ESI):427.1[2M+H] + .
第三步third step
将3-乙酰基-3-甲基氮杂环丁烷-1-甲酸叔丁酯76c(4.24g，11.15mmol)和N,N-二甲基甲酰胺二甲基缩醛(8.93g,75.02mmol)的N,N-二甲基甲酰胺(15mL)溶液升温到100℃搅拌16小时。反应结束后，将反应液使用乙酸乙酯(160mL)稀释，使用水和食盐水洗涤，有机相合并浓缩，残余物用正相硅胶柱色谱法(洗脱剂体系A)分离得到标题产物3-[(E)-3-(二甲基氨基)丙烷-2-烯酰基]-3-甲基-氮杂环丁烷-1-甲酸叔丁酯76d(1.60g)，产率：79.5％。3-Acetyl-3-methylazetidine-1-carboxylic acid tert-butyl ester 76c (4.24g, 11.15mmol) and N,N-dimethylformamide dimethyl acetal (8.93g, 75.02 mmol) in N,N-dimethylformamide (15 mL) was heated to 100°C and stirred for 16 hours. After the reaction, the reaction solution was diluted with ethyl acetate (160 mL), washed with water and brine, the organic phases were combined and concentrated, and the residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product 3-[ (E)-tert-butyl 3-(dimethylamino)propane-2-enoyl]-3-methyl-azetidine-1-carboxylate 76d (1.60 g), yield: 79.5%.
MS m/z(ESI):269.2[M+H]+.MS m/z(ESI):269.2[M+H] + .
第四步the fourth step
将3-[(E)-3-(二甲基氨基)丙烷-2-烯酰基]-3-甲基-氮杂环丁烷-1-甲酸叔丁酯76d(1.20g，4.47mmol)和水合肼(1.69g,44.72mmol，含量：85％)的乙醇(20mL)溶液升温到50℃搅拌16小时。反应结束后，将反应液浓缩，残余物用正相硅胶柱色谱法(洗脱剂体系A)分离得到标题产物3-甲基-3-(1H-吡唑-3-基)氮杂环丁烷-1-甲酸叔丁酯76e(810mg)，产率：76.3％。3-[(E)-3-(Dimethylamino)propane-2-enoyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester 76d (1.20 g, 4.47 mmol) and Hydrazine hydrate (1.69 g, 44.72 mmol, content: 85%) in ethanol (20 mL) was heated to 50° C. and stirred for 16 hours. After the reaction, the reaction solution was concentrated, and the residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product 3-methyl-3-(1H-pyrazol-3-yl)azetidin tert-Butyl alkane-1-carboxylate 76e (810 mg), yield: 76.3%.
MS m/z(ESI):475.2[2M+H]+.MS m/z(ESI):475.2[2M+H] + .
第五步the fifth step
将产物3-甲基-3-(1H-吡唑-3-基)氮杂环丁烷-1-甲酸叔丁酯76e(155mg，0.65mmol)，48a(200mg，0.44mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(25mg， 0.17mmol)，碳酸铯(212mg 0.65mmol)，和碘化亚铜(33mg，0.17mmol)溶解到二氧六环(3mL)中。反应在100℃下搅拌3小时。将反应液浓缩，使用正相硅胶柱色谱法(洗脱剂体系A)分离得到标题产物3-[1-[4-[3-氯-4-[二氘-(3,5-二氟-2-吡啶基)甲氧基]-6-甲基-2-羰基-1-吡啶基]-5-甲基-2-吡啶基]吡唑-3-基]-3-甲基-氮杂环丁烷-1-甲酸叔丁酯76f(200mg)，产率：74.6％。The product tert-butyl 3-methyl-3-(1H-pyrazol-3-yl)azetidine-1-carboxylate 76e (155 mg, 0.65 mmol), 48a (200 mg, 0.44 mmol), (1S, 2S)-N1,N2-dimethylcyclohexane-1,2-diamine (25mg, 0.17 mmol), cesium carbonate (212 mg 0.65 mmol), and cuprous iodide (33 mg, 0.17 mmol) were dissolved in dioxane (3 mL). The reaction was stirred at 100°C for 3 hours. The reaction solution was concentrated and separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product 3-[1-[4-[3-chloro-4-[dideuterium-(3,5-difluoro- 2-pyridyl)methoxy]-6-methyl-2-carbonyl-1-pyridyl]-5-methyl-2-pyridyl]pyrazol-3-yl]-3-methyl-aza Cyclobutane-1-carboxylic acid tert-butyl ester 76f (200 mg), yield: 74.6%.
MS m/z(ESI):615.2[M+H]+.MS m/z(ESI):615.2[M+H] + .
第六步step six
将3-[1-[4-[3-氯-4-[二氘-(3,5-二氟-2-吡啶基)甲氧基]-6-甲基-2-羰基-1-吡啶基]-5-甲基-2-吡啶基]吡唑-3-基]-3-甲基-氮杂环丁烷-1-甲酸叔丁酯76f(200mg，0.32mmol)和盐酸的二氧六环溶液(4M,1mL)的四氢呋喃(3mL)溶液于27℃搅拌16小时。反应结束后，将反应液浓缩，得到标题产物3-氯-4-[二氘-(3,5-二氟-2-吡啶基)甲氧基]-6-甲基-1-[5-甲基-2-[3-(3-甲基氮杂环丁烷-3-基)吡唑-1-基]-4-吡啶基]吡啶-2-酮76g(150mg)，产物不经纯化直接用于下一步反应中。3-[1-[4-[3-chloro-4-[dideuterium-(3,5-difluoro-2-pyridyl)methoxy]-6-methyl-2-carbonyl-1-pyridine Dioxo]-5-methyl-2-pyridyl]pyrazol-3-yl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester 76f (200mg, 0.32mmol) and hydrochloric acid A solution of hexacyclic solution (4M, 1 mL) in THF (3 mL) was stirred at 27°C for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain the title product 3-chloro-4-[dideuterium-(3,5-difluoro-2-pyridyl)methoxy]-6-methyl-1-[5- Methyl-2-[3-(3-methylazetidin-3-yl)pyrazol-1-yl]-4-pyridyl]pyridin-2-one 76g (150mg), the product was not purified used directly in the next reaction.
MS m/z(ESI):515.2[M+H]+.MS m/z(ESI):515.2[M+H] + .
第七步step seven
将乙酰氯(73mg，0.93mmol)于冰浴下滴加到3-氯-4-[二氘-(3,5-二氟-2-吡啶基)甲氧基]-6-甲基-1-[5-甲基-2-[3-(3-甲基氮杂环丁烷-3-基)吡唑-1-基]-4-吡啶基]吡啶-2-酮76g(160mg，0.31mmol)和三乙胺(126mg,1.24mmol)的二氯甲烷(3mL)溶液中，升温到25℃搅2小时。反应结束后，将反应液浓缩，使用Prep-HPLC色谱柱法(甲酸体系)分离得到标题产物2'-(3-(1-乙酰基-3-甲基氮杂环丁烷-3-基)-1H-吡唑-1-基)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮76(100mg)，产率：57.8％。Acetyl chloride (73mg, 0.93mmol) was added dropwise to 3-chloro-4-[dideuterium-(3,5-difluoro-2-pyridyl)methoxy]-6-methyl-1 under ice bath -[5-methyl-2-[3-(3-methylazetidin-3-yl)pyrazol-1-yl]-4-pyridyl]pyridin-2-one 76g (160mg, 0.31 mmol) and triethylamine (126 mg, 1.24 mmol) in dichloromethane (3 mL), heated to 25°C and stirred for 2 hours. After the reaction, the reaction solution was concentrated, and the title product 2'-(3-(1-acetyl-3-methylazetidin-3-yl) was obtained by separation using Prep-HPLC column method (formic acid system) -1H-pyrazol-1-yl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[ 1,4'-bipyridyl]-2-one 76 (100 mg), yield: 57.8%.
MS m/z(ESI):557.2[M+H]+.MS m/z(ESI):557.2[M+H] + .
实施例76的拆分Splitting of Example 76
(S)-2'-(3-(1-乙酰基-3-甲基氮杂环丁烷-3-基)-1H-吡唑-1-基)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-2'-(3-(1-乙酰基-3-甲基氮杂环丁烷-3-基)-1H-吡唑-1-基)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-2'-(3-(1-acetyl-3-methylazetidin-3-yl)-1H-pyrazol-1-yl)-3-chloro-4-((3 ,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one and (R)-2'- (3-(1-acetyl-3-methylazetidin-3-yl)-1H-pyrazol-1-yl)-3-chloro-4-((3,5-difluoropyridine- 2-yl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
实施例76(90mg，0.161mmol)经手性拆分(OD柱)得到76-1(40mg，R.T＝4.780min)，产率：44.4％；76-2(40mg，R.T＝6.957min)，产率：44.4％。Example 76 (90mg, 0.161mmol) was obtained by chiral resolution (OD column) to obtain 76-1 (40mg, R.T=4.780min), yield: 44.4%; 76-2 (40mg, R.T=6.957min), yield : 44.4%.
实施例76-1：MS m/z(ESI):557.2[M+H]+； Embodiment 76-1: MS m/z (ESI): 557.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.51(d,1H),8.38(m,2H),7.76(s,1H),7.33(m,1H),6.43(s,1H),6.36(d,1H),4.44(dd,2H),4.00(d,2H),2.11(s,3H),2.05(s,3H),1.96(s,3H),1.70(s,3H).1H NMR (400MHz, CDCl3) δ8.51(d,1H),8.38(m,2H),7.76(s,1H),7.33(m,1H),6.43(s,1H),6.36(d,1H) ,4.44(dd,2H),4.00(d,2H),2.11(s,3H),2.05(s,3H),1.96(s,3H),1.70(s,3H).
实施例76-2：MS m/z(ESI):557.2[M+H]+；Example 76-2: MS m/z (ESI): 557.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.51(d,1H),8.38(m,2H),7.76(s,1H),7.33(m,1H),6.43(s,1H),6.36(d,1H),4.44(dd,2H),4.00(d,2H),2.11(s,3H),2.05(s,3H),1.96(s,3H),1.70(s,3H).1H NMR (400MHz, CDCl3) δ8.51(d,1H),8.38(m,2H),7.76(s,1H),7.33(m,1H),6.43(s,1H),6.36(d,1H) ,4.44(dd,2H),4.00(d,2H),2.11(s,3H),2.05(s,3H),1.96(s,3H),1.70(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例78Example 78
3-氯-4-(3,5-二氟吡啶-2-基)甲氧基-d2)-2’-(4-氟-3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5’，6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-(3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(4-fluoro-3-(2-hydroxypropan-2-yl)-1H- Pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例48的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-氟-3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡 啶]-2-酮78。Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(4-fluoro-3- (2-Hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-dipyr Pyridine]-2-one 78.
MS m/z(ESI):522.1[M+H]+.MS m/z(ESI):522.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.62(d,1H),8.60(d,1H),8.54(s,1H),8.12-8.06(m,1H),7.81(s,1H),6.80(s,1H),5.20(s,1H),2.01(s,3H),1.98(s,3H),1.52(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.62(d,1H),8.60(d,1H),8.54(s,1H),8.12-8.06(m,1H),7.81(s,1H), 6.80(s,1H),5.20(s,1H),2.01(s,3H),1.98(s,3H),1.52(s,6H).
实施例78的拆分Splitting of Example 78
(S)-3-氯-4-(3,5-二氟吡啶-2-基)甲氧基-d2)-2’-(4-氟-3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5’，6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-(3,5-二氟吡啶-2-基)甲氧基-d2)-2’-(4-氟-3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5’，6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-(3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(4-fluoro-3-(2-hydroxypropan-2-yl) )-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-(3, 5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5 ',6-Dimethyl-2H-[1,4'-bipyridyl]-2-one
实施例78(70mg，0.134mmol)经SFC手性拆分(IB柱)得到78-1(24mg，R.T＝0.707min)，产率：33％；78-2(30mg，R.T＝3.134min)，产率：43％。Example 78 (70mg, 0.134mmol) was subjected to SFC chiral resolution (IB column) to obtain 78-1 (24mg, R.T=0.707min), yield: 33%; 78-2 (30mg, R.T=3.134min), Yield: 43%.
实施例78-1：MS m/z(ESI):522.1[M+H]+；Example 78-1: MS m/z (ESI): 522.1[M+H] + ;
实施例78-2：MS m/z(ESI):522.1[M+H]+；Example 78-2: MS m/z (ESI): 522.1[M+H] + ;
SFC手性拆分条件：
SFC chiral resolution conditions:
SFC手性分析方法：

SFC chiral analysis method:

实施例79Example 79
3-氯-2'-(4-氯-3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-chloro-2'-(4-chloro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-4-((3,5-difluoropyridin-2-yl )methoxy-d 2 )-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例48的合成方法，合成得到目标产物3-氯-2'-(4-氯-3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮79。Referring to the synthesis method of Example 48, the target product 3-chloro-2'-(4-chloro-3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-4-( (3,5-Difluoropyridin-2-yl)methoxy-d 2 )-5′,6-dimethyl-2H-[1,4′-bipyridyl]-2-one 79 .
MS m/z(ESI):538.1[M+H]+.MS m/z(ESI):538.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.72(s,1H),8.60(d,1H),8.56(s,1H),8.12-8.06(m,1H),7.83(s,1H),6.80(s,1H),5.13(s,1H),2.02(s,3H),1.98(s,3H),1.55(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.72(s,1H),8.60(d,1H),8.56(s,1H),8.12-8.06(m,1H),7.83(s,1H), 6.80(s,1H),5.13(s,1H),2.02(s,3H),1.98(s,3H),1.55(s,6H).
实施例79的拆分Splitting of Example 79
(S)-3-氯-2'-(4-氯-3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-2'-(4-氯-3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-2'-(4-chloro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-4-((3,5-difluoropyridine -2-yl)methoxy-d 2 )-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one and (R)-3-chloro-2'-( 4-Chloro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 ) -5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
实施例79(60mg，0.111mmol)经SFC手性拆分(AD柱)得到79-1(26mg，R.T＝1.229min)，产率：41％；79-2(26mg，R.T＝3.311min)，产率：41％。Example 79 (60mg, 0.111mmol) was subjected to SFC chiral resolution (AD column) to obtain 79-1 (26mg, R.T=1.229min), yield: 41%; 79-2 (26mg, R.T=3.311min), Yield: 41%.
实施例79-1：MS m/z(ESI):538.1[M+H]+； Example 79-1: MS m/z (ESI): 538.1[M+H] + ;
实施例79-2：MS m/z(ESI):538.1[M+H]+；Example 79-2: MS m/z (ESI): 538.1[M+H] + ;
SFC手性拆分条件：
SFC chiral resolution conditions:
SFC手性分析方法：
SFC chiral analysis method:
实施例83Example 83
3-(1-(3-氯-4-(3,5-二氟吡啶-2-基)甲氧基-d2)-5'，6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)-3-甲基丁腈

3-(1-(3-chloro-4-(3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H-[1 ,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)-3-methylbutyronitrile

第一步first step
将(1H-吡唑-3-基)乙酸乙酯(1.5g,9.73mmol)溶解在无水N,N-二甲基甲酰胺(15mL)中搅拌，加入碳酸钾(2.69g,19.5mmol)和2-(三甲基硅烷基)乙氧甲基氯(1.95g,11.7mmol)，反应在室温下搅拌3小时。将反应液倒入水(50mL)中，水相用甲基叔丁基醚萃取(50mL×2)。有机相合并，依次用水(50mL×2)和饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-基)乙酸乙酯83a(2.3g)，产率：83.1％。Dissolve ethyl (1H-pyrazol-3-yl)acetate (1.5g, 9.73mmol) in anhydrous N,N-dimethylformamide (15mL) and stir, add potassium carbonate (2.69g, 19.5mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.95 g, 11.7 mmol), and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with methyl tert-butyl ether (50 mL×2). The organic phases were combined, washed successively with water (50mL×2) and saturated sodium chloride solution (50mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-(1-((2 -Ethyl (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)acetate 83a (2.3 g), yield: 83.1%.
MS m/z(ESI):285.2[M+H]+.MS m/z(ESI):285.2[M+H] + .
第二步second step
在0℃下将83a(2.3g,8.09mmol)溶解在无水四氢呋喃(30mL)中搅拌，向反应液分批加入氢化钠(582mg,24mmol，含量：60％)，反应恢复至室温继续搅拌0.5小时。向反应液加入碘甲烷(3.44g,24.3mmol)，反应在室温下搅拌1.5小时。将反应液倒入冰水(50mL)中，水相用乙酸乙酯萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，得到2-甲基-2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-基)丙酸乙酯83b(2.5g)，产物不经纯化直接用于下步反应。Dissolve 83a (2.3g, 8.09mmol) in anhydrous tetrahydrofuran (30mL) at 0°C and stir, add sodium hydride (582mg, 24mmol, content: 60%) to the reaction solution in batches, return to room temperature and continue stirring for 0.5 Hour. Iodomethane (3.44 g, 24.3 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 1.5 hours. The reaction solution was poured into ice water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, and concentrated to give 2-methyl-2-(1-((2-(trimethylsilyl)ethoxy )methyl)-1H-pyrazol-3-yl)ethyl propionate 83b (2.5g), the product was directly used in the next reaction without purification.
MS m/z(ESI):313.2[M+H]+.MS m/z(ESI):313.2[M+H] + .
第三步third step
将83b(2.5g,8.00mmol)溶解在无水四氢呋喃(50mL)中，冰浴下滴加四氢锂铝的四氢呋喃溶液(1M，12mL，12mmol)，反应室温搅拌2小时。向反应液缓慢滴加水(1mL)和15％氢氧化钠溶液(0.5mL)反应在室温下继续搅拌0.5小时。反应液过滤，干燥，浓缩，得到2-甲基-2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-基)丙烷-1-醇83c(2.15g)，产物不经纯化直接用于下步反应。83b (2.5g, 8.00mmol) was dissolved in anhydrous tetrahydrofuran (50mL), and lithium aluminum tetrahydrogen in tetrahydrofuran (1M, 12mL, 12mmol) was added dropwise under ice cooling, and the reaction was stirred at room temperature for 2 hours. Water (1 mL) and 15% sodium hydroxide solution (0.5 mL) were slowly added dropwise to the reaction solution, and the reaction was continued to stir at room temperature for 0.5 hours. The reaction solution was filtered, dried, and concentrated to obtain 2-methyl-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propane- 1-alcohol 83c (2.15g), the product was directly used in the next reaction without purification.
MS m/z(ESI):271.2[M+H]+.MS m/z(ESI):271.2[M+H] + .
第四步 the fourth step
将83c(1g,3.70mmol)和三乙胺(1.12g,11.1mmol)溶解在无水二氯甲烷(20mL)中搅拌，冰浴下向反应液滴加甲基磺酰氯(847mg,7.40mmol)，反应在室温下搅拌1小时。将反应液倒入水(50mL)中，水相用二氯甲烷萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到2-甲基-2-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-基)丙基甲磺酸酯83d(850mg)，产率：66.0％。83c (1g, 3.70mmol) and triethylamine (1.12g, 11.1mmol) were dissolved in anhydrous dichloromethane (20mL) and stirred, and methanesulfonyl chloride (847mg, 7.40mmol) was added dropwise to the reaction solution under ice cooling , and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with dichloromethane (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-methyl-2-(1- ((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propyl methanesulfonate 83d (850 mg), yield: 66.0%.
MS m/z(ESI):349.2[M+H]+.MS m/z(ESI):349.2[M+H] + .
1H NMR(400MHz,CDCl3)δ7.50(d,1H),6.25(d,1H),5.42(s,2H),4.30(s,2H),3.58(t,2H),2.92(s,3H),1.40(s,6H),0.91-0.87(m,2H),-0.02(s,9H). 1 H NMR (400MHz, CDCl 3 )δ7.50(d,1H),6.25(d,1H),5.42(s,2H),4.30(s,2H),3.58(t,2H),2.92(s, 3H),1.40(s,6H),0.91-0.87(m,2H),-0.02(s,9H).
第五步the fifth step
将83d(850mg，2.44mmol)溶解在二甲亚砜(10mL)中，搅拌下加入氰化钠(359mg,7.32mmol)，反应加热至100℃搅拌36小时。将反应液冷却至室温，倒入水中(50mL)，水相用甲基叔丁基醚萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到3-甲基-3-(1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-基)丁腈83e(620mg)，产率：91.0％。83d (850mg, 2.44mmol) was dissolved in dimethylsulfoxide (10mL), sodium cyanide (359mg, 7.32mmol) was added with stirring, and the reaction was heated to 100°C and stirred for 36 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with methyl tert-butyl ether (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 3-methyl-3-(1- ((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)butyronitrile 83e (620 mg), yield: 91.0%.
MS m/z(ESI):280.3[M+H]+.MS m/z(ESI):280.3[M+H] + .
第六步step six
将83e(570mg,2.04mmol)溶解在四丁基氟化胺的四氢呋喃溶液(1M，5mL，5mmol)中加热至50℃搅拌16小时。将反应液冷却至室温，倒入水(50mL)中，水相用二氯甲烷萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到3-甲基-3-(1H-吡唑-3-基)丁腈83f(140mg)，产率：46.0％。83e (570 mg, 2.04 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (1M, 5 mL, 5 mmol) and heated to 50°C for 16 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with dichloromethane (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 3-methyl-3-(1H- Pyrazol-3-yl)butyronitrile 83f (140 mg), yield: 46.0%.
MS m/z(ESI):150.1[M+H]+.MS m/z(ESI):150.1[M+H] + .
第七步step seven
将83f(52mg,0.349mmol)，48a(80mg,0.174mmol)，反-N,N'-二甲基1,2-环己烷二胺(12mg,0.087mmol)，碳酸铯(114mg,0.349mmol)和碘化亚铜(50mg,0.262mmol)溶解在1,4-二氧六环(2mL)中，反应氮气保护下加热至100℃搅拌2小时。反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，浓缩，残余物用反相色谱法以洗脱剂体系C纯化，得到3-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)-3-甲基丁腈83(30mg)，产率：32.6％。83f (52mg, 0.349mmol), 48a (80mg, 0.174mmol), trans-N,N'-dimethyl 1,2-cyclohexanediamine (12mg, 0.087mmol), cesium carbonate (114mg, 0.349mmol ) and cuprous iodide (50mg, 0.262mmol) were dissolved in 1,4-dioxane (2mL), heated to 100°C and stirred for 2 hours under the protection of reaction nitrogen. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by reverse phase chromatography with eluent system C to give 3-(1-(3-chloro- 4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2 '-yl)-1H-pyrazol-3-yl)-3-methylbutyronitrile 83 (30 mg), yield: 32.6%.
MS m/z(ESI):527.2[M+H]+. MS m/z(ESI):527.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.58(d,1H),8.56(s,1H),8.13-8.08(m,1H),7.81(s,1H),6.82(s,1H),6.64(d,1H),2.95(s,2H),2.02(s,3H),2.00(s,3H),1.41(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.61(d,1H),8.58(d,1H),8.56(s,1H),8.13-8.08(m,1H),7.81(s,1H), 6.82(s,1H),6.64(d,1H),2.95(s,2H),2.02(s,3H),2.00(s,3H),1.41(s,6H).
实施例83的拆分Splitting of Example 83
(S)-3-(1-(3-氯-4-(3,5-二氟吡啶-2-基)甲氧基-d2)-5'，6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)-3-甲基丁腈和(R)-3-(1-(3-氯-4-(3,5-二氟吡啶-2-基)甲氧基-d2)-5'，6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)-3-甲基丁腈
(S)-3-(1-(3-chloro-4-(3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl- 2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)-3-methylbutyronitrile and (R)-3-(1-(3-chloro-4 -(3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'- Base)-1H-pyrazol-3-yl)-3-methylbutyronitrile
实施例83(30mg，0.060mmol)经手性拆分(OD柱)得到83-1(9mg，R.T＝3.923min)，产率：29％；83-2(10mg，R.T＝5.647min)，产率：33％。Example 83 (30mg, 0.060mmol) was resolved by chiral resolution (OD column) to obtain 83-1 (9mg, R.T=3.923min), yield: 29%; 83-2 (10mg, R.T=5.647min), yield : 33%.
实施例83-1：MS m/z(ESI):527.1[M+H]+；Embodiment 83-1: MS m/z (ESI): 527.1[M+H] + ;
实施例83-2：MS m/z(ESI):527.2[M+H]+；Example 83-2: MS m/z (ESI): 527.2[M+H] + ;
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例86 Example 86
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-1,2,4-三唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-1,2 ,4-triazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例48的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-1,2,4-三唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮86。Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(2-hydroxyl Propan-2-yl)-1H-1,2,4-triazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 86.
MS m/z(ESI):505.1[M+H]+.MS m/z(ESI):505.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.63(s,1H),8.60(d,1H),8.11-8.06(m,1H),7.82(s,1H),6.80(s,1H),5.21(s,1H),2.05(s,3H),1.99(s,3H),1.53(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ9.28(s,1H),8.63(s,1H),8.60(d,1H),8.11-8.06(m,1H),7.82(s,1H), 6.80(s,1H),5.21(s,1H),2.05(s,3H),1.99(s,3H),1.53(s,6H).
实施例90Example 90
N-(2-(2-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-4-基)丙烷-2-基)乙酰胺
N-(2-(2-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H -[1,4'-bipyridine]-2'-yl)thiazol-4-yl)propan-2-yl)acetamide
参照实施例56的合成方法，合成得到目标产物N-(2-(2-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-4-基)丙烷-2-基)乙酰胺90。Referring to the synthesis method of Example 56, the target product N-(2-(2-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5' , 6-Dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-4-yl)propan-2-yl)acetamide 90.
MS m/z(ESI):562.1[M+H]+；MS m/z(ESI):562.1[M+H] + ;
实施例90的拆分Splitting of Example 90
(S)-N-(2-(2-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-4-基)丙烷-2-基)乙酰胺和(R)-N-(2-(2-(3-氯-4-((3,5- 二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-4-基)丙烷-2-基)乙酰胺
(S)-N-(2-(2-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2 -carbonyl-2H-[1,4'-bipyridine]-2'-yl)thiazol-4-yl)propan-2-yl)acetamide and (R)-N-(2-(2-(3- Chloro-4-((3,5- Difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazol-4-yl )propan-2-yl)acetamide
实施例90(50mg,0.089mmol)经手性拆分(AD柱)得到标题产物90-1(17.8mg，R.T＝4.713min)，产率：35.60％；90-2(19.2mg，R.T＝5.793min)，产率：38.40％。Example 90 (50mg, 0.089mmol) was subjected to chiral resolution (AD column) to obtain the title product 90-1 (17.8mg, R.T=4.713min), yield: 35.60%; 90-2 (19.2mg, R.T=5.793min ), yield: 38.40%.
实施例90-1，MS m/z(ESI):562.1[M+H]+；Embodiment 90-1, MS m/z (ESI): 562.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.61(d,1H),8.15-8.07(m,1H),7.99(s,1H),7.97(s,1H),7.47(s,1H),6.82(s,1H),2.06(s,3H),1.99(s,3H),1.83(s,3H),1.64(s,3H),1.62(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.73(s,1H),8.61(d,1H),8.15-8.07(m,1H),7.99(s,1H),7.97(s,1H), 7.47(s,1H),6.82(s,1H),2.06(s,3H),1.99(s,3H),1.83(s,3H),1.64(s,3H),1.62(s,3H).
实施例90-2，MS m/z(ESI):562.1[M+H]+；Embodiment 90-2, MS m/z (ESI): 562.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.61(d,1H),8.15-8.07(m,1H),7.99(s,1H),7.97(s,1H),7.47(s,1H),6.82(s,1H),2.06(s,3H),1.99(s,3H),1.83(s,3H),1.64(s,3H),1.62(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.73(s,1H),8.61(d,1H),8.15-8.07(m,1H),7.99(s,1H),7.97(s,1H), 7.47(s,1H),6.82(s,1H),2.06(s,3H),1.99(s,3H),1.83(s,3H),1.64(s,3H),1.62(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例91Example 91
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(3-甲基噁丁 环-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyloxetane Cyclo-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one
第一步first step
将1-(3-甲基噁丁环-3-基)乙烷-1-酮91a(1g,8.76mmol)溶解于N,N-二甲基甲酰胺二甲基缩醛(10mL)中，反应加热至100℃搅拌20小时。反应液浓缩，得到(E)-3-(二甲氨基)-1-(3-甲基噁丁环-3-基)丙烷-2-烯-1-酮91b(1.23g)，产率：82.97％，产物不经纯化直接用于下一步反应中。1-(3-Methyloxetan-3-yl)ethan-1-one 91a (1 g, 8.76 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (10 mL), The reaction was heated to 100°C and stirred for 20 hours. The reaction solution was concentrated to obtain (E)-3-(dimethylamino)-1-(3-methyloxetan-3-yl)propane-2-en-1-one 91b (1.23g), yield: 82.97%, the product was directly used in the next reaction without purification.
MS m/z(ESI):170.1[M+H]+；MS m/z(ESI):170.1[M+H] + ;
第二步second step
将(E)-3-(二甲氨基)-1-(3-甲基噁丁环-3-基)丙烷-2-烯-1-酮91b(1.23g,7.27mmol)和水合肼(3mL)溶解于乙醇(9mL)中，反应加热至90℃，搅拌2小时。反应液浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到3-(3-甲基噁丁环-3-基)-1H-吡唑91c(778mg)，产率：77.47％。(E)-3-(Dimethylamino)-1-(3-methyloxetan-3-yl)propane-2-en-1-one 91b (1.23g, 7.27mmol) and hydrazine hydrate (3mL ) was dissolved in ethanol (9 mL), and the reaction was heated to 90° C. and stirred for 2 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 3-(3-methyloxetan-3-yl)-1H-pyrazole 91c (778mg), yield: 77.47%.
MS m/z(ESI):139.1[M+H]+；MS m/z(ESI):139.1[M+H] + ;
第三步third step
氮气保护下，将3-(3-甲基噁丁环-3-基)-1H-吡唑91c(54mg,0.392mmol)，48a(90mg,0.196mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(28mg,0.196mmol)，碘化亚铜(37mg,0.196mmol)和碳酸铯(128mg,0.392mmol)溶解于1，4-二氧六环(2mL)中，反应加热至100℃搅拌2小时。向反应液中加入饱和碳酸氢钠溶液(30mL)，水相用乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到3-氯-4-((3,5-二氟 吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(3-甲基噁丁环-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮91(60mg)，产率：59.27％。Under nitrogen protection, 3-(3-methyloxetan-3-yl)-1H-pyrazole 91c (54mg, 0.392mmol), 48a (90mg, 0.196mmol), (1S,2S)-N1,N2 -Dimethylcyclohexane-1,2-diamine (28mg, 0.196mmol), cuprous iodide (37mg, 0.196mmol) and cesium carbonate (128mg, 0.392mmol) dissolved in 1,4-dioxane (2 mL), the reaction was heated to 100°C and stirred for 2 hours. Saturated sodium bicarbonate solution (30mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 3-chloro-4-((3,5-difluoro Pyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyloxetan-3-yl)-1H-pyrazol-1-yl )-2H-[1,4'-bipyridyl]-2-one 91 (60 mg), yield: 59.27%.
MS m/z(ESI):516.1[M+H]+；MS m/z(ESI):516.1[M+H] + ;
实施例91的拆分Splitting of Example 91
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(3-甲基噁丁环-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(3-甲基噁丁环-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyl Oxetan-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one and (R)-3-chloro-4-((3, 5-Difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyloxetan-3-yl)-1H-pyrazole -1-yl)-2H-[1,4'-bipyridine]-2-one
实施例91(60mg,0.116mmol)经手性拆分(OD柱)得到标题产物91-1(5mg，R.T＝4.297min)，产率：8.33％；91-2(17mg，R.T＝5.570min)，产率：28.33％。Example 91 (60mg, 0.116mmol) was subjected to chiral resolution (OD column) to obtain the title product 91-1 (5mg, R.T=4.297min), yield: 8.33%; 91-2 (17mg, R.T=5.570min), Yield: 28.33%.
实施例91-1，MS m/z(ESI):516.2[M+H]+；Embodiment 91-1, MS m/z (ESI): 516.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.62-8.60(m,2H),8.56(s,1H),8.14-8.06(m,1H),7.86(s,1H),6.80(d,1H),6.65(d,1H),4.92-4.84(m,2H),4.49(d,2H),2.02(s,3H),2.00(s,3H),1.69(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.62-8.60(m,2H),8.56(s,1H),8.14-8.06(m,1H),7.86(s,1H),6.80(d,1H ),6.65(d,1H),4.92-4.84(m,2H),4.49(d,2H),2.02(s,3H),2.00(s,3H),1.69(s,3H).
实施例91-2，MS m/z(ESI):516.2[M+H]+；Embodiment 91-2, MS m/z (ESI): 516.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.62-8.60(m,2H),8.56(s,1H),8.14-8.06(m,1H),7.86(s,1H),6.80(d,1H),6.65(d,1H),4.92-4.84(m,2H),4.49(d,2H),2.02(s,3H),2.00(s,3H),1.69(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.62-8.60(m,2H),8.56(s,1H),8.14-8.06(m,1H),7.86(s,1H),6.80(d,1H ),6.65(d,1H),4.92-4.84(m,2H),4.49(d,2H),2.02(s,3H),2.00(s,3H),1.69(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

HPLC chiral analysis method:

实施例93Example 93
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(甲磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H- Pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one
第一步first step
-78℃下，搅拌下向正丁基锂(2.5M,1.26mL)的四氢呋喃(4mL)溶液中滴加N,N-二甲基-1H-吡唑-1-磺酰胺93a(500mg,2.85mmol)的四氢呋喃(2mL)溶液。反应在-78℃下搅拌10分钟后，向反应液中滴加二甲基二硫(403mg,4.28mmol)，反应升至室温继续搅拌4小时。0℃下向反应液中加入饱和氯化铵溶液(30mL)淬灭反应，水相用乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到N,N-二甲基-5-(甲硫基)-1H-吡唑-1-磺酰胺93b(489mg)，产率：77.4％。At -78°C, N,N-dimethyl-1H-pyrazole-1-sulfonamide 93a (500mg, 2.85 mmol) in tetrahydrofuran (2 mL). After the reaction was stirred at -78°C for 10 minutes, dimethyl disulfide (403 mg, 4.28 mmol) was added dropwise to the reaction solution, and the reaction was raised to room temperature and stirred for 4 hours. Add saturated ammonium chloride solution (30mL) to the reaction solution at 0°C to quench the reaction, the aqueous phase is extracted with ethyl acetate (20mL×2), the organic phases are combined, dried, concentrated, and the residue is subjected to silica gel column chromatography (washing Desystemation B) N,N-dimethyl-5-(methylthio)-1H-pyrazole-1-sulfonamide 93b (489 mg) was isolated, yield: 77.4%.
MS m/z(ESI):222.0[M+H]+；MS m/z(ESI):222.0[M+H] + ;
第二步second step
将N,N-二甲基-5-(甲硫基)-1H-吡唑-1-磺酰胺93b(300mg,1.36mmol)溶解于丙酮(5mL)和水(5mL)的混合溶剂中搅拌，0℃下向以上反应液依次加 入碳酸氢钠(569mg,6.78mmol)和过氧单磺酸钾(2.08g,3.39mmol)。反应升至室温搅拌1小时，向反应液中加入饱和碳酸氢钠溶液(30mL)，水相用乙酸乙酯(25mL×2)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到N,N-二甲基-5-(甲磺酰)-1H-吡唑-1-磺酰胺93c(262mg)，产率：76.3％。Dissolve N,N-dimethyl-5-(methylthio)-1H-pyrazole-1-sulfonamide 93b (300mg, 1.36mmol) in a mixed solvent of acetone (5mL) and water (5mL) and stir, To the above reaction solution at 0°C, add Sodium bicarbonate (569 mg, 6.78 mmol) and potassium peroxymonosulfonate (2.08 g, 3.39 mmol) were added. The reaction was raised to room temperature and stirred for 1 hour, saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried, concentrated, and the residue was subjected to silica gel column chromatography (Eluent system B) N,N-dimethyl-5-(methylsulfonyl)-1H-pyrazole-1-sulfonamide 93c (262 mg) was isolated, yield: 76.3%.
MS m/z(ESI):254.1[M+H]+；MS m/z(ESI):254.1[M+H] + ;
第三步third step
室温下向N,N-二甲基-5-(甲磺酰)-1H-吡唑-1-磺酰胺93c(262mg,1.03mmol)的二氯甲烷(2mL)溶液中滴加三氟乙酸(1mL)，反应搅拌1小时。0℃下向反应液中加入饱和碳酸氢钠溶液至pH>7，水相用乙酸乙酯(20mL×3)萃取，有机相合并，干燥，浓缩得到粗产物3-(甲磺酰)-1H-吡唑93d(80mg)，产物不经进纯化直接用于下一步反应中。Trifluoroacetic acid ( 1 mL), and the reaction was stirred for 1 hour. Add saturated sodium bicarbonate solution to the reaction solution at 0°C until pH>7, extract the aqueous phase with ethyl acetate (20mL×3), combine the organic phases, dry, and concentrate to obtain the crude product 3-(methylsulfonyl)-1H - Pyrazole 93d (80 mg), the product was directly used in the next reaction without further purification.
MS m/z(ESI):147.1[M+H]+；MS m/z(ESI):147.1[M+H] + ;
第四步the fourth step
氮气保护下，将3-(甲磺酰)-1H-吡唑93d(33mg,0.227mmol)，48a(80mg,0.174mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(25mg,0.174mmol)，碘化亚铜(33mg,0.174mmol)和碳酸铯(114mg,0.349mmol)溶解于1，4-二氧六环(2mL)中，反应加热至100℃搅拌2小时。向反应液中加入饱和碳酸氢钠溶液(30mL)，水相用乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(甲磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮93(50mg)，产率：54.72％。Under nitrogen protection, 3-(methylsulfonyl)-1H-pyrazole 93d (33mg, 0.227mmol), 48a (80mg, 0.174mmol), (1S,2S)-N1,N2-dimethylcyclohexane- 1,2-diamine (25mg, 0.174mmol), cuprous iodide (33mg, 0.174mmol) and cesium carbonate (114mg, 0.349mmol) were dissolved in 1,4-dioxane (2mL) and the reaction was heated to Stir at 100°C for 2 hours. Saturated sodium bicarbonate solution (30mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H- Pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one 93 (50 mg), yield: 54.72%.
MS m/z(ESI):524.0[M+H]+；MS m/z(ESI):524.0[M+H] + ;
实施例93的拆分Splitting of Example 93
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(甲磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(甲磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl )-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoropyridine-2- Base)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine ]-2-one
实施例93(58mg,0.111mmol)经手性拆分(OD柱)得到标题产物93-1(24.0 mg，R.T＝7.023min)，产率：41.38％；93-2(19.0mg，R.T＝10.733min)，产率：32.76％。Example 93 (58 mg, 0.111 mmol) was subjected to chiral resolution (OD column) to obtain the title product 93-1 (24.0 mg, RT=7.023min), yield: 41.38%; 93-2 (19.0mg, RT=10.733min), yield: 32.76%.
实施例93-1，MS m/z(ESI):524.1[M+H]+；Embodiment 93-1, MS m/z (ESI): 524.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.87(d,1H),8.68(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.03(s,1H),7.12(d,1H),6.82(d,1H),3.37(s,3H),2.07(s,3H),2.01(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.87(d,1H),8.68(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.03(s,1H), 7.12(d,1H),6.82(d,1H),3.37(s,3H),2.07(s,3H),2.01(s,3H).
实施例93-2，MS m/z(ESI):524.1[M+H]+；Embodiment 93-2, MS m/z (ESI): 524.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.87(d,1H),8.68(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.03(s,1H),7.12(d,1H),6.82(d,1H),3.37(s,3H),2.07(s,3H),2.01(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.87(d,1H),8.68(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.03(s,1H), 7.12(d,1H),6.82(d,1H),3.37(s,3H),2.07(s,3H),2.01(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例94Example 94
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(3-甲基-2-羰基吡咯烷-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮

3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(3-methyl-2- Carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one

第一步first step
室温下将吡咯烷-2-酮94a(4g,47mmol)溶解于乙腈(50mL)中，搅拌下加入4-二甲氨基吡啶(574mg,4.70mmol)和二碳酸二叔丁酯(11.28g,51.70mmol)。反应在20℃下搅拌2小时。用薄层色谱板检测反应显示反应完全。浓缩反应液，残余物用乙酸乙酯(100mL)溶解后，有机相用饱和氯化铵洗涤，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系B)分离得到2-羰基吡咯烷-1-甲酸叔丁酯94b(8g,43.19mmol)，产率：91.90％。Pyrrolidin-2-one 94a (4g, 47mmol) was dissolved in acetonitrile (50mL) at room temperature, and 4-dimethylaminopyridine (574mg, 4.70mmol) and di-tert-butyl dicarbonate (11.28g, 51.70 mmol). The reaction was stirred at 20°C for 2 hours. Detection of the reaction by TLC plate showed complete reaction. The reaction solution was concentrated, the residue was dissolved in ethyl acetate (100 mL), and the organic phase was washed with saturated ammonium chloride, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to obtain tert-butyl 2-carbonylpyrrolidine-1-carboxylate 94b (8 g, 43.19 mmol), yield: 91.90%.
MS m/z(ESI):130.0[M-55]+.MS m/z(ESI):130.0[M-55] + .
第二步second step
氮气保护下,将2-羰基吡咯烷-1-甲酸叔丁酯94b(1g,5.40mmol)溶解于四氢呋喃(20mL)中冷却至-78℃搅拌。向反应液中滴加二异丙基氨基锂(2M,3.24mL)，滴加完成后，反应继续在-78℃搅拌1小时。向反应液中一次性加入1-(1H-咪唑-1-基)乙烷-1-酮(654mg,5.94mmol)，加入完成后，反应在-78℃下搅拌1小时。用薄层色谱板检测反应显示反应完全。-78℃下向反应液中加入饱和氯化铵溶液(10mL)，混合液升温至室温。有机相分离，干燥，浓缩，残余物用硅胶柱色谱法(洗脱剂体系B)分离得到3-乙酰基-2-羰基吡咯烷-1-甲酸叔丁酯94c(1g)，产率：81.50％。Under nitrogen protection, tert-butyl 2-carbonylpyrrolidine-1-carboxylate 94b (1 g, 5.40 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to -78 °C with stirring. Lithium diisopropylamide (2M, 3.24 mL) was added dropwise to the reaction solution. After the dropwise addition was completed, the reaction was continued to stir at -78°C for 1 hour. 1-(1H-imidazol-1-yl)ethan-1-one (654 mg, 5.94 mmol) was added in one portion to the reaction solution, and after the addition was complete, the reaction was stirred at -78°C for 1 hour. Detection of the reaction by TLC plate showed complete reaction. Saturated ammonium chloride solution (10 mL) was added to the reaction solution at -78°C, and the mixture was warmed to room temperature. The organic phase was separated, dried and concentrated, and the residue was separated by silica gel column chromatography (eluent system B) to obtain tert-butyl 3-acetyl-2-carbonylpyrrolidine-1-carboxylate 94c (1g), yield: 81.50 %.
MS m/z(ESI):172.0[M-55]+.MS m/z(ESI):172.0[M-55] + .
第三步third step
氮气保护下,将3-乙酰基-2-羰基吡咯烷-1-甲酸叔丁酯94c(1g,4.40mmol)溶解在四氢呋喃(20mL)中，冷却至0℃搅拌。向反应液中加入氢化钠(211mg,5.28mmol，含量：60％)。反应在0℃下搅拌0.5小时。向反应液中加入碘甲烷(687g,19.36mmol,0.3mL)，反应在0℃下搅拌1小时。向反应液中加入乙酸乙酯(20mL)和饱和氯化铵(10mL)。有机相分离，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系B)分离得到3-乙酰基-3-甲基-2-羰基吡咯烷-1-甲酸叔丁酯94d(1g)，产率：94.19％。 Under nitrogen protection, tert-butyl 3-acetyl-2-carbonylpyrrolidine-1-carboxylate 94c (1 g, 4.40 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C and stirred. Sodium hydride (211 mg, 5.28 mmol, content: 60%) was added to the reaction solution. The reaction was stirred at 0°C for 0.5 hours. Iodomethane (687 g, 19.36 mmol, 0.3 mL) was added to the reaction solution, and the reaction was stirred at 0° C. for 1 hour. Ethyl acetate (20 mL) and saturated ammonium chloride (10 mL) were added to the reaction solution. The organic phase was separated, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system B) to obtain tert-butyl 3-acetyl-3-methyl-2-carbonylpyrrolidine-1-carboxylate 94d (1 g), yield: 94.19%.
MS m/z(ESI):242.1[M+1]+.MS m/z(ESI):242.1[M+1] + .
第四步the fourth step
将3-乙酰基-3-甲基-2-羰基吡咯烷-1-甲酸叔丁酯94d(1g,4.15mmol)溶解于N,N-二甲基甲酰胺二甲基缩醛(10mL)中加热至100℃搅拌16小时。向反应液中加入乙酸乙酯(30mL)，有机相用饱和氯化铵洗涤，干燥，浓缩得到3-(3-(二甲氨基)丙烯酰)-3-甲基-2-羰基吡咯烷-1-甲酸叔丁酯94e(1g)，产物不经纯化直接用于下一步反应。Dissolve tert-butyl 3-acetyl-3-methyl-2-carbonylpyrrolidine-1-carboxylate 94d (1 g, 4.15 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) Heat to 100°C and stir for 16 hours. Ethyl acetate (30 mL) was added to the reaction solution, and the organic phase was washed with saturated ammonium chloride, dried, and concentrated to obtain 3-(3-(dimethylamino)acryloyl)-3-methyl-2-carbonylpyrrolidine- 1-tert-butyl carboxylate 94e (1 g), the product was directly used in the next reaction without purification.
MS m/z(ESI):197.2[M-100]+.MS m/z(ESI):197.2[M-100] + .
第五步the fifth step
将3-(3-(二甲氨基)丙烯酰)-3-甲基-2-羰基吡咯烷-1-甲酸叔丁酯94e(1g,3.37mmol)和水合肼(254mg,6.75mmol，含量：85％)溶解于乙醇(3mL)中加热至90℃搅拌2小时。浓缩反应液，残余物用反相柱分离(甲酸体系)得到3-甲基-3-(1H-吡唑-3-基)吡咯烷-2-酮94f(0.6g)，产率：67.2％。3-(3-(Dimethylamino)acryloyl)-3-methyl-2-carbonylpyrrolidine-1-carboxylic acid tert-butyl ester 94e (1g, 3.37mmol) and hydrazine hydrate (254mg, 6.75mmol, content: 85%) was dissolved in ethanol (3 mL) and heated to 90°C and stirred for 2 hours. The reaction solution was concentrated, and the residue was separated by reverse-phase column (formic acid system) to obtain 3-methyl-3-(1H-pyrazol-3-yl)pyrrolidin-2-one 94f (0.6g), yield: 67.2% .
MS m/z(ESI):166.1[M-100]+.MS m/z(ESI):166.1[M-100] + .
第六步step six
氮气保护下，将3-甲基-3-(1H-吡唑-3-基)吡咯烷-2-酮94f(100mg,0.605mmol)，48a(185mg,0.404mmol)，碳酸铯(263mg,0.807mmol)和碘化亚铜(15mg,0.081mmol)溶解于1,4-二氧六环(2mL)中加热至100℃搅拌4小时。过滤反应液，滤渣用乙酸乙酯洗涤，有机相合并，用饱和氯化铵(10mL)洗涤，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系A)分离得到3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(3-甲基-2-羰基吡咯烷-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮94(80mg)，产率：36.5％。Under nitrogen protection, 3-methyl-3-(1H-pyrazol-3-yl)pyrrolidin-2-one 94f (100mg, 0.605mmol), 48a (185mg, 0.404mmol), cesium carbonate (263mg, 0.807 mmol) and cuprous iodide (15mg, 0.081mmol) were dissolved in 1,4-dioxane (2mL) and heated to 100°C and stirred for 4 hours. The reaction solution was filtered, the filter residue was washed with ethyl acetate, the organic phases were combined, washed with saturated ammonium chloride (10 mL), dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl Base-2'-(3-(3-methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one 94 (80 mg), yield: 36.5%.
MS m/z(ESI):543.1[M+1]+.MS m/z(ESI):543.1[M+1] + .
实施例94的拆分Splitting of Example 94
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-((S)-3-甲基-2-羰基吡咯烷-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮，(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-((R)-3-甲基-2-羰基吡咯烷-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮，(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-((S)-3-甲基-2-羰基吡咯烷-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-((R)-3-甲基-2-羰基吡咯烷-3-基)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-((S) -3-Methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one, (S)-3-chloro -4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-((R)-3-methyl-2 -Carbonylpyrrolidin-3-yl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one, (R)-3-chloro-4-((3, 5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-((S)-3-methyl-2-carbonylpyrrolidine-3- base)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoropyridine-2 -yl)methoxy-d2)-5',6-dimethyl-2'-(3-((R)-3-methyl-2-carbonylpyrrolidin-3-yl)-1H-pyrazole -1-yl)-2H-[1,4'-bipyridine]-2-one
实施例94(80mg,0.147mmol)经手性拆分(OJ柱)得到94A(18mg，R.T＝4.7min)，产率：22.5％；94B(32mg，R.T＝9.6min)，产率：40％。Example 94 (80mg, 0.147mmol) was resolved by chiral resolution (OJ column) to obtain 94A (18mg, R.T=4.7min), yield: 22.5%; 94B (32mg, R.T=9.6min), yield: 40%.
实施例94A，MS m/z(ESI):543.1[M+1]+；Example 94A, MS m/z (ESI): 543.1 [M+1] + ;
实施例94B，MS m/z(ESI):543.1[M+1]+。Example 94B, MS m/z (ESI): 543.1 [M+1] + .
实施例94B(32mg,0.059mmol)经手性拆分(AS柱)得到94-1(14mg,R.T＝6.76min)，产率：43.75％；94-2(12mg，R.T＝8.987min)，产率：37.5％。Example 94B (32mg, 0.059mmol) was resolved by chiral resolution (AS column) to obtain 94-1 (14mg, R.T = 6.76min), yield: 43.75%; 94-2 (12mg, R.T = 8.987min), yield : 37.5%.
实施例94-1，MS m/z(ESI):543.1[M+1]+；Embodiment 94-1, MS m/z (ESI): 543.1[M+1] + ;
1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.55(d,2H),8.10(ddd,1H),7.81(s,1H),7.74(s,1H),6.81(d,1H),6.52(d,1H),3.31–3.20(m,2H),2.70(ddd,1H),2.11–2.02(m,1H),2.02–1.94(m,6H),1.44(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.61(d,1H),8.55(d,2H),8.10(ddd,1H),7.81(s,1H),7.74(s,1H),6.81( d,1H),6.52(d,1H),3.31–3.20(m,2H),2.70(ddd,1H),2.11–2.02(m,1H),2.02–1.94(m,6H),1.44(s, 3H).
实施例94-2，MS m/z(ESI):543.1[M+1]+；Embodiment 94-2, MS m/z (ESI): 543.1[M+1] + ;
1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.55(d,2H),8.10(t,1H),7.80(s,1H),7.72(s,1H),6.80(d,1H),6.53(d,1H),3.26(dd,2H),2.71(ddd,1H),2.06(ddd,1H),2.00(d,6H),1.43(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.61(d,1H),8.55(d,2H),8.10(t,1H),7.80(s,1H),7.72(s,1H),6.80( d,1H),6.53(d,1H),3.26(dd,2H),2.71(ddd,1H),2.06(ddd,1H),2.00(d,6H),1.43(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例96Example 96
3-氯-4-((2,4-二氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮

3-Chloro-4-((2,4-difluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl )-5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one

第一步first step
将2,4-二氟苯甲酸甲酯96a(0.5g,2.90mmol)溶于四氢呋喃(8mL)中搅拌，冰浴下向反应液加入氘化锂铝(122mg,2.90mmol)的四氢呋喃溶液(5mL)。反应在冰浴下搅拌1小时，反应液用饱和氯化铵淬灭，水相用乙酸乙酯(20mL×3)萃取，有机相合并，用饱和氯化钠洗涤，干燥，浓缩，残余物用硅胶柱层析(洗脱体系B)得(2,4-二氟苯基)甲醇-d2-醇96b(0.4g)，产率：94％。Dissolve methyl 2,4-difluorobenzoate 96a (0.5g, 2.90mmol) in tetrahydrofuran (8mL) and stir, add a solution of lithium aluminum deuteride (122mg, 2.90mmol) in tetrahydrofuran (5mL) to the reaction solution under ice cooling ). The reaction was stirred under ice bath for 1 hour, the reaction solution was quenched with saturated ammonium chloride, the aqueous phase was extracted with ethyl acetate (20mL×3), the organic phases were combined, washed with saturated sodium chloride, dried, concentrated, and the residue was washed with Silica gel column chromatography (elution system B) gave (2,4-difluorophenyl)methanol-d 2 -ol 96b (0.4g), yield: 94%.
第二步second step
将(2,4-二氟苯基)甲醇-d2-醇96b(400mg,2.74mmol)和N,N-二甲基甲酰胺(0.05mL)溶于二氯甲烷(10mL)中搅拌，冰浴下向反应液缓慢滴加氯化亚砜(749mg,6.30mmol)。反应转至室温搅拌1小时。反应液浓缩，残余物加入饱和碳酸氢钠溶液稀释，水相用二氯甲烷(20mL×3)萃取，有机向合并，用饱和氯化钠洗涤，干燥，浓缩得到1-(氯甲基-d2)-2,4-二氟苯96c(0.42g)，产物无需纯化，直接用于下步反应。Dissolve (2,4-difluorophenyl)methanol-d 2 -ol 96b (400mg, 2.74mmol) and N,N-dimethylformamide (0.05mL) in dichloromethane (10mL) and stir, ice Thionyl chloride (749 mg, 6.30 mmol) was slowly added dropwise to the reaction solution under the bath. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was diluted with saturated sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (20mL×3), the organic phases were combined, washed with saturated sodium chloride, dried, and concentrated to obtain 1-(chloromethyl-d2 )-2,4-Difluorobenzene 96c (0.42g), the product was directly used in the next step without purification.
第三步third step
参照实施例57第二步的合成方法，合成得到目标产物3-氯-4-((2,4-二氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮96。Referring to the synthesis method in the second step of Example 57, the target product 3-chloro-4-((2,4-difluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxyl Propan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 96.
MS m/z(ESI):503.1[M+H]+.MS m/z(ESI):503.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.55–8.44(m,1H),8.40(s,1H),7.76(s,1H),7.58(td,1H),7.02–6.95(m,1H),6.89(ddd,1H),6.39(s,1H),6.19(d,1H),2.10(s,3H),2.03(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.55–8.44(m,1H),8.40(s,1H),7.76(s,1H),7.58(td,1H),7.02–6.95(m,1H), 6.89(ddd,1H),6.39(s,1H),6.19(d,1H),2.10(s,3H),2.03(s,3H),1.59(d,6H).
实施例96的拆分Splitting of Example 96
(S)-3-氯-4-((2,4-二氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((2,4-二氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-Chloro-4-((2,4-difluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole -1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((2,4-difluorobenzene Base) methoxy-d 2 )-2'-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1 ,4'-bipyridyl]-2-one
实施例96(25mg，0.050mmol)经手性拆分(AS柱)得到96-1(11mg，R.T＝2.660min)，产率：44％；96-2(10mg，R.T＝3.580min)，产率：40％。Example 96 (25mg, 0.050mmol) was obtained by chiral resolution (AS column) to obtain 96-1 (11mg, R.T=2.660min), yield: 44%; 96-2 (10mg, R.T=3.580min), yield : 40%.
实施例96-1：MS m/z(ESI):503.1[M+H]+；Embodiment 96-1: MS m/z (ESI): 503.1 [M+H] + ;
实施例96-2：MS m/z(ESI):503.1[M+H]+.Example 96-2: MS m/z (ESI): 503.1[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例97Example 97
3-氯-4-((4-氯-2-氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-chloro-4-((4-chloro-2-fluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole-1- base)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例96的合成方法，合成得到目标产物3-氯-4-((4-氯-2-氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮97。Referring to the synthesis method of Example 96, the target product 3-chloro-4-((4-chloro-2-fluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropane- 2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one 97.
MS m/z(ESI):519.1[M+H]+.MS m/z(ESI):519.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.49(d,1H),8.41(s,1H),7.77(s,1H),7.55(t,1H),7.26–7.22(m,1H),7.17(dd,1H),6.40(s,1H),6.17(d,1H),2.10(s,3H),2.03(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.49(d,1H),8.41(s,1H),7.77(s,1H),7.55(t,1H),7.26–7.22(m,1H),7.17( dd,1H),6.40(s,1H),6.17(d,1H),2.10(s,3H),2.03(s,3H),1.59(d,6H).
实施例97的拆分Splitting of Example 97
(S)-3-氯-4-((4-氯-2-氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((4-氯-2-氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((4-chloro-2-fluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyridine Azol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((4-chloro-2- Fluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H- [1,4'-bipyridyl]-2-one
实施例97(60mg，0.115mmol)经手性拆分(AS柱)得到97-1(30mg，R.T＝2.650min)，产率：50％；97-2(20mg，R.T＝3.970min)，产率：33％。Example 97 (60mg, 0.115mmol) was obtained by chiral resolution (AS column) to obtain 97-1 (30mg, R.T=2.650min), yield: 50%; 97-2 (20mg, R.T=3.970min), yield : 33%.
实施例97-1：MS m/z(ESI):519.1[M+H]+；Embodiment 97-1: MS m/z (ESI): 519.1 [M+H] + ;
实施例97-2：MS m/z(ESI):519.1[M+H]+；Embodiment 97-2: MS m/z (ESI): 519.1 [M+H] + ;
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例98Example 98
3-氯-4-((2-氯-4-氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-chloro-4-((2-chloro-4-fluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazole-1- base)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例96的合成方法，合成得到目标产物3-氯-4-((2-氯-4-氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮98。Referring to the synthesis method of Example 96, the target product 3-chloro-4-((2-chloro-4-fluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropane- 2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 98.
MS m/z(ESI):519.1[M+H]+.MS m/z(ESI):519.1[M+H] + .
1H NMR(400MHz,CDCl3)δ8.48(d,1H),8.41(s,1H),7.77(s,1H),7.65(dd,1H),7.20(dd,1H),7.14–7.06(m,1H),6.39(d,1H),6.16(d,1H),2.11(s,3H),2.04(s,3H),1.59(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.48(d,1H),8.41(s,1H),7.77(s,1H),7.65(dd,1H),7.20(dd,1H),7.14–7.06( m,1H),6.39(d,1H),6.16(d,1H),2.11(s,3H),2.04(s,3H),1.59(d,6H).
实施例98的拆分Splitting of Example 98
(S)-3-氯-4-((2-氯-4-氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((2-氯-4-氟苯基)甲氧基-d2)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((2-chloro-4-fluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyridine Azol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((2-chloro-4- Fluorophenyl)methoxy-d 2 )-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H- [1,4'-bipyridyl]-2-one
实施例98(60mg，0.115mmol)经手性拆分(AS柱)得到98-1(20mg，R.T＝2.660min)，产率：33％；98-2(17mg，R.T＝3.747min)，产率：28％。Example 98 (60mg, 0.115mmol) was obtained by chiral resolution (AS column) to obtain 98-1 (20mg, R.T=2.660min), yield: 33%; 98-2 (17mg, R.T=3.747min), yield : 28%.
实施例98-1：MS m/z(ESI):519.1[M+H]+；Embodiment 98-1: MS m/z (ESI): 519.1 [M+H] + ;
实施例98-2：MS m/z(ESI):519.1[M+H]+；Embodiment 98-2: MS m/z (ESI): 519.1 [M+H] + ;
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例99Example 99
3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((2,4,6-三氟苯甲基)氧代)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,6- Trifluorobenzyl)oxo)-2H-[1,4'-bipyridyl]-2-one
参照实施例57的合成方法，合成得到目标产物3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((2,4,6-三氟苯甲基)氧代)-2H-[1,4'-联吡啶]-2-酮99。Referring to the synthesis method of Example 57, the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized yl-4-((2,4,6-trifluorobenzyl)oxo)-2H-[1,4'-bipyridyl]-2-one 99.
MS m/z(ESI):519.1[M+H]+.MS m/z(ESI):519.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.51(d,1H),7.79(s,1H),7.44–7.32(m,2H),6.84(s,1H),6.56(d,1H),5.33(s,2H),5.09(s,1H),2.02(s,6H),1.48(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.54(s,1H),8.51(d,1H),7.79(s,1H),7.44–7.32(m,2H),6.84(s,1H), 6.56(d,1H),5.33(s,2H),5.09(s,1H),2.02(s,6H),1.48(s,6H).
实施例100Example 100
3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((2,4,6-三氟苯基)甲氧基-d2)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-4-((2,4,6- Trifluorophenyl)methoxy-d2)-2H-[1,4'-bipyridyl]-2-one
参照实施例96的合成方法，合成得到目标产物3-氯-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-4-((2,4,6-三氟苯基)甲氧基-d2)-2H-[1,4'-联吡啶]-2-酮100。Referring to the synthesis method of Example 96, the target product 3-chloro-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl was synthesized Base-4-((2,4,6-trifluorophenyl)methoxy-d2)-2H-[1,4'-bipyridyl]-2-one 100.
MS m/z(ESI):521.1[M+H]+.MS m/z(ESI):521.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.51(d,1H),7.79(s,1H),7.44–7.32(m,2H),6.84(s,1H),6.56(d,1H),5.09(s,1H),2.02(s,6H),1.48(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.54(s,1H),8.51(d,1H),7.79(s,1H),7.44–7.32(m,2H),6.84(s,1H), 6.56(d,1H),5.09(s,1H),2.02(s,6H),1.48(s,6H).
实施例101Example 101
3-氯-4-((5-氟噻唑-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮

3-Chloro-4-((5-fluorothiazol-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5 ',6-Dimethyl-2H-[1,4'-bipyridyl]-2-one

第一步first step
冰浴下将(5-溴噻唑-2-基)甲醇(1g,5.15mmol)和咪唑(1.05g,15.5mmol)溶解在无水二氯甲烷(20mL)中，搅拌下向反应液加入叔丁基二甲基氯硅烷(1.17g,7.73mmol)。反应在室温下搅拌3小时。将反应液依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到5-溴-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)噻唑101a(1.5g)，产物不经纯化直接用于下步反应。Dissolve (5-bromothiazol-2-yl)methanol (1g, 5.15mmol) and imidazole (1.05g, 15.5mmol) in anhydrous dichloromethane (20mL) under ice-cooling, and add tert-butyl to the reaction solution under stirring. Dimethylchlorosilane (1.17 g, 7.73 mmol). The reaction was stirred at room temperature for 3 hours. The reaction solution was washed with water (30mL) and saturated sodium chloride solution (30mL) successively, dried, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 5-bromo-2-(((tert Butyldimethylsilyl)oxo)methyl)thiazole 101a (1.5g), the product was directly used in the next step without purification.
第二步second step
氮气保护下将101a(1.2g,3.89mmol)溶解在无水四氢呋喃(20mL)中，-78℃下滴加正丁基锂的正己烷溶液(1.6M,3.16mL)，搅拌0.5小时后，加入N-氟代双苯磺酰胺(1.60g,5.06mmol)。反应在-78℃下搅拌2小时。将反应液倒入饱和氯化铵溶液(50mL)中，水相用乙酸乙酯萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-5-氟噻唑101b(460mg)，产率：47.8％。Dissolve 101a (1.2g, 3.89mmol) in anhydrous tetrahydrofuran (20mL) under nitrogen protection, add n-butyl lithium in n-hexane solution (1.6M, 3.16mL) dropwise at -78°C, stir for 0.5 hours, then add N-Fluorobisbenzenesulfonamide (1.60 g, 5.06 mmol). The reaction was stirred at -78°C for 2 hours. The reaction solution was poured into saturated ammonium chloride solution (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-(((tert-butyldi Methylsilyl)oxo)methyl)-5-fluorothiazole 101b (460 mg), yield: 47.8%.
MS m/z(ESI):248.1[M+H]+.MS m/z(ESI):248.1[M+H] + .
第三步third step
将101b(460mg,1.86mmol)溶解在四丁基氟化铵的四氢呋喃溶液(1M,10mL)中，反应在室温下搅拌3小时。将反应液倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到(5-氟噻唑-2-基)甲醇101c(190mg)，产率：76.8％。101b (460 mg, 1.86 mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (1M, 10 mL), and the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain (5-fluorothiazol-2-yl ) methanol 101c (190 mg), yield: 76.8%.
MS m/z(ESI):134.1[M+H]+.MS m/z(ESI):134.1[M+H] + .
第四步the fourth step
将101c(190mg,1.43mmol)和二氯亚砜(509mg,4.28mmol)溶解在无水二氯甲烷(4mL)中，反应在室温下搅拌2小时。将反应液倒入饱和碳酸氢钠溶液(50mL)中，二氯甲烷萃取(30mL×2)。有机相合并，依次用水(30mL) 和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，得到2-(氯甲基)-5-氟噻唑101d(190mg)，产物不经纯化直接用于下步反应。101c (190 mg, 1.43 mmol) and thionyl chloride (509 mg, 4.28 mmol) were dissolved in anhydrous dichloromethane (4 mL), and the reaction was stirred at room temperature for 2 hours. The reaction solution was poured into saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (30 mL×2). The organic phases were combined, followed by water (30mL) Washed with saturated sodium chloride solution (30 mL), dried, and the filtrate was concentrated to obtain 2-(chloromethyl)-5-fluorothiazole 101d (190 mg), which was directly used in the next reaction without purification.
第五步the fifth step
氮气保护下将57a(150mg,0.400mmol)、碳酸钾(166mg,1.20mmol)和18-冠-6(159mg,0.600mmol)溶解在N,N-二甲基甲酰胺(3mL)中，加热至75℃，搅拌下滴加101d(190mg，1.25mmol)。反应在75℃下搅拌1小时，将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，滤液浓缩，残余物用反相色谱法以洗脱剂体系C纯化，得到3-氯-4-((5-氟噻唑-2-基)甲氧基)-2'-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮101(9.8mg)，产率：5.0％。Under nitrogen protection, 57a (150mg, 0.400mmol), potassium carbonate (166mg, 1.20mmol) and 18-crown-6 (159mg, 0.600mmol) were dissolved in N,N-dimethylformamide (3mL) and heated to At 75°C, 101d (190mg, 1.25mmol) was added dropwise with stirring. The reaction was stirred at 75 °C for 1 hour, the reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, the filtrate was concentrated, and the residue was purified by reverse phase chromatography with eluent system C to give 3-chloro-4-((5 -Fluorothiazol-2-yl)methoxy)-2'-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H -[1,4'-bipyridyl]-2-one 101 (9.8 mg), yield: 5.0%.
MS m/z(ESI):490.1[M+H]+.MS m/z(ESI):490.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.51(d,1H),7.78(s,1H),7.72(d,1H),6.78(s,1H),6.57(d,1H),5.56(d,2H),5.13(s,1H),2.00(s,6H),1.48(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.55(s,1H),8.51(d,1H),7.78(s,1H),7.72(d,1H),6.78(s,1H),6.57( d,1H),5.56(d,2H),5.13(s,1H),2.00(s,6H),1.48(s,6H).
实施例102Example 102
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(1-羟基环戊基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(1-hydroxycyclopentyl)-1H-pyrazole-1- base)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
参照实施例48的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(1-羟基环戊基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮102。Referring to the synthesis method of Example 48, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(1-hydroxyl Cyclopentyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 102.
MS m/z(ESI):530.1[M+H]+.MS m/z(ESI):530.1[M+H] + .
实施例102的拆分Splitting of Example 102
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(1-羟基环戊基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(1-羟基环戊基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(1-hydroxycyclopentyl)-1H-pyridine Azol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoro Pyridin-2-yl)methoxy-d 2 )-2'-(3-(1-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H- [1,4'-bipyridyl]-2-one
实施例102(35mg，0.066mmol)经手性拆分(OD柱)得到102-1(11.0mg，R.T＝4.537min)，产率：31％；102-2(13.2mg，R.T＝8.973min)，产率：37％。Example 102 (35mg, 0.066mmol) was resolved by chiral resolution (OD column) to obtain 102-1 (11.0mg, R.T=4.537min), yield: 31%; 102-2 (13.2mg, R.T=8.973min), Yield: 37%.
实施例102-1：MS m/z(ESI):527.1[M+H]+；Example 102-1: MS m/z (ESI): 527.1 [M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.54(s,1H),8.52(d,1H),8.12-8.07(m,1H),7.79(s,1H),6.80(s,1H),6.57(d,1H),4.99(s,1H),2.03-1.96(m,8H),1.86-1.81(d,4H),1.70-1.66(d,2H). 1 H NMR (400MHz,DMSO-d 6 )δ8.61(d,1H),8.54(s,1H),8.52(d,1H),8.12-8.07(m,1H),7.79(s,1H), 6.80(s,1H),6.57(d,1H),4.99(s,1H),2.03-1.96(m,8H),1.86-1.81(d,4H),1.70-1.66(d,2H).
实施例102-2：MS m/z(ESI):527.2[M+H]+；Embodiment 102-2: MS m/z (ESI): 527.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.54(s,1H),8.52(d,1H),8.12-8.07(m,1H),7.79(s,1H),6.80(s,1H),6.57(d,1H),4.99(s,1H),2.03-1.96(m,8H),1.86-1.81(d,4H),1.70-1.66(d,2H). 1 H NMR (400MHz,DMSO-d 6 )δ8.61(d,1H),8.54(s,1H),8.52(d,1H),8.12-8.07(m,1H),7.79(s,1H), 6.80(s,1H),6.57(d,1H),4.99(s,1H),2.03-1.96(m,8H),1.86-1.81(d,4H),1.70-1.66(d,2H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例103Example 103
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(1,1,1,3,3,3-hexafluoro- 2-Hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
第一步first step
将72a(1.0g,3.90mmol)溶解在甲醇(15mL)和水(5mL)中，加入氢氧化钠(468mg,11.7mmol)，反应加热至50℃搅拌2小时。将反应液冷却至室温，倒入水(50mL)中，混合液用稀盐酸调pH至5，水相用乙酸乙酯萃取(50mL×2)。有机相合并，依次用水(50mL)、饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，得到1-(2-三甲基甲硅烷基乙氧基甲基)吡唑-3-甲酸103a(750mg)，产物不经纯化直接用于下步反应。72a (1.0 g, 3.90 mmol) was dissolved in methanol (15 mL) and water (5 mL), sodium hydroxide (468 mg, 11.7 mmol) was added, and the reaction was heated to 50° C. and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), the pH of the mixture was adjusted to 5 with dilute hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL), saturated sodium chloride solution (50 mL), dried, and concentrated to give 1-(2-trimethylsilylethoxymethyl)pyrazole-3-carboxylic acid 103a ( 750 mg), the product was directly used in the next step without purification.
MS m/z(ESI):243.1[M+H]+.MS m/z(ESI):243.1[M+H] + .
第二步second step
将103a(750mg,3.09mmol)溶解在无水二氯甲烷(15mL)中搅拌，加入2,2,2-三氟乙醇(619mg,6.19mmol)，1-羟基苯并三唑(502mg,3.71mmol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(712mg,3.71mmol)和三乙胺(939mg,9.28mmol)，反应在室温下搅拌16小时。反应液依次用水(50mL)、饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到1-(2-三甲基甲硅烷基乙氧基甲基)吡唑-3-甲酸-2,2,2-三氟乙酯103b(530mg)，产率：52.8％。Dissolve 103a (750mg, 3.09mmol) in anhydrous dichloromethane (15mL) and stir, add 2,2,2-trifluoroethanol (619mg, 6.19mmol), 1-hydroxybenzotriazole (502mg, 3.71mmol ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (712mg, 3.71mmol) and triethylamine (939mg, 9.28mmol), the reaction was stirred at room temperature for 16 hours. The reaction solution was washed with water (50mL) and saturated sodium chloride solution (50mL) successively, dried and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 1-(2-trimethylsilyl ethyl Oxymethyl)pyrazole-3-carboxylic acid-2,2,2-trifluoroethyl ester 103b (530 mg), yield: 52.8%.
MS m/z(ESI):325.1[M+H]+.MS m/z(ESI):325.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.09(d,1H),6.90(d,1H),5.52(s,2H),4.97(q,2H),3.57-3.53(m,2H),0.86-0.82(m,2H),-0.05(s,9H). 1 H NMR (400MHz,DMSO-d 6 )δ8.09(d,1H),6.90(d,1H),5.52(s,2H),4.97(q,2H),3.57-3.53(m,2H), 0.86-0.82(m,2H),-0.05(s,9H).
第三步 third step
将103b(430mg,1.33mmol)溶解在无水四氢呋喃(10mL)中，加入四丁基氟化铵的四氢呋喃溶液(1.3mL，1M，1.3mmol)搅拌，冰浴下向反应液滴加(三氟甲基)三甲基硅烷(943mg,6.63mmol)，反应恢复至室温搅拌3小时。将反应液倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到1,1,1,3,3,3-六氟-2-[1-(2-三甲基甲硅烷基乙氧基甲基)吡唑-3-基]丙烷-2-醇103c(240mg)，产率：49.7％。Dissolve 103b (430mg, 1.33mmol) in anhydrous tetrahydrofuran (10mL), add tetrabutylammonium fluoride in tetrahydrofuran (1.3mL, 1M, 1.3mmol) and stir, and add (trifluoro Methyl)trimethylsilane (943mg, 6.63mmol), the reaction was returned to room temperature and stirred for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 1,1,1,3,3, 3-Hexafluoro-2-[1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]propan-2-ol 103c (240 mg), yield: 49.7%.
MS m/z(ESI):365.0[M+H]+.MS m/z(ESI):365.0[M+H] + .
第四步the fourth step
将103c(240mg,0.659mmol)溶解在四丁基氟化铵的四氢呋喃溶液(3mL，1M，3.0mmol)中，反应加热至60℃搅拌24小时。将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)、饱和氯化钠溶液(30mL)洗涤，干燥，浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到1,1,1,3,3,3-六氟-2-(1H-吡唑-3-基)丙烷-2-醇103d(55mg)，产率：35.7％。103c (240mg, 0.659mmol) was dissolved in tetrabutylammonium fluoride in tetrahydrofuran (3mL, 1M, 3.0mmol), and the reaction was heated to 60°C and stirred for 24 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL), saturated sodium chloride solution (30 mL), dried, concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 1,1,1,3,3, 3-Hexafluoro-2-(1H-pyrazol-3-yl)propan-2-ol 103d (55 mg), Yield: 35.7%.
MS m/z(ESI):235.1[M+H]+.MS m/z(ESI):235.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.27(s,1H),7.86(s,1H),6.48(s,1H). 1 H NMR (400MHz,DMSO-d 6 )δ13.27(s,1H),8.27(s,1H),7.86(s,1H),6.48(s,1H).
第五步the fifth step
将48a(150mg,0.327mmol)溶解在1,4-二氧六环(3mL)中，加入103d(45mg,0.192mmol)，反-二甲基1,2-环己烷二胺(23mg,0.164mmol)，碳酸铯(213mg,0.654mmol)和碘化亚铜(93mg,0.490mmol)，反应在氮气保护下加热至100℃搅拌2小时。将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，浓缩，残余物用反相色谱法以洗脱剂体系C纯化，得到3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(1,1,1,3,3,3-六氟-2-羟基丙烷-2-基)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮103(4.8mg)，产率：2.2％。48a (150 mg, 0.327 mmol) was dissolved in 1,4-dioxane (3 mL), and 103d (45 mg, 0.192 mmol), trans-dimethyl 1,2-cyclohexanediamine (23 mg, 0.164 mmol), cesium carbonate (213mg, 0.654mmol) and cuprous iodide (93mg, 0.490mmol), the reaction was heated to 100°C under nitrogen protection and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, concentrated, and the residue was purified by reverse phase chromatography with eluent system C to obtain 3-chloro-4-((3, 5-Difluoropyridin-2-yl)methoxy-d 2 )-2'-(3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- 1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 103 (4.8 mg), yield: 2.2%.
MS m/z(ESI):612.1[M+H]+.MS m/z(ESI):612.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.78(d,1H),8.69(br s,1H),8.63(s,1H),8.61(d,1H),8.12-8.07(m,1H),7.90(s,1H),6.82-6.81(m,2H),2.05(s,3H),2.00(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.78(d,1H),8.69(br s,1H),8.63(s,1H),8.61(d,1H),8.12-8.07(m,1H) ,7.90(s,1H),6.82-6.81(m,2H),2.05(s,3H),2.00(s,3H).
实施例107Example 107
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[ 1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
第一步first step
将11b(400mg,3.17mmol)和乙腈(781mg,19.02mmol)溶解于醋酸(1.52g,25.37mmol)中搅拌，0℃下向反应液中滴加浓硫酸(1.52mL,28.54mmol)。反应升至60℃搅拌2小时。0℃下向反应液中加入饱和碳酸氢钠溶液(40mL)，搅拌0.5小时，水相用乙酸乙酯(25mL×3)萃取，有机相合并，干燥，浓缩，经反相HPLC(碳酸氢铵体系)制备得到N-(2-(1H-吡唑-3-基)丙烷-2-基)乙酰胺107a(53mg)，产率：10％。11b (400mg, 3.17mmol) and acetonitrile (781mg, 19.02mmol) were dissolved in acetic acid (1.52g, 25.37mmol) and stirred, and concentrated sulfuric acid (1.52mL, 28.54mmol) was added dropwise to the reaction solution at 0°C. The reaction was warmed to 60°C and stirred for 2 hours. Added saturated sodium bicarbonate solution (40mL) to the reaction solution at 0°C, stirred for 0.5 hours, extracted the aqueous phase with ethyl acetate (25mL×3), combined the organic phases, dried, concentrated, and analyzed by reverse phase HPLC (ammonium bicarbonate System) to prepare N-(2-(1H-pyrazol-3-yl)propan-2-yl)acetamide 107a (53 mg), yield: 10%.
MS m/z(ESI):168.1[M+H]+；MS m/z(ESI):168.1[M+H] + ;
第二步second step
氮气保护下，将N-(2-(1H-吡唑-3-基)丙烷-2-基)乙酰胺107a(17.9mg,0.107mmol)，11f(35mg,0.077mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(2mg,0.015mmol)，碘化亚铜(3mg,0.015mmol)和碳酸铯(50mg,0.153mmol)溶解于1，4-二氧六环(1.5mL)中，反应加热至100℃搅拌16小时。向反应液中加入饱和氯化铵溶液(30mL)，水相用乙酸乙酯(15mL×2)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺107(28.6mg)，产率：68.8％。Under nitrogen protection, N-(2-(1H-pyrazol-3-yl)propan-2-yl)acetamide 107a (17.9mg, 0.107mmol), 11f (35mg, 0.077mmol), (1S, 2S) -N1,N2-Dimethylcyclohexane-1,2-diamine (2mg, 0.015mmol), cuprous iodide (3mg, 0.015mmol) and cesium carbonate (50mg, 0.153mmol) were dissolved in 1,4- In dioxane (1.5 mL), the reaction was heated to 100° C. and stirred for 16 hours. Saturated ammonium chloride solution (30mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (15mL×2), the organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[ 1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 107 (28.6 mg), yield: 68.8%.
MS m/z(ESI):543.1[M+H]+；MS m/z(ESI):543.1[M+H] + ;
实施例107的拆分 Splitting of Example 107
(S)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl -2H-[1,4'-bipyridine]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-( 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]- 2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例107(45mg，0.083mmol)经手性拆分(OD柱)得到标题产物107-1(14.9mg，R.T＝3.14min)，产率：33.11％；107-2(13.9mg，R.T＝3.62min)，产率：30.89％。Example 107 (45mg, 0.083mmol) was subjected to chiral resolution (OD column) to obtain the title product 107-1 (14.9mg, R.T=3.14min), yield: 33.11%; 107-2 (13.9mg, R.T=3.62min ), yield: 30.89%.
实施例107-1，MS m/z(ESI):543.1[M+H]+；Embodiment 107-1, MS m/z (ESI): 543.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.14-8.04(m,1H),7.93(s,1H),7.77(s,1H),6.80(s,1H),6.42(d,1H),5.48(d,2H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.14-8.04(m,1H),7.93(s,1H), 7.77(s,1H),6.80(s,1H),6.42(d,1H),5.48(d,2H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57 (s,3H).
实施例107-2，MS m/z(ESI):543.1[M+H]+；Embodiment 107-2, MS m/z (ESI): 543.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.14-8.04(m,1H),7.93(s,1H),7.77(s,1H),6.80(s,1H),6.42(d,1H),5.48(d,2H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.14-8.04(m,1H),7.93(s,1H), 7.77(s,1H),6.80(s,1H),6.42(d,1H),5.48(d,2H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57 (s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

HPLC chiral analysis method:

实施例108Example 108
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H -[1,4'-bipyridine]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
参照实施例107的合成方法，合成得到目标产物N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺108。Referring to the synthesis method of Example 107, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5' , 6-Dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 108.
MS m/z(ESI):545.2[M+H]+；MS m/z(ESI):545.2[M+H] + ;
实施例108的拆分Splitting of Example 108
(S)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2 -carbonyl-2H-[1,4'-bipyridine]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1 -(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'- Bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例108(75mg，0.138mmol)经手性拆分(OD柱)得到标题产物108-1(24.3mg，R.T＝3.123min)，产率：32.4％；108-2(24.6mg，R.T＝3.627min)，产率：32.8％。Example 108 (75mg, 0.138mmol) was subjected to chiral resolution (OD column) to obtain the title product 108-1 (24.3mg, R.T=3.123min), yield: 32.4%; 108-2 (24.6mg, R.T=3.627min ), yield: 32.8%.
实施例108-1，MS m/z(ESI):545.2[M+H]+；Embodiment 108-1, MS m/z (ESI): 545.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.13-8.06(m,,1H),7.93(s,1H),7.77(s,1H),6.80(d,1H),6.42(d,1H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.13-8.06(m,,1H),7.93(s,1H) ,7.77(s,1H),6.80(d,1H),6.42(d,1H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57(s,3H).
实施例108-2，MS m/z(ESI):545.2[M+H]+； Embodiment 108-2, MS m/z (ESI): 545.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.13-8.06(m,,1H),7.93(s,1H),7.77(s,1H),6.80(d,1H),6.42(d,1H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.54(s,1H),8.48(d,1H),8.13-8.06(m,,1H),7.93(s,1H) ,7.77(s,1H),6.80(d,1H),6.42(d,1H),2.01(s,6H),1.82(s,3H),1.61(s,3H),1.57(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例109Example 109
N-(2-(1-(3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺

N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1 ,4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide

第一步first step
氮气保护下将11e(400mg,1.21mmol)，碳酸钾(503mg,3.64mmol)和18-冠-6(481mg,1.82mmol)溶解于无水N,N-二甲基甲酰胺(6mL)中，加热至75℃搅拌，向反应液中滴加96c(300mg,1.82mmol)。反应在75℃下搅拌1小时。向反应液中加入水(50mL)，水相用乙酸乙酯萃取(50mL×2)。有机相合并，依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法(洗脱体系B)分离得到2'-溴-3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮109a(480mg)，产率：86.4％。Under nitrogen protection, 11e (400mg, 1.21mmol), potassium carbonate (503mg, 3.64mmol) and 18-crown-6 (481mg, 1.82mmol) were dissolved in anhydrous N,N-dimethylformamide (6mL), Heat to 75°C and stir, and add 96c (300mg, 1.82mmol) dropwise to the reaction liquid. The reaction was stirred at 75°C for 1 hour. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed successively with water (50 mL) and saturated sodium chloride solution (50 mL), dried, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 2'-bromo-3-chloro-4 -((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 109a (480 mg), yield : 86.4%.
MS m/z(ESI):457.0[M+H]+.MS m/z(ESI):457.0[M+H] + .
第二步second step
氮气保护下，将2'-溴-3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮109a(100mg,0.218mmol)，107a(73mg,0.437mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(31mg,0.218mmol)，碘化亚铜(42mg,0.218mmol)和碳酸铯(142mg,0.437mmol)溶解于1，4-二氧六环(2mL)中，反应加热至100℃，搅拌2小时。向反应液中加入饱和碳酸氢钠溶液(30mL)，乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法分离得到N-(2-(1-(3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺109(75mg)，产率：63.10％。Under nitrogen protection, 2'-bromo-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2H-[1,4' -Bipyridine]-2-one 109a (100mg, 0.218mmol), 107a (73mg, 0.437mmol), (1S, 2S)-N1, N2-dimethylcyclohexane-1,2-diamine (31mg, 0.218mmol), cuprous iodide (42mg, 0.218mmol) and cesium carbonate (142mg, 0.437mmol) were dissolved in 1,4-dioxane (2mL), and the reaction was heated to 100°C and stirred for 2 hours. Saturated sodium bicarbonate solution (30mL) was added to the reaction solution, extracted with ethyl acetate (20mL×2), the organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography to obtain N-(2-(1-( 3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2 '-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 109 (75 mg), yield: 63.10%.
MS m/z(ESI):544.2[M+H]+.MS m/z(ESI):544.2[M+H] + .
实施例109的拆分Splitting of Example 109
(S)-N-(2-(1-(3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2-carbonyl- 2H-[1,4'-bipyridine]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-(3 -Chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2' -yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例109(75mg，0.138mmol)经手性拆分(AD柱)得到标题产物109-1(27.2mg，R.T＝4.827min)，产率：36.27％；109-2(27.9mg，R.T＝5.697min)，产率：37.2％。Example 109 (75mg, 0.138mmol) was subjected to chiral resolution (AD column) to obtain the title product 109-1 (27.2mg, R.T=4.827min), yield: 36.27%; 109-2 (27.9mg, R.T=5.697min ), yield: 37.2%.
实施例109-1，MS m/z(ESI):544.2[M+H]+；Embodiment 109-1, MS m/z (ESI): 544.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.49(d,1H),7.96(s,1H),7.78(s,1H),7.76-7.68(m,1H),7.40-7.35(m,1H),7.25-7.19(m,1H),6.83(d,1H),6.43(d,1H),2.02(s,3H),2.01(s,3H),1.82(s,3H),1.61(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.55(s,1H),8.49(d,1H),7.96(s,1H),7.78(s,1H),7.76-7.68(m,1H), 7.40-7.35(m,1H),7.25-7.19(m,1H),6.83(d,1H),6.43(d,1H),2.02(s,3H),2.01(s,3H),1.82(s, 3H), 1.61(s,3H), 1.57(s,3H).
实施例109-2，MS m/z(ESI):544.2[M+H]+；Embodiment 109-2, MS m/z (ESI): 544.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.49(d,1H),7.96(s,1H),7.78(s,1H),7.76-7.68(m,1H),7.40-7.35(m,1H),7.25-7.19(m,1H),6.83(d,1H),6.43(d,1H),2.02(s,3H),2.01(s,3H),1.82(s,3H),1.61(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.55(s,1H),8.49(d,1H),7.96(s,1H),7.78(s,1H),7.76-7.68(m,1H), 7.40-7.35(m,1H),7.25-7.19(m,1H),6.83(d,1H),6.43(d,1H),2.02(s,3H),2.01(s,3H),1.82(s, 3H), 1.61(s,3H), 1.57(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例110 Example 110
N-(2-(1-(3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H-[ 1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
参照实施例109的合成方法，合成得到目标产物N-(2-(1-(3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺110。Referring to the synthesis method of Example 109, the target product N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d 2 )-5',6 -Dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 110.
MS m/z(ESI):562.1[M+H]+.MS m/z(ESI):562.1[M+H] + .
实施例110的拆分Splitting of Example 110
(S)-N-(2-(1-(3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(3-chloro-4-((2,4-difluorophenyl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl -2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2- (1-(3-chloro-4-((2,4-difluorophenyl)methoxy- d 2 )-5',6-dimethyl-2-carbonyl-2H-[1,4'- Bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例110(60mg，0.107mmol)经手性拆分(OD柱)得到110-1(19.4mg，R.T＝4.397min)，产率：32％；110-2(9.7mg，R.T＝5.757min)，产率：16％。Example 110 (60mg, 0.107mmol) was subjected to chiral resolution (OD column) to obtain 110-1 (19.4mg, R.T=4.397min), yield: 32%; 110-2 (9.7mg, R.T=5.757min), Yield: 16%.
实施例110-1：MS m/z(ESI):562.2[M+H]+；Example 110-1: MS m/z (ESI): 562.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.55(s,1H),8.11(s,1H),7.79(s,1H),7.74-7.68(m,1H),7.42-7.39(m,1H),7.24-7.19(m,1H),6.83(s,1H),2.02(s,3H),2.01(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.57(d,1H),8.55(s,1H),8.11(s,1H),7.79(s,1H),7.74-7.68(m,1H), 7.42-7.39(m,1H),7.24-7.19(m,1H),6.83(s,1H),2.02(s,3H),2.01(s,3H),1.80(s,3H),1.60(s, 3H), 1.57(s, 3H).
实施例110-2：MS m/z(ESI):562.2[M+H]+； Example 110-2: MS m/z (ESI): 562.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.55(s,1H),8.11(s,1H),7.79(s,1H),7.73-7.68(m,1H),7.41-7.39(m,1H),7.25-7.18(m,1H),6.83(s,1H),2.02(s,3H),2.01(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.57(d,1H),8.55(s,1H),8.11(s,1H),7.79(s,1H),7.73-7.68(m,1H), 7.41-7.39(m,1H),7.25-7.18(m,1H),6.83(s,1H),2.02(s,3H),2.01(s,3H),1.80(s,3H),1.60(s, 3H), 1.57(s, 3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例111Example 111
N-(2-(1-(3-氯-5',6-二甲基-2-羰基-4-((2,4,6-三氟苯基)甲氧基-d2)-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(3-chloro-5',6-dimethyl-2-carbonyl-4-((2,4,6-trifluorophenyl)methoxy-d 2 )-2H -[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
参照实施例109的合成方法，合成得到目标产物N-(2-(1-(3-氯-5',6-二甲基-2-羰基-4-((2,4,6-三氟苯基)甲氧基-d2)-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺111。Referring to the synthetic method of Example 109, the target product N-(2-(1-(3-chloro-5',6-dimethyl-2-carbonyl-4-((2,4,6-trifluoro Phenyl)methoxy-d2)-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 111 .
MS m/z(ESI):580.2[M+H]+. MS m/z(ESI):580.2[M+H] + .
实施例111的拆分Splitting of Example 111
(S)-N-(2-(1-(3-氯-5',6-二甲基-2-羰基-4-((2,4,6-三氟苯基)甲氧基-d2)-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(3-氯-5',6-二甲基-2-羰基-4-((2,4,6-三氟苯基)甲氧基-d2)-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(3-chloro-5',6-dimethyl-2-carbonyl-4-((2,4,6-trifluorophenyl)methoxy-d 2 )-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-( 2-(1-(3-chloro-5',6-dimethyl-2-carbonyl-4-((2,4,6-trifluorophenyl)methoxy-d 2 )-2H-[1 ,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例111(60mg，0.107mmol)经手性拆分(OD柱)得到111-1(19.4mg，Example 111 (60mg, 0.107mmol) obtained 111-1 (19.4mg,
R.T＝4.397min)，产率：32％；111-2(9.7mg，R.T＝5.757min)，产率：16％。R.T=4.397min), yield: 32%; 111-2 (9.7mg, R.T=5.757min), yield: 16%.
实施例111-1：MS m/z(ESI):580.2[M+H]+；Example 111-1: MS m/z (ESI): 580.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.54(s,1H),8.10(s,1H),7.80(s,1H),7.39-7.34(m,2H),6.84(s,1H),2.01(s,6H),1.80(s,3H),1.60(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.57(d,1H),8.54(s,1H),8.10(s,1H),7.80(s,1H),7.39-7.34(m,2H), 6.84(s,1H),2.01(s,6H),1.80(s,3H),1.60(s,3H),1.57(s,3H).
实施例111-2：MS m/z(ESI):580.2[M+H]+；Example 111-2: MS m/z (ESI): 580.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.54(s,1H),8.10(s,1H),7.80(s,1H),7.39-7.34(m,2H),6.84(s,1H),2.01(s,6H),1.80(s,3H),1.60(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.57(d,1H),8.54(s,1H),8.10(s,1H),7.80(s,1H),7.39-7.34(m,2H), 6.84(s,1H),2.01(s,6H),1.80(s,3H),1.60(s,3H),1.57(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

HPLC chiral analysis method:

实施例112Example 112
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)丙酰胺
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H -[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide
第一步first step
将硫酸(3.40g,34.69mmol)于冰浴下滴加到73a(500mg，3.47mmol)的3-溴丙腈(4.65g，34.69mmol)溶液中搅拌。将反应液升温到30℃搅拌16小时。反应液浓缩，残余物使用Prep-HPLC色谱柱法(甲酸体系)分离得到标题产物3-溴-N-(2-(4-氟-1H-吡唑-3-基)丙烷-2-基)丙酰胺112b(520mg)，产率：53.9％。Add sulfuric acid (3.40g, 34.69mmol) dropwise to a solution of 73a (500mg, 3.47mmol) in 3-bromopropionitrile (4.65g, 34.69mmol) under ice-cooling and stir. The reaction solution was warmed up to 30°C and stirred for 16 hours. The reaction solution was concentrated, and the residue was separated by Prep-HPLC column method (formic acid system) to obtain the title product 3-bromo-N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl) Propionamide 112b (520 mg), yield: 53.9%.
MS m/z(ESI):278.0[M+H]+.MS m/z(ESI):278.0[M+H] + .
第二步second step
将3-溴-N-(2-(4-氟-1H-吡唑-3-基)丙烷-2-基)丙酰胺112b(500mg,1.80mmol)和锌粉(1.17g，17.98mmol)溶解在醋酸(10mL)和四氢呋喃(5mL)溶液中，反应 在25℃下搅拌16小时。反应液过滤，滤液浓缩，残余物用Prep-HPLC色谱柱法(甲酸体系)分离得到标题产物N-(2-(4-氟-1H-吡唑-3-基)丙烷-2-基)丙酰胺112c(260mg)，产率：72.6％。3-Bromo-N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide 112b (500 mg, 1.80 mmol) and zinc powder (1.17 g, 17.98 mmol) were dissolved In a solution of acetic acid (10 mL) and tetrahydrofuran (5 mL), the reaction Stir at 25°C for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by Prep-HPLC column method (formic acid system) to obtain the title product N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propane Amide 112c (260 mg), yield: 72.6%.
MS m/z(ESI):200.1[M+H]+.MS m/z(ESI):200.1[M+H] + .
第三步third step
将N-(2-(4-氟-1H-吡唑-3-基)丙烷-2-基)丙酰胺112c(65mg，0.33mmol)，48a(100mg，0.22mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(12mg，0.09mmol)，碳酸铯(106mg 0.33mmol)，和碘化亚铜(17mg，0.09mmol)溶解到二氧六环(2mL)中，反应加热至100℃搅拌3小时。反应液过滤，滤液浓缩，残余物使用正相硅胶柱色谱法(洗脱剂体系A)分离得到标题产物N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)丙酰胺112(80mg)，产率：63.6％。N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide 112c (65mg, 0.33mmol), 48a (100mg, 0.22mmol), (1S,2S)- N1,N2-Dimethylcyclohexane-1,2-diamine (12mg, 0.09mmol), cesium carbonate (106mg 0.33mmol), and cuprous iodide (17mg, 0.09mmol) were dissolved in dioxane ( 2 mL), the reaction was heated to 100°C and stirred for 3 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by normal phase silica gel column chromatography (eluent system A) to obtain the title product N-(2-(1-(3-chloro-4-((3,5-difluoro Pyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H- Pyrazol-3-yl)propan-2-yl)propanamide 112 (80 mg), yield: 63.6%.
MS m/z(ESI):577.2[M+H]+.MS m/z(ESI):577.2[M+H] + .
实施例112的拆分Splitting of Example 112
(S)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)丙酰胺和(R)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)丙酰胺
(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2 -carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide and (R)-N-( 2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1 ,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)propanamide
实施例112(80mg，0.138mmol)经手性拆分(OD柱)得到112-1(31mg，R.T＝2.840min)，产率：38％；112-2(27mg，R.T＝3.380min)，产率：33％。Example 112 (80mg, 0.138mmol) was subjected to chiral resolution (OD column) to obtain 112-1 (31mg, R.T=2.840min), yield: 38%; 112-2 (27mg, R.T=3.380min), yield : 33%.
实施例112-1：MS m/z(ESI):577.2[M+H]+；Embodiment 112-1: MS m/z (ESI): 577.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.59(m,3H),8.11(m,1H),8.02(s,1H),7.79(s,1H),6.81(d,1H),2.09(q,2H),2.01(d,6H),1.59(d,6H),0.95(t,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.59(m,3H),8.11(m,1H),8.02(s,1H),7.79(s,1H),6.81(d,1H),2.09( q,2H),2.01(d,6H),1.59(d,6H),0.95(t,3H).
实施例112-2：MS m/z(ESI):577.2[M+H]+；Embodiment 112-2: MS m/z (ESI): 577.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.59(m,3H),8.11(m,1H),8.02(s,1H),7.79(s,1H),6.81(d,1H),2.09(q,2H),2.01(d,6H),1.59(d,6H),0.95(t,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.59(m,3H),8.11(m,1H),8.02(s,1H),7.79(s,1H),6.81(d,1H),2.09( q,2H),2.01(d,6H),1.59(d,6H),0.95(t,3H).
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例113Example 113
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺-2,2,2-d3
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H -[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide-2,2,2-d3
参照实施例73的合成方法，合成得到目标产物N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺-2,2,2-d3 113。Referring to the synthesis method of Example 73, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5' ,6-Dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide -2,2,2-d3 113.
MS m/z(ESI):566.2[M+H]+.MS m/z(ESI):566.2[M+H] + .
实施例113的拆分Splitting of Example 113
(S)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺-2,2,2-d3和(R)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺-2,2,2-d3
(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2 -Carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide-2,2,2-d3 and (R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl- 2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide-2,2,2- d3
实施例113(60mg，0.106mmol)经手性拆分(OD柱)得到113-1(23mg，R.T＝3.003min)，产率：38％；113-2(27mg，R.T＝3.943min)，产率：33％。Example 113 (60mg, 0.106mmol) was resolved by chiral resolution (OD column) to obtain 113-1 (23mg, R.T=3.003min), yield: 38%; 113-2 (27mg, R.T=3.943min), yield : 33%.
实施例113-1：MS m/z(ESI):566.2[M+H]+；Embodiment 113-1: MS m/z (ESI): 566.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.36(m,3H),7.67(s,1H),7.33(m,1H),6.41(d,1H),6.34(s,1H),2.06(d,6H),1.76(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.36(m,3H),7.67(s,1H),7.33(m,1H),6.41(d,1H),6.34(s,1H),2.06(d, 6H), 1.76(d, 6H).
实施例113-2：MS m/z(ESI):566.2[M+H]+；Embodiment 113-2: MS m/z (ESI): 566.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.36(m,3H),7.67(s,1H),7.33(m,1H),6.41(d,1H),6.34(s,1H),2.06(d,6H),1.76(d,6H). 1 H NMR (400MHz, CDCl 3 )δ8.36(m,3H),7.67(s,1H),7.33(m,1H),6.41(d,1H),6.34(s,1H),2.06(d, 6H), 1.76(d, 6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例114Example 114
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-(三氟甲基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-oxo -2H-[1,4'-bipyridine]-2'-yl)-4-(trifluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
第一步first step
冰浴下将4,4,4-三氟丁-2-壬酸乙酯114a(2.0g,12.0mmol)溶于四氢呋喃(30mL)中搅拌，氮气氛围下向反应液中加入三甲基硅烷化重氮甲烷(2M,7.22mL)。反应转至室温搅拌2小时，反应液浓缩后经硅胶柱层析(洗脱体系B)得4-(三氟甲基)-1H-吡唑-3-甲酸乙酯114b(1.5g)，产率：60％。Dissolve 4,4,4-trifluorobutan-2-nonanoic acid ethyl ester 114a (2.0g, 12.0mmol) in tetrahydrofuran (30mL) under ice bath and stir, add trimethylsilylation to the reaction solution under nitrogen atmosphere Diazomethane (2M, 7.22 mL). The reaction was stirred at room temperature for 2 hours, and the reaction solution was concentrated and subjected to silica gel column chromatography (elution system B) to obtain 4-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid ethyl ester 114b (1.5g), producing Rate: 60%.
MS m/z(ESI):209.1[M+H]+.MS m/z(ESI):209.1[M+H] + .
第二步second step
参照实施例73第一步的合成方法，合成得到2-(4-(三氟甲基)-1H-吡唑-3-基)丙烷-2-醇114c。Referring to the synthesis method in the first step of Example 73, 2-(4-(trifluoromethyl)-1H-pyrazol-3-yl)propan-2-ol 114c was synthesized.
MS m/z(ESI):195.1[M+H]+.MS m/z(ESI):195.1[M+H] + .
第三步third step
参照实施例73第二步的合成方法，合成得到N-(2-(4-(三氟甲基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺114d。Referring to the synthesis method in the second step of Example 73, N-(2-(4-(trifluoromethyl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 114d was synthesized.
MS m/z(ESI):236.1[M+H]+.MS m/z(ESI):236.1[M+H] + .
第四步the fourth step
参照实施例73第三步的合成方法，合成得到目标产物N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-(三氟甲基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺114。Referring to the synthesis method in the third step of Example 73, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-Dimethyl-2-oxo-2H-[1,4'-bipyridine]-2'-yl)-4-(trifluoromethyl)-1H-pyrazole-3- yl)propan-2-yl)acetamide 114.
MS m/z(ESI):613.2[M+H]+.MS m/z(ESI):613.2[M+H] + .
1H NMR(400MHz,CDCl3)δ8.79(s,1H),8.48–8.34(m,2H),7.75(s,1H), 7.32(ddd,1H),6.42(s,1H),6.00(s,1H),2.11(s,3H),2.03(s,3H),1.96(s,3H),1.84(s,3H),1.59(s,3H). 1 H NMR (400MHz, CDCl 3 )δ8.79(s,1H),8.48–8.34(m,2H),7.75(s,1H), 7.32(ddd,1H),6.42(s,1H),6.00(s,1H),2.11(s,3H),2.03(s,3H),1.96(s,3H),1.84(s,3H),1.59 (s,3H).
实施例115Example 115
N-(1-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)环丁基)乙酰胺
N-(1-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H -[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)cyclobutyl)acetamide
参照实施例73的合成方法，合成得到目标产物N-(1-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)环丁基)乙酰胺115。Referring to the synthesis method of Example 73, the target product N-(1-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5' , 6-Dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)cyclobutyl)acetamide 115.
MS m/z(ESI):575.2[M+H]+.MS m/z(ESI):575.2[M+H] + .
实施例115的拆分Splitting of Example 115
(S)-N-(1-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)环丁基)乙酰胺和(R)-N-(1-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)环丁基)乙酰胺
(S)-N-(1-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2 -carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)cyclobutyl)acetamide and (R)-N-(1- (1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H-[1,4 '-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)cyclobutyl)acetamide
实施例115(50mg，0.087mmol)经手性拆分(OD柱)得到115-1(18mg，R.T＝5.590min)，产率：36％；115-2(16mg，R.T＝7.427min)，产率：32％。Example 115 (50mg, 0.087mmol) was resolved by chiral resolution (OD column) to obtain 115-1 (18mg, R.T=5.590min), yield: 36%; 115-2 (16mg, R.T=7.427min), yield : 32%.
实施例115-1：MS m/z(ESI):575.2[M+H]+；Example 115-1: MS m/z (ESI): 575.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.37(m,3H),7.73(s,1H),7.32(m,1H),6.40(s,1H),2.08(s,3H),2.02(d,6H),1.28(m,6H). 1 H NMR (400MHz, CDCl 3 )δ8.37(m,3H),7.73(s,1H),7.32(m,1H),6.40(s,1H),2.08(s,3H),2.02(d, 6H),1.28(m,6H).
实施例115-2：MS m/z(ESI):575.2[M+H]+；Example 115-2: MS m/z (ESI): 575.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.37(m,3H),7.73(s,1H),7.32(m,1H),6.40(s,1H),2.08(s,3H),2.02(d,6H),1.28(m,6H). 1 H NMR (400MHz, CDCl3) δ8.37(m,3H),7.73(s,1H),7.32(m,1H),6.40(s,1H),2.08(s,3H),2.02(d,6H ),1.28(m,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例116Example 116
N-(2-(4-氯-1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(4-chloro-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl- 2-Carbonyl-2H-[1,4'-bipyridine]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
参照实施例73的合成方法，合成得到目标产物N-(2-(4-氯-1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺116。Referring to the synthesis method of Example 73, the target product N-(2-(4-chloro-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-Dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-1H-pyrazol-3-yl)propane-2-yl)B Amide 116.
MS m/z(ESI):579.1[M+H]+.MS m/z(ESI):579.1[M+H] + .
实施例116的拆分Splitting of Example 116
(S)-N-(2-(4-氯-1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(4-氯 (S)-N-(2-(4-chloro-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6- Dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N- (2-(4-chloro
-1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
-1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H-[1, 4'-bipyridyl]-2'-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例116(70mg，0.107mmol)经手性拆分(OJ柱)得到116-1(34.3mg，R.T＝3.080min)，产率：48％；116-2(30.2mg，R.T＝5.023min)，产率：42％。Example 116 (70mg, 0.107mmol) was resolved by chiral resolution (OJ column) to obtain 116-1 (34.3mg, R.T=3.080min), yield: 48%; 116-2 (30.2mg, R.T=5.023min), Yield: 42%.
实施例116-1：MS m/z(ESI):579.1[M+H]+；Example 116-1: MS m/z (ESI): 579.1 [M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.61(d,1H),8.56(s,1H),8.14(s,1H),8.14-8.07(m,1H),7.81(s,1H),6.81(s,1H),2.01(s,3H),2.00(s,3H),1.81(s,3H),1.60(s,3H),1.56(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.67(s,1H),8.61(d,1H),8.56(s,1H),8.14(s,1H),8.14-8.07(m,1H), 7.81(s,1H),6.81(s,1H),2.01(s,3H),2.00(s,3H),1.81(s,3H),1.60(s,3H),1.56(s,3H).
实施例116-2：MS m/z(ESI):579.1[M+H]+；Embodiment 116-2: MS m/z (ESI): 579.1 [M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.61(d,1H),8.56(s,1H),8.14(s,1H),8.12-8.09(m,1H),7.81(s,1H),6.81(s,1H),2.01(s,3H),2.00(s,3H),1.81(s,3H),1.60(s,3H),1.56(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.67(s,1H),8.61(d,1H),8.56(s,1H),8.14(s,1H),8.12-8.09(m,1H), 7.81(s,1H),6.81(s,1H),2.01(s,3H),2.00(s,3H),1.81(s,3H),1.60(s,3H),1.56(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例117Example 117
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧代 -2H-[1,4'-联吡啶]-2'-基)-4-甲基-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-oxo -2H-[1,4'-bipyridine]-2'-yl)-4-methyl-1H-pyrazol-3-yl)propan-2-yl)acetamide
参照实施例73的合成方法，合成得到目标产物N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-甲基-1H-吡唑-3-基)丙烷-2-基)乙酰胺117。Referring to the synthesis method of Example 73, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5 ',6-Dimethyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-methyl-1H-pyrazol-3-yl)propan-2-yl ) Acetamide 117.
MS m/z(ESI):559.2[M+H]+.MS m/z(ESI):559.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.49(s,1H),8.28(d,1H),8.09(ddd,1H),8.04(s,1H),7.70(s,1H),6.80(d,1H),2.06(d,3H),2.02–1.97(m,6H),1.58(s,3H),1.53(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.60(d,1H),8.49(s,1H),8.28(d,1H),8.09(ddd,1H),8.04(s,1H),7.70( s,1H),6.80(d,1H),2.06(d,3H),2.02–1.97(m,6H),1.58(s,3H),1.53(s,3H).
实施例117的拆分Splitting of Example 117
(S)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-甲基-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-甲基-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl- 2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-methyl-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)- N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-oxo -2H-[1,4'-bipyridine]-2'-yl)-4-methyl-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例117(120mg，0.215mmol)经手性拆分(OD柱)得到117-1(53mg，R.T＝3.000min)，产率：44％；117-2(56mg，R.T＝3.577min)，产率：46％。Example 117 (120mg, 0.215mmol) was obtained by chiral resolution (OD column) to obtain 117-1 (53mg, R.T=3.000min), yield: 44%; 117-2 (56mg, R.T=3.577min), yield : 46%.
实施例117-1：MS m/z(ESI):559.2[M+H]+；Example 117-1: MS m/z (ESI): 559.2[M+H] + ;
实施例117-2：MS m/z(ESI):559.2[M+H]+；Embodiment 117-2: MS m/z (ESI): 559.2[M+H] + ;
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例119Example 119
3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2'-(3-(甲磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazole- 1-yl)-2H-[1,4'-bipyridyl]-2-one
第一步first step
参照实施例93的合成方法，合成得到目标产物3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2'-(3-(甲磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮119(75mg)，产率：65.64％。Referring to the synthesis method of Example 93, the target product 3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2'-(3 -(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one 119 (75 mg), yield: 65.64%.
MS m/z(ESI):523.1[M+H]+.MS m/z(ESI):523.1[M+H] + .
实施例119的拆分Splitting of Example 119
(S)-3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2'-(3-(甲磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((2,4-二氟苯基)甲氧基-d2)-5',6-二甲基-2'-(3-(甲磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5',6-dimethyl-2'-(3-(methylsulfonyl)-1H -pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((2,4-difluorophenyl)methoxy- d2)-5',6-Dimethyl-2'-(3-(methylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one
实施例119(75mg，0.143mmol)经手性拆分(OD柱)得到标题产物119-1(24.1mg，R.T＝6.287min)，产率：32.13％；119-2(25.7mg，R.T＝7.620min)，产率：34.27％。Example 119 (75mg, 0.143mmol) was subjected to chiral resolution (OD column) to obtain the title product 119-1 (24.1mg, R.T=6.287min), yield: 32.13%; 119-2 (25.7mg, R.T=7.620min ), yield: 34.27%.
实施例119-1，MS m/z(ESI):523.1[M+H]+；Embodiment 119-1, MS m/z (ESI): 523.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.87(d,1H),8.68(s,1H),8.03(s,1H),7.76-7.67(m,1H),7.39-7.35(m,1H),7.24-7.18(m,1H),7.12(d,1H),6.84(d,1H),3.37(s,3H),2.07(s,3H),2.02(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.87(d,1H),8.68(s,1H),8.03(s,1H),7.76-7.67(m,1H),7.39-7.35(m,1H ),7.24-7.18(m,1H),7.12(d,1H),6.84(d,1H),3.37(s,3H),2.07(s,3H),2.02(s,3H).
实施例119-2，MS m/z(ESI):523.1[M+H]+；Embodiment 119-2, MS m/z (ESI): 523.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.87(d,1H),8.68(s,1H),8.03(s,1H),7.76-7.67(m,1H),7.39-7.35(m,1H),7.24-7.18(m,1H),7.12(d,1H),6.84(d,1H),3.37(s,3H),2.07(s,3H),2.02(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.87(d,1H),8.68(s,1H),8.03(s,1H),7.76-7.67(m,1H),7.39-7.35(m,1H ),7.24-7.18(m,1H),7.12(d,1H),6.84(d,1H),3.37(s,3H),2.07(s,3H),2.02(s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例120Example 120
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(乙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(ethylsulfonyl)-1H-pyrazol-1-yl)- 5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
参照实施例93的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(乙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮120。Referring to the synthesis method of Example 93, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(ethylsulfonyl) was synthesized )-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 120.
MS m/z(ESI):538.0[M+H]+；MS m/z(ESI):538.0[M+H] + ;
实施例120的拆分Splitting of Example 120
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(乙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(乙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(ethylsulfonyl)-1H-pyrazole-1 -yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoropyridine-2 -yl)methoxy-d2)-2'-(3-(ethylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'- Bipyridyl]-2-one
实施例120(65mg，0.121mmol)经手性拆分(OD柱)得到标题产物120-1(27.8mg，R.T＝6.047min)，产率：42.77％；120-2(26.0mg，R.T＝8.483min)，产率：40％。Example 120 (65mg, 0.121mmol) was subjected to chiral resolution (OD column) to obtain the title product 120-1 (27.8mg, R.T=6.047min), yield: 42.77%; 120-2 (26.0mg, R.T=8.483min ), yield: 40%.
实施例120-1，MS m/z(ESI):538.1[M+H]+；Embodiment 120-1, MS m/z (ESI): 538.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.88(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.02(s,1H),7.11(d,1H),6.81(d,1H),3.44(q,2H),2.07(s,3H),2.00(s,3H),1.20(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.88(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.02(s,1H), 7.11(d,1H),6.81(d,1H),3.44(q,2H),2.07(s,3H),2.00(s,3H),1.20(t,3H).
实施例120-2，MS m/z(ESI):538.1[M+H]+；Embodiment 120-2, MS m/z (ESI): 538.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.88(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.02(s,1H),7.11(d,1H),6.81(d,1H),3.44(q,2H),2.07(s,3H),2.00(s,3H),1.20(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.88(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.07(m,1H),8.02(s,1H), 7.11(d,1H),6.81(d,1H),3.44(q,2H),2.07(s,3H),2.00(s,3H),1.20(t,3H).
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例121Example 121
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl) -5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
参照实施例93的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮121。Referring to the synthesis method of Example 93, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(isopropylsulfonyl) was synthesized Acyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 121.
MS m/z(ESI):552.1[M+H]+；MS m/z(ESI):552.1[M+H] + ;
实施例121的拆分Splitting of Example 121
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazole- 1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoropyridine- 2-yl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4 '-bipyridyl]-2-one
实施例121(75mg，0.136mmol)经手性拆分(OD柱)得到标题产物121-1(27.8mg，R.T＝5.080min)，产率：37.07％；121-2(34.8mg，R.T＝6.020min)，产率：46.40％。Example 121 (75mg, 0.136mmol) obtained the title product 121-1 (27.8mg, R.T=5.080min) through chiral resolution (OD column), yield: 37.07%; 121-2 (34.8mg, R.T=6.020min ), yield: 46.40%.
实施例121-1，MS m/z(ESI):552.1[M+H]+；Embodiment 121-1, MS m/z (ESI): 552.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.89(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.06(m,1H),8.02(s,1H),7.10(d,1H),6.81(d,1H),3.60-3.51(m,1H),2.07(s,3H),2.00(s,3H),1.24(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.89(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.06(m,1H),8.02(s,1H), 7.10(d,1H),6.81(d,1H),3.60-3.51(m,1H),2.07(s,3H),2.00(s,3H),1.24(s,6H).
实施例121-2，MS m/z(ESI):552.1[M+H]+；Embodiment 121-2, MS m/z (ESI): 552.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.89(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.06(m,1H),8.02(s,1H),7.10(d,1H),6.81(d,1H),3.60-3.51(m,1H),2.07(s,3H),2.00(s,3H),1.24(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.89(d,1H),8.67(s,1H),8.61(d,1H),8.14-8.06(m,1H),8.02(s,1H), 7.10(d,1H),6.81(d,1H),3.60-3.51(m,1H),2.07(s,3H),2.00(s,3H),1.24(s,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例122Example 122
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(丙基磺 酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(propylsulfonyl Acyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one
参照实施例93的合成方法，合成得到目标产物3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(丙基磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮122。Referring to the synthesis method of Example 93, the target product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2' was synthesized -(3-(Propylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridyl]-2-one 122.
MS m/z(ESI):552.1[M+H]+；MS m/z(ESI):552.1[M+H] + ;
实施例122的拆分Splitting of Example 122
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(丙基磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2'-(3-(丙基磺酰)-1H-吡唑-1-基)-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2'-(3-(propylsulfonyl Acyl)-1H-pyrazol-1-yl)-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5-difluoropyridine-2 -yl)methoxy-d2)-5',6-dimethyl-2'-(3-(propylsulfonyl)-1H-pyrazol-1-yl)-2H-[1,4'- Bipyridyl]-2-one
实施例122(75mg，0.136mmol)经手性拆分(OD柱)得到标题产物122-1(35.1mg，R.T＝5.693min)，产率：46.80％；122-2(34.0mg，R.T＝7.963min)，产率：45.33％。Example 122 (75mg, 0.136mmol) was subjected to chiral resolution (OD column) to obtain the title product 122-1 (35.1mg, R.T=5.693min), yield: 46.80%; 122-2 (34.0mg, R.T=7.963min ), yield: 45.33%.
实施例122-1，MS m/z(ESI):552.1[M+H]+；Embodiment 122-1, MS m/z (ESI): 552.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.87(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.07(m,1H),8.01(s,1H),7.10(d,1H),6.81(s,1H),3.46-3.38(m,2H),2.06(s,3H),2.00(s,3H),1.75-1.61(m,2H),0.96(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.87(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.07(m,1H),8.01(s,1H), 7.10(d,1H),6.81(s,1H),3.46-3.38(m,2H),2.06(s,3H),2.00(s,3H),1.75-1.61(m,2H),0.96(t, 3H).
实施例122-2，MS m/z(ESI):552.1[M+H]+；Embodiment 122-2, MS m/z (ESI): 552.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.87(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.07(m,1H),8.01(s,1H),7.10(d,1H),6.81(s,1H),3.46-3.38(m,2H),2.06(s,3H),2.00(s,3H),1.75-1.61(m,2H),0.96(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.87(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.07(m,1H),8.01(s,1H), 7.10(d,1H),6.81(s,1H),3.46-3.38(m,2H),2.06(s,3H),2.00(s,3H),1.75-1.61(m,2H),0.96(t, 3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例124Example 124
3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-氟-3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-fluoro-3-(isopropylsulfonyl)-1H-pyrazole- 1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one
第一步first step
0℃向4-氟吡唑124a(1.15g,13.36mmol)的四氢呋喃(34.8mL)溶液中加入氢化钠(695mg,17.37mmol,含量：60％)，搅拌20分钟后向反应液中加入N,N-二甲基磺酰氯(2.11g,14.70mmol,1.58mL)，反应升至室温，搅拌40分钟。0℃下向反应液中缓慢滴加饱和氯化铵溶液(30mL)，水相用乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到4-氟-N,N-二甲基-1H-吡唑-1-磺酰胺124b(2.3g),产率：89.10％。Sodium hydride (695 mg, 17.37 mmol, content: 60%) was added to a solution of 4-fluoropyrazole 124a (1.15 g, 13.36 mmol) in tetrahydrofuran (34.8 mL) at 0°C, stirred for 20 minutes, and N was added to the reaction solution. N-Dimethylsulfonyl chloride (2.11g, 14.70mmol, 1.58mL), the reaction was warmed to room temperature and stirred for 40 minutes. Slowly add saturated ammonium chloride solution (30mL) dropwise to the reaction solution at 0°C, the aqueous phase is extracted with ethyl acetate (20mL×2), the organic phases are combined, dried, concentrated, and the residue is subjected to silica gel column chromatography (elution System B) isolated 4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124b (2.3g), yield: 89.10%.
MS m/z(ESI):194.1[M+H]+；MS m/z(ESI):194.1[M+H] + ;
第二步second step
-78℃下向正丁基锂(2.5M,2.7mL)的四氢呋喃(8mL)溶液中滴加4-氟-N,N-二甲基-1H-吡唑-1-磺酰胺124b(1g,5.18mmol)的四氢呋喃(4mL)溶液，搅拌10分钟后再向以上反应液中滴加二异丙基二硫醚(1.17g,7.76mmol,)，反应升至室温，搅拌16小时。0℃下向反应液中加入饱和氯化铵溶液(30mL)淬灭反应，水相用乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩，残余物经反相HPLC制备得到4-氟-5-(异丙基硫代)-N,N-二甲基-1H-吡唑-1-磺酰胺124c(283mg)，产率：20.45％。Add 4-fluoro-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124b (1g, 5.18mmol) in tetrahydrofuran (4mL), stirred for 10 minutes, and then diisopropyl disulfide (1.17g, 7.76mmol,) was added dropwise to the above reaction solution, and the reaction was raised to room temperature and stirred for 16 hours. Add saturated ammonium chloride solution (30mL) to the reaction solution at 0°C to quench the reaction, the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phases were combined, dried, concentrated, and the residue was prepared by reverse-phase HPLC to obtain 4 -Fluoro-5-(isopropylthio)-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124c (283 mg), yield: 20.45%.
MS m/z(ESI):268.0[M+H]+；MS m/z(ESI):268.0[M+H] + ;
第三步third step
0℃下向4-氟-5-(异丙基硫代)-N,N-二甲基-1H-吡唑-1-磺酰胺124c(215mg,0.804mmol)的二氯甲烷(8mL)溶液中加入间氯过氧苯甲酸(359mg，1.77mmol，纯度：85％)，反应升至室温，搅拌2小时后补加间氯过氧苯甲酸(180mg，0.885mmol，纯度：85％)，反应继续搅拌2小时。向反应液中加入饱和碳酸钠(30mL)溶液，水相用乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到4-氟-5-(异丙基磺酰)-N,N-二甲基-1H-吡唑-1-磺酰胺124d(97mg)，产率：40.29％。4-fluoro-5-(isopropylthio)-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124c (215 mg, 0.804 mmol) in dichloromethane (8 mL) at 0°C Add m-chloroperoxybenzoic acid (359mg, 1.77mmol, purity: 85%), the reaction rises to room temperature, and add m-chloroperoxybenzoic acid (180mg, 0.885mmol, purity: 85%) after stirring for 2 hours, react Stirring was continued for 2 hours. Saturated sodium carbonate (30mL) solution was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phases were combined, dried and concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain 4 -Fluoro-5-(isopropylsulfonyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124d (97 mg), yield: 40.29%.
MS m/z(ESI):300.0[M+H]+；MS m/z(ESI):300.0[M+H] + ;
第四步the fourth step
将4-氟-5-(异丙基磺酰)-N,N-二甲基-1H-吡唑-1-磺酰胺124d(97mg,0.324mmol)溶解于二氯甲烷(2mL)中，向反应液中加入三氟乙酸(1mL)，室温搅拌45分钟。反应液浓缩，残余物经反相HPLC制备得到4-氟-5-(异丙基磺酰)-1H-吡唑124e(60mg)，产率：96.33％。4-Fluoro-5-(isopropylsulfonyl)-N,N-dimethyl-1H-pyrazole-1-sulfonamide 124d (97 mg, 0.324 mmol) was dissolved in dichloromethane (2 mL) and dissolved in Trifluoroacetic acid (1 mL) was added to the reaction solution, and stirred at room temperature for 45 minutes. The reaction solution was concentrated, and the residue was prepared by reverse-phase HPLC to obtain 4-fluoro-5-(isopropylsulfonyl)-1H-pyrazole 124e (60 mg), yield: 96.33%.
MS m/z(ESI):193.0[M+H]+；MS m/z(ESI):193.0[M+H] + ;
第五步 the fifth step
氮气保护下，将48a(45mg,0.098mmol)，4-氟-5-(异丙基磺酰)-1H-吡唑124e(28mg,0.147mmol)，(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(14mg,0.098mmol)，碘化亚铜(19mg,0.098mmol)和碳酸铯(64mg,0.196mmol)溶解于1，4-二氧六环(1mL)中，反应加热至100℃，搅拌2小时。向反应液中加入饱和碳酸氢钠溶液(30mL)，水相用乙酸乙酯(20mL×2)萃取，有机相合并，干燥，浓缩，残余物经反相HPLC制备得到3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-氟-3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮124(45mg)，产率：80.47％。Under nitrogen protection, 48a (45mg, 0.098mmol), 4-fluoro-5-(isopropylsulfonyl)-1H-pyrazole 124e (28mg, 0.147mmol), (1S,2S)-N1,N2-di Methylcyclohexane-1,2-diamine (14mg, 0.098mmol), cuprous iodide (19mg, 0.098mmol) and cesium carbonate (64mg, 0.196mmol) were dissolved in 1,4-dioxane (1mL ), the reaction was heated to 100°C and stirred for 2 hours. Saturated sodium bicarbonate solution (30mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phases were combined, dried, concentrated, and the residue was prepared by reverse phase HPLC to obtain 3-chloro-4-( (3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-fluoro-3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5' , 6-Dimethyl-2H-[1,4'-bipyridine]-2-one 124 (45 mg), yield: 80.47%.
MS m/z(ESI):570.1[M+H]+；MS m/z(ESI):570.1[M+H] + ;
实施例124的拆分Splitting of Example 124
(S)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-氟-3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2'-(4-氟-3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2'-(4-fluoro-3-(isopropylsulfonyl)-1H -pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((3,5- Difluoropyridin-2-yl)methoxy-d2)-2'-(4-fluoro-3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl Base-2H-[1,4'-bipyridyl]-2-one
实施例124(57mg，0.1mmol)经手性拆分(OD柱)得到标题产物124-1(24.8mg，R.T＝5.177min)，产率：43.51％；124-2(22.1mg，R.T＝7.007min)，产率：38.77％。Example 124 (57mg, 0.1mmol) was subjected to chiral resolution (OD column) to obtain the title product 124-1 (24.8mg, R.T=5.177min), yield: 43.51%; 124-2 (22.1mg, R.T=7.007min ), yield: 38.77%.
实施例124-1，MS m/z(ESI):570.1[M+H]+；Embodiment 124-1, MS m/z (ESI): 570.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ9.08(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.06(m,1H),8.02(s,1H),6.80(d,1H),3.60-3.51(m,1H),2.07(s,3H),1.99(s,3H),1.29(d,3H),1.27(d,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.08(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.06(m,1H),8.02(s,1H), 6.80(d,1H),3.60-3.51(m,1H),2.07(s,3H),1.99(s,3H),1.29(d,3H),1.27(d,3H).
实施例124-2，MS m/z(ESI):570.2[M+H]+；Embodiment 124-2, MS m/z (ESI): 570.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ9.08(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.06(m,1H),8.02(s,1H),6.80(d,1H),3.60-3.51(m,1H),2.07(s,3H),1.99(s,3H),1.29(d,3H),1.27(d,3H). 1 H NMR (400MHz,DMSO-d 6 )δ9.08(d,1H),8.67(s,1H),8.60(d,1H),8.14-8.06(m,1H),8.02(s,1H), 6.80(d,1H),3.60-3.51(m,1H),2.07(s,3H),1.99(s,3H),1.29(d,3H),1.27(d,3H).
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例130Example 130
N-(2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)丙烷-2-基)乙酰胺
N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[ 1,4'-bipyridyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide
第一步first step
氮气保护下，将56b(83mg,0.364mmol)，中间体1(100mg,0.243mmol)，1,1-双(二苯基膦)二茂铁二氯化钯(18mg,0.024mmol)和碳酸铯(158mg,0.485mmol)溶解于1，4-二氧六环(1.5mL)和水(0.5mL)的混合溶剂中，反应加热至100℃搅拌2.5小时。反应液浓缩，残余物经硅胶柱色谱法(洗脱体系B)分离得到N-(2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基 -2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)丙烷-2-基)乙酰胺130(60mg)，产率：44.16％。Under nitrogen protection, 56b (83mg, 0.364mmol), intermediate 1 (100mg, 0.243mmol), 1,1-bis(diphenylphosphine)ferrocenepalladium dichloride (18mg, 0.024mmol) and cesium carbonate (158mg, 0.485mmol) was dissolved in a mixed solvent of 1,4-dioxane (1.5mL) and water (0.5mL), and the reaction was heated to 100°C and stirred for 2.5 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (elution system B) to obtain N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy) base)-5',6-dimethyl-2-carbonyl -2H-[1,4'-bipyridyl]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide 130 (60 mg), yield: 44.16%.
MS m/z(ESI):560.2[M+H]+；MS m/z(ESI):560.2[M+H] + ;
实施例130的拆分Splitting of Example 130
(S)-N-(2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)丙烷-2-基)乙酰胺和(R)-N-(2-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)丙烷-2-基)乙酰胺
(S)-N-(2-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl -2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)propan-2-yl)acetamide and (R)-N-(2-(4-(3-chloro- 4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl )thiazol-2-yl)propan-2-yl)acetamide
实施例130(60mg,0.107mmol)经手性拆分(AD柱)得到标题产物130-1(23.7mg，R.T＝4.617min)，产率：39.50％；130-2(22.7mg，R.T＝5.800min)，产率：37.83％。Example 130 (60mg, 0.107mmol) was subjected to chiral resolution (AD column) to obtain the title product 130-1 (23.7mg, R.T=4.617min), yield: 39.50%; 130-2 (22.7mg, R.T=5.800min ), yield: 37.83%.
实施例130-1，MS m/z(ESI):560.1[M+H]+；Embodiment 130-1, MS m/z (ESI): 560.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.15-8.06(m,1H),7.85(s,1H),6.81(s,1H),5.48(d,2H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.15-8.06(m,1H), 7.85(s,1H),6.81(s,1H),5.48(d,2H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63 (s,3H).
实施例130-2，MS m/z(ESI):560.1[M+H]+；Embodiment 130-2, MS m/z (ESI): 560.1[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.15-8.06(m,1H),7.85(s,1H),6.81(s,1H),5.48(d,2H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.70(s,1H),8.61(d,1H),8.48(s,1H),8.16(s,1H),8.15-8.06(m,1H), 7.85(s,1H),6.81(s,1H),5.48(d,2H),2.03(s,3H),1.98(s,3H),1.86(s,3H),1.69(s,3H),1.63 (s,3H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

HPLC chiral analysis method:

实施例131Example 131
N-(2-(1-(3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-6-甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-6-methyl-2-oxo -2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
第一步first step
将49a(120mg,0.393mmol)，73b(73mg,0.393mmol)和碳酸铯(256mg,0.785mmol)溶解于二甲亚砜(4mL)中。反应加热至110℃搅拌16小时。反应液用反相柱(甲酸体系)纯化得产物N-(2-(1-(3,5'-二氯-4-羟基-6-甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺131a(30mg)，收率：19％。49a (120 mg, 0.393 mmol), 73b (73 mg, 0.393 mmol) and cesium carbonate (256 mg, 0.785 mmol) were dissolved in dimethylsulfoxide (4 mL). The reaction was heated to 110°C and stirred for 16 hours. The reaction solution was purified by a reverse-phase column (formic acid system) to obtain the product N-(2-(1-(3,5'-dichloro-4-hydroxyl-6-methyl-2-oxo-2H-[1,4 '-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 131a (30 mg), yield: 19%.
MS m/z(ESI):454.1[M+H]+.MS m/z(ESI):454.1[M+H] + .
第二步second step
将N-(2-(1-(3,5'-二氯-4-羟基-6-甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺131a(30mg,0.066mmol)，7b(22mg,0.132mmol),18-冠-6醚(26mg,0.099mmol)和碳酸钾(27mg,0.198mmol)溶解于N,N-二甲基甲酰胺(1mL)中。反应加热至70℃搅拌2小时。反应液用乙酸乙酯(20mL) 稀释后，有机相用饱和氯化钠(5mL×2)洗涤，干燥，浓缩，残余物用制备型硅胶色谱板纯化(洗脱体系A)得到目标产物N-(2-(1-(3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-6-甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺131。N-(2-(1-(3,5'-dichloro-4-hydroxy-6-methyl-2-oxo-2H-[1,4'-bipyridyl]-2'-yl)- 4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 131a (30mg, 0.066mmol), 7b (22mg, 0.132mmol), 18-crown-6 ether (26mg, 0.099mmol) and Potassium carbonate (27 mg, 0.198 mmol) was dissolved in N,N-dimethylformamide (1 mL). The reaction was heated to 70°C and stirred for 2 hours. Ethyl acetate (20mL) was used for the reaction solution After dilution, the organic phase was washed with saturated sodium chloride (5mL×2), dried and concentrated, and the residue was purified by preparative silica gel chromatography (elution system A) to obtain the target product N-(2-(1-(3, 5'-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-6-methyl-2-oxo-2H-[1,4'-bipyridine ]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 131.
MS m/z(ESI):583.1[M+H]+.MS m/z(ESI):583.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.63–8.57(m,2H),8.14–8.11(m,1H),8.11(s,1H),8.11–8.06(m,1H),6.83(d,1H),2.04(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.81(s,1H),8.63–8.57(m,2H),8.14–8.11(m,1H),8.11(s,1H),8.11–8.06(m ,1H),6.83(d,1H),2.04(s,3H),1.80(s,3H),1.60(s,3H),1.57(s,3H).
实施例131的拆分Splitting of Example 131
(S)-N-(2-(1-(3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-6-甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(3,5'-二氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-6-甲基-2-氧代-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-6-methyl- 2-oxo-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N -(2-(1-(3,5'-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-6-methyl-2-oxo- 2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例131(35mg，0.060mmol)经手性拆分(OD柱)得到131-1(13mg，R.T＝3.033min)，产率：37％；131-2(13mg，R.T＝3.713min)，产率：37％。Example 131 (35mg, 0.060mmol) was resolved by chiral resolution (OD column) to obtain 131-1 (13mg, R.T=3.033min), yield: 37%; 131-2 (13mg, R.T=3.713min), yield : 37%.
实施例131-1：MS m/z(ESI):583.1[M+H]+；Example 131-1: MS m/z (ESI): 583.1 [M+H] + ;
实施例131-2：MS m/z(ESI):583.1[M+H]+；Embodiment 131-2: MS m/z (ESI): 583.1 [M+H] + ;
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

HPLC chiral analysis method:

实施例134Example 134
3-氯-4-((2,4-二氟苯基)甲氧基-d2)-2'-(3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
3-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-Dimethyl-2H-[1,4'-bipyridine]-2-one
参照实施例93的合成方法，合成得到目标产物3-氯-4-((2,4-二氟苯基)甲氧基-d2)-2'-(3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮134。Referring to the synthesis method of Example 93, the target product 3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2'-(3-(isopropylsulfonyl)- 1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridyl]-2-one 134.
MS m/z(ESI):551.1[M+H]+.MS m/z(ESI):551.1[M+H] + .
实施例134的拆分Splitting of Example 134
(S)-3-氯-4-((2,4-二氟苯基)甲氧基-d2)-2'-(3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮和(R)-3-氯-4-((2,4-二氟苯基)甲氧基-d2)-2'-(3-(异丙基磺酰)-1H-吡唑-1-基)-5',6-二甲基-2H-[1,4'-联吡啶]-2-酮
(S)-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl )-5',6-dimethyl-2H-[1,4'-bipyridine]-2-one and (R)-3-chloro-4-((2,4-difluorophenyl)methoxy Base-d2)-2'-(3-(isopropylsulfonyl)-1H-pyrazol-1-yl)-5',6-dimethyl-2H-[1,4'-bipyridine]- 2-keto
实施例134(55mg，0.1mmol)经手性拆分(AD柱)得到标题产物134-1(25.3mg，R.T＝8.657min)，产率：46％；134-2(23.2mg，R.T＝10.253min)，产率：42.18％。Example 134 (55mg, 0.1mmol) obtained the title product 134-1 (25.3mg, R.T=8.657min) through chiral resolution (AD column), yield: 46%; 134-2 (23.2mg, R.T=10.253min ), yield: 42.18%.
实施例134-1，MS m/z(ESI):551.1[M+H]+；Embodiment 134-1, MS m/z (ESI): 551.1 [M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.89(d,1H),8.68(s,1H),8.01(s,1H),7.76-7.67(m,1H),7.39-7.34(m,1H),7.24-7.18(m,1H),7.10(d,1H),6.83(d,1H),3.60-3.50(m,1H),2.06(s,3H),2.01(s,3H),1.24(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.89(d,1H),8.68(s,1H),8.01(s,1H),7.76-7.67(m,1H),7.39-7.34(m,1H ),7.24-7.18(m,1H),7.10(d,1H),6.83(d,1H),3.60-3.50(m,1H),2.06(s,3H),2.01(s,3H),1.24( s,6H).
实施例134-2，MS m/z(ESI):551.1[M+H]+； Embodiment 134-2, MS m/z (ESI): 551.1 [M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.89(d,1H),8.68(s,1H),8.01(s,1H),7.76-7.67(m,1H),7.39-7.34(m,1H),7.24-7.18(m,1H),7.10(d,1H),6.83(d,1H),3.60-3.50(m,1H),2.06(s,3H),2.01(s,3H),1.24(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.89(d,1H),8.68(s,1H),8.01(s,1H),7.76-7.67(m,1H),7.39-7.34(m,1H ),7.24-7.18(m,1H),7.10(d,1H),6.83(d,1H),3.60-3.50(m,1H),2.06(s,3H),2.01(s,3H),1.24( s,6H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例136Example 136
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧代-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)环丙烷甲酰胺
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H -[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanecarboxamide
参照实施例73的合成方法，合成得到目标产物N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧代-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)环丙烷甲酰胺136。Referring to the synthesis method of Example 73, the target product N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5' ,6-Dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropane Formamide 136.
MS m/z(ESI):589.2[M+H]+.MS m/z(ESI):589.2[M+H] + .
实施例136的拆分 Splitting of Example 136
(S)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧代-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)环丙烷甲酰胺和(R)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧代-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)环丙烷甲酰胺
(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2 -carbonyl-2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanecarboxamide and (R)-N -(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5',6-dimethyl-2-carbonyl-2H- [1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanecarboxamide
实施例136(60mg，0.102mmol)经手性拆分(OD柱)得到136-1(22mg，R.T＝2.923min)，产率：36.7％；136-2(23mg，R.T＝4.257min)，产率：38.3％。Example 136 (60mg, 0.102mmol) was resolved by chiral resolution (OD column) to obtain 136-1 (22mg, R.T=2.923min), yield: 36.7%; 136-2 (23mg, R.T=4.257min), yield : 38.3%.
实施例136-1：MS m/z(ESI):589.2[M+H]+；Example 136-1: MS m/z (ESI): 589.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.59(m,3H),8.30(s,1H),8.11(m,1H),7.79(s,1H),6.81(s,1H),2.00(d,6H),1.61(d,7H),0.58(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ8.59(m,3H),8.30(s,1H),8.11(m,1H),7.79(s,1H),6.81(s,1H),2.00( d,6H),1.61(d,7H),0.58(m,4H).
实施例136-2：MS m/z(ESI):589.2[M+H]+；Embodiment 136-2: MS m/z (ESI): 589.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.59(m,3H),8.30(s,1H),8.11(m,1H),7.79(s,1H),6.81(s,1H),2.00(d,6H),1.61(d,7H),0.58(m,4H). 1 H NMR (400MHz,DMSO-d 6 )δ8.59(m,3H),8.30(s,1H),8.11(m,1H),7.79(s,1H),6.81(s,1H),2.00( d,6H),1.61(d,7H),0.58(m,4H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析条件：
HPLC chiral analysis conditions:
实施例139 Example 139
N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)-N-甲基乙酰胺
N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl- 2H-[1,4'-bipyridyl]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide
第一步first step
将73b(150mg,0.810mmol)、碳酸钾(336mg,2.43mmol)和2-(三甲基硅烷基)乙氧甲基氯(162mg,0.972mmol)溶解在N,N-二甲基甲酰胺(2mL)中，反应在室温下搅拌3小时。将反应液倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到N-(2-(4-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺139a(230mg)，产率：90.0％。73b (150 mg, 0.810 mmol), potassium carbonate (336 mg, 2.43 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (162 mg, 0.972 mmol) were dissolved in N,N-dimethylformamide ( 2 mL), the reaction was stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30mL) and saturated sodium chloride solution (30mL), dried, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro -1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 139a (230 mg), yield: 90.0% .
MS m/z(ESI):316.1[M+H]+.MS m/z(ESI):316.1[M+H] + .
第二步second step
冰浴下将139a(230mg,0.729mmol)溶解在无水四氢呋喃(5mL)中，搅拌下加入氢化钠(87mg,2.19mmol,含量：60％)。反应在室温下搅拌0.5小时后，加入碘甲烷(310mg,2.19mmol)，然后在室温下继续搅拌1.5小时。将反应液倒入冰水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到N-(2-(4-氟-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑-3-基)丙烷-2-基)-N-甲基乙酰胺139b(190mg)，产率：79.1％。139a (230mg, 0.729mmol) was dissolved in anhydrous THF (5mL) under ice-cooling, and sodium hydride (87mg, 2.19mmol, content: 60%) was added with stirring. After the reaction was stirred at room temperature for 0.5 hours, iodomethane (310 mg, 2.19 mmol) was added and stirring was continued at room temperature for 1.5 hours. The reaction solution was poured into ice water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30mL) and saturated sodium chloride solution (30mL), dried, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro -1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide 139b (190 mg), Yield: 79.1%.
MS m/z(ESI):330.2[M+H]+.MS m/z(ESI):330.2[M+H] + .
第三步third step
将139b(190mg,0.577mmol)溶解在四丁基氟化胺的四氢呋喃溶液中(1M, 4mL)，反应加热至65℃搅拌6小时。将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到N-(2-(4-氟-1H-吡唑-3-基)丙烷-2-基)-N-甲基乙酰胺139c(70mg)，产率：60.9％。Dissolve 139b (190mg, 0.577mmol) in a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 4 mL), the reaction was heated to 65°C and stirred for 6 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30mL) and saturated sodium chloride solution (30mL), dried, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro -1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide 139c (70 mg), yield: 60.9%.
MS m/z(ESI):200.0[M+H]+.MS m/z(ESI):200.0[M+H] + .
第四步the fourth step
氮气保护下将48a(120mg,0.262mmol)、139c(52mg,0.262mmol)、反-N,N'-二甲基1,2-环己烷二胺(7mg,0.052mmol)、碘化亚铜(75mg,0.392mmol)和碳酸铯(256mg,0.785mmol)溶解在1,4-二氧六环(3mL)中，反应加热至100℃搅拌2小时。将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用反相色谱法以洗脱剂体系C纯化，得到N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)-N-甲基乙酰胺139(70mg)，产率：46.4％。Under nitrogen protection, 48a (120mg, 0.262mmol), 139c (52mg, 0.262mmol), trans-N,N'-dimethyl 1,2-cyclohexanediamine (7mg, 0.052mmol), cuprous iodide (75mg, 0.392mmol) and cesium carbonate (256mg, 0.785mmol) were dissolved in 1,4-dioxane (3mL), and the reaction was heated to 100°C and stirred for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, the filtrate was concentrated, and the residue was purified by reverse phase chromatography with eluent system C to obtain N-(2-(1-( 3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2-carbonyl-2H-[1,4'-bi Pyridin]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide 139 (70 mg), yield: 46.4%.
MS m/z(ESI):577.2[M+H]+.MS m/z(ESI):577.2[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.54(m,2H),8.13-8.08(m,1H),7.76(s,1H),6.81(s,1H),3.02(s,3H),2.01(s,3H),2.00(s,3H),1.99(s,3H),1.64(s,3H),1.62(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.61(d,1H),8.54(m,2H),8.13-8.08(m,1H),7.76(s,1H),6.81(s,1H), 3.02(s,3H),2.01(s,3H),2.00(s,3H),1.99(s,3H),1.64(s,3H),1.62(s,3H).
实施例139的拆分Splitting of Example 139
(S)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)-N-甲基乙酰胺和(R)-N-(2-(1-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)-N-甲基乙酰胺
(S)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl- 2-carbonyl-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide and ( R)-N-(2-(1-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d 2 )-5',6-dimethyl-2 -Carbonyl-2H-[1,4'-bipyridine]-2'-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)-N-methylacetamide
实施例139(70mg，0.107mmol)经手性拆分(OJ柱)得到139-1(34.3mg，R.T＝3.080min)，产率：48％；139-2(30.2mg，R.T＝5.023min)，产率：42％。Example 139 (70mg, 0.107mmol) was subjected to chiral resolution (OJ column) to obtain 139-1 (34.3mg, R.T=3.080min), yield: 48%; 139-2 (30.2mg, R.T=5.023min), Yield: 42%.
实施例139-1：MS m/z(ESI):577.2[M+H]+；Example 139-1: MS m/z (ESI): 577.2[M+H] + ;
实施例139-2：MS m/z(ESI):577.2[M+H]+；Embodiment 139-2: MS m/z (ESI): 577.2[M+H] + ;
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例148Example 148
3-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5'，6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-3-甲基丁腈
3-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4 '-bipyridyl]-2'-yl)thiazol-2-yl)-3-methylbutyronitrile
第一步first step
冰浴下将34d(2.5g,8.99mmol)溶解在无水四氢呋喃(25mL)中，搅拌下向反应液中滴加四氢锂铝的四氢呋喃溶液(1M,8.99mL,8.99mmol)。反应在0℃下搅拌2小时，向反应液中依次滴加水(0.4mL)、15％氢氧化钠溶液(0.4mL) 和水(0.4mL)，混合物在室温下搅拌0.5小时，过滤，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到2-(4-溴噻唑-2-基)-2-甲基丙烷-1-醇148a(450mg)，产率：21.2％。34d (2.5g, 8.99mmol) was dissolved in anhydrous tetrahydrofuran (25mL) under ice-cooling, and a tetrahydrofuran solution of lithium aluminum tetrahydrogen (1M, 8.99mL, 8.99mmol) was added dropwise to the reaction solution with stirring. The reaction was stirred at 0°C for 2 hours, and water (0.4mL) and 15% sodium hydroxide solution (0.4mL) were successively added dropwise to the reaction solution and water (0.4 mL), the mixture was stirred at room temperature for 0.5 hours, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-(4-bromothiazol-2-yl)-2 -Methylpropan-1-ol 148a (450 mg), yield: 21.2%.
MS m/z(ESI):236.0[M+1]+.MS m/z(ESI):236.0[M+1] + .
第二步second step
冰浴下将148a(320mg,1.36mmol)和三乙胺(411mg,4.07mmol)溶解在无水二氯甲烷(10mL)中，搅拌下向反应液滴加甲基磺酰氯(233mg,2.03mmol)，反应在室温下搅拌1小时。将反应液倒入水(50mL)中，水相用二氯甲烷萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到2-(4-溴噻唑-2-基)-2-甲基丙基甲磺酸酯148b(420mg)，产率：98.6％。Dissolve 148a (320mg, 1.36mmol) and triethylamine (411mg, 4.07mmol) in anhydrous dichloromethane (10mL) under ice-cooling, add methanesulfonyl chloride (233mg, 2.03mmol) dropwise to the reaction solution under stirring , and the reaction was stirred at room temperature for 1 hour. The reaction solution was poured into water (50 mL), and the aqueous phase was extracted with dichloromethane (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-(4-bromothiazole-2 -yl)-2-methylpropyl methanesulfonate 148b (420 mg), yield: 98.6%.
MS m/z(ESI):313.9[M+1]+.MS m/z(ESI):313.9[M+1] + .
1H NMR(400MHz,CDCl3)δ7.17(s,1H),4.38(s,2H),2.95(s,3H),1.50(s,6H). 1 H NMR (400MHz, CDCl 3 )δ7.17(s,1H),4.38(s,2H),2.95(s,3H),1.50(s,6H).
第三步third step
氮气保护下将148b(420mg,1.34mmol)和氰化钠(131mg,2.67mmol)溶解在二甲基亚砜(6mL)中，反应加热至80℃搅拌16小时。将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用硅胶柱色谱法纯化(洗脱体系B)，得到3-(4-溴噻唑-2-基)-3-甲基丁腈148c(240mg)，产率：73.3％。148b (420 mg, 1.34 mmol) and sodium cyanide (131 mg, 2.67 mmol) were dissolved in dimethyl sulfoxide (6 mL) under nitrogen protection, and the reaction was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 3-(4-bromothiazole-2 -yl)-3-methylbutyronitrile 148c (240 mg), yield: 73.3%.
MS m/z(ESI):244.9[M+1]+.MS m/z(ESI):244.9[M+1] + .
1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),3.03(s,2H),1.48(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ7.83(s,1H),3.03(s,2H),1.48(s,6H).
第四步the fourth step
氮气保护下将148c(55mg,0.225mmol)，中间体4(100mg,0.150mmol)和双三苯基磷二氯化钯(21mg,0.030mmol)溶解在1,4-二氧六环(2mL)中，反应用微波加热至110℃搅拌1.5小时。将反应液冷却至室温，倒入水(50mL)中，水相用乙酸乙酯萃取(30mL×2)。有机相合并，依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤，干燥，滤液浓缩，残余物用反相色谱法以洗脱剂体系C纯化，得到3-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-3-甲基丁腈148(17mg)，产率：20.3％。Under nitrogen protection, 148c (55mg, 0.225mmol), intermediate 4 (100mg, 0.150mmol) and bistriphenylphosphinepalladium dichloride (21mg, 0.030mmol) were dissolved in 1,4-dioxane (2mL) , the reaction was heated to 110° C. with microwave and stirred for 1.5 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed successively with water (30 mL) and saturated sodium chloride solution (30 mL), dried, the filtrate was concentrated, and the residue was purified by reverse phase chromatography with eluent system C to give 3-(4-(3-chloro -4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridine]-2'- yl)thiazol-2-yl)-3-methylbutyronitrile 148 (17 mg), yield: 20.3%.
MS m/z(ESI):542.1[M+1]+.MS m/z(ESI):542.1[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.60(d,1H),8.28(s,1H),8.12-8.07(m,1H),7.93(s,1H),6.81(s,1H),5.49(s,2H),3.11(s,2H),2.04(s,3H),1.98(s,3H),1.54(s,3H),1.53(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.71(s,1H),8.60(d,1H),8.28(s,1H),8.12-8.07(m,1H),7.93(s,1H), 6.81(s,1H),5.49(s,2H),3.11(s,2H),2.04(s,3H),1.98(s,3H),1.54(s,3H),1.53(s,3H).
实施例148的拆分Splitting of Example 148
(S)-3-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基 -2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-3-甲基丁腈和(R)-3-(4-(3-氯-4-((3,5-二氟吡啶-2-基)甲氧基)-5',6-二甲基-2-羰基-2H-[1,4'-联吡啶]-2'-基)噻唑-2-基)-3-甲基丁腈
(S)-3-(4-(3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl -2H-[1,4'-bipyridine]-2'-yl)thiazol-2-yl)-3-methylbutyronitrile and (R)-3-(4-(3-chloro-4-(( 3,5-difluoropyridin-2-yl)methoxy)-5',6-dimethyl-2-carbonyl-2H-[1,4'-bipyridyl]-2'-yl)thiazole-2 -yl)-3-methylbutyronitrile
实施例148(17mg，0.031mmol)经SFC手性拆分(AD柱)得到148-1(8mg，R.T＝0.792min)，产率：47％；148-2(6mg，R.T＝1.704min)，产率：35％。Example 148 (17mg, 0.031mmol) obtained 148-1 (8mg, R.T=0.792min) through SFC chiral resolution (AD column), yield: 47%; 148-2 (6mg, R.T=1.704min), Yield: 35%.
实施例148-1：MS m/z(ESI):542.1[M+H]+；Example 148-1: MS m/z (ESI): 542.1 [M+H] + ;
实施例148-2：MS m/z(ESI):542.1[M+H]+；Embodiment 148-2: MS m/z (ESI): 542.1 [M+H] + ;
SFC手性拆分条件：
SFC chiral resolution conditions:
SFC手性分析方法：
SFC chiral analysis method:
实施例149Example 149
N-(2-(1-(4-(5-氯-4-((2,4-二氟苯基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H) -yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
第一步first step
氮气保护下，将2-氟-4-碘-5-甲基吡啶149a(2.5g，8.44mmol)，乙脒盐酸盐(1.86g，19.7mmol)，碘化亚铜(188mg，0.986mmol)和碳酸铯(9.64g，29.6mmol)溶于N,N-二甲基甲酰胺(15mL)中。反应加热至100℃搅拌16小时。向反应液加入乙腈(40mL)，经硅藻土过滤后，滤液浓缩。残留物用硅胶柱色谱法(洗脱剂体系A)得产物N-(2-氟-5-甲基吡啶-4-基)乙酰脒149b(650mg)，产率：36％Under nitrogen protection, 2-fluoro-4-iodo-5-methylpyridine 149a (2.5g, 8.44mmol), acetamidine hydrochloride (1.86g, 19.7mmol), cuprous iodide (188mg, 0.986mmol) and cesium carbonate (9.64 g, 29.6 mmol) were dissolved in N,N-dimethylformamide (15 mL). The reaction was heated to 100°C and stirred for 16 hours. Acetonitrile (40 mL) was added to the reaction solution, and after filtration through celite, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluent system A) to obtain the product N-(2-fluoro-5-methylpyridin-4-yl)acetamidine 149b (650mg), yield: 36%
MS m/z(ESI):168.1[M+H]+.MS m/z(ESI):168.1[M+H] + .
第二步second step
将149b(300mg，1.63mmol)、双(2,4,6-三氯苯基)丙二酸酯(832mg，1.8mmol)溶于四氢呋喃(8mL)中。反应液加热至90℃搅拌8小时。反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离，得到产物3-(2-氟-5-甲基吡啶-4-基)-6-羟基-2-甲基嘧啶-4(3H)-酮149c(180mg)，产率：42.7％。149b (300 mg, 1.63 mmol), bis(2,4,6-trichlorophenyl)malonate (832 mg, 1.8 mmol) were dissolved in tetrahydrofuran (8 mL). The reaction solution was heated to 90°C and stirred for 8 hours. The reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 3-(2-fluoro-5-methylpyridin-4-yl)-6-hydroxyl-2-methylpyrimidine- 4(3H)-Kone 149c (180 mg), Yield: 42.7%.
MS m/z(ESI):236.1[M+H]+.MS m/z(ESI):236.1[M+H] + .
第三步third step
将149c(800mg，3.42mmol)，2-(氯甲基-d2)-2,4-二氟苯基(843mg，5.12mmol)，碳酸钾(1.18g，8.54mmol)和18-冠-6醚(903mg，3.42mmol)溶解在N,N-二甲基甲酰胺(10mL)中，反应加热至70℃搅拌3小时。向反应液中加入乙酸乙酯(100mL)，有机相用水洗涤3次，干燥，浓缩。残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物6-((2,4-二氟苯基)甲氧基-d2)-3-(2-氟-5-甲基吡啶-4-基)-2-甲基吡啶-4(3H)-酮149d(820mg)，产率：66.1％。149c (800mg, 3.42mmol), 2-(chloromethyl-d2)-2,4-difluorophenyl (843mg, 5.12mmol), potassium carbonate (1.18g, 8.54mmol) and 18-crown-6 ether (903 mg, 3.42 mmol) was dissolved in N,N-dimethylformamide (10 mL), and the reaction was heated to 70° C. and stirred for 3 hours. Ethyl acetate (100 mL) was added to the reaction solution, and the organic phase was washed with water three times, dried and concentrated. The residue was separated by silica gel column chromatography (eluent system A) to give the product 6-((2,4-difluorophenyl)methoxy-d2)-3-(2-fluoro-5-methylpyridine- 4-yl)-2-methylpyridin-4(3H)-one 149d (820 mg), yield: 66.1%.
MS m/z(ESI):364.1[M+H]+.MS m/z(ESI):364.1[M+H] + .
第四步 the fourth step
将149d(800mg,2.20mmol)和N-氯代丁二酰亚胺(323mg,2.42mmol)溶解于异丙醇(30mL)中，反应加热至60℃搅拌6小时。将反应冷却至室温，反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离得到产物5-氯-6-((2,4-二氟苯基)甲氧基-d2)-3-(2-氟-5-甲基吡啶-4-基)-2-甲基吡啶-4(3H)-酮149e(450mg)，产率：51.4％。149d (800 mg, 2.20 mmol) and N-chlorosuccinimide (323 mg, 2.42 mmol) were dissolved in isopropanol (30 mL), and the reaction was heated to 60° C. and stirred for 6 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product 5-chloro-6-((2,4-difluorophenyl)methoxy-d2) -3-(2-Fluoro-5-methylpyridin-4-yl)-2-methylpyridin-4(3H)-one 149e (450 mg), yield: 51.4%.
MS m/z(ESI):398.1[M+H]+.MS m/z(ESI):398.1[M+H] + .
第五步the fifth step
将149e(800mg,2.20mmol)、73b(800mg,2.20mmol)和碳酸铯(800mg,2.20mmol)溶于乙腈(5mL)中，反应加热至80℃搅拌2小时。将反应冷却至室温，反应液浓缩，残余物用硅胶柱色谱法(洗脱剂体系A)分离，得到产物N-(2-(1-(4-(5-氯-4-((2,4-二氟苯基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺149(70mg)，产率：76.1％。149e (800mg, 2.20mmol), 73b (800mg, 2.20mmol) and cesium carbonate (800mg, 2.20mmol) were dissolved in acetonitrile (5mL), and the reaction was heated to 80°C and stirred for 2 hours. The reaction was cooled to room temperature, the reaction solution was concentrated, and the residue was separated by silica gel column chromatography (eluent system A) to obtain the product N-(2-(1-(4-(5-chloro-4-((2, 4-Difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyridine Azol-3-yl)propan-2-yl)acetamide 149 (70 mg), yield: 76.1%.
MS m/z(ESI):563.2[M+H]+.MS m/z(ESI):563.2[M+H] + .
实施例149的拆分Splitting of Example 149
(S)-N-(2-(1-(4-(5-氯-4-((2,4-二氟苯基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(4-(5-氯-4-((2,4-二氟苯基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone- 1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propane-2-yl)acetamide and (R)-N-(2- (1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinon-1(6H)-yl)-5 -methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例149(70mg，0.124mmol)经手性拆分(IB柱)得到149-1(20.1mg，R.T＝2.720min)，产率：28.7％；149-2(21.1mg，R.T＝3.863min)，产率：30.1％。Example 149 (70mg, 0.124mmol) was resolved by chiral resolution (IB column) to obtain 149-1 (20.1mg, R.T=2.720min), yield: 28.7%; 149-2 (21.1mg, R.T=3.863min), Yield: 30.1%.
实施例149-1：MS m/z(ESI):563.2[M+H]+；Example 149-1: MS m/z (ESI): 563.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.50(d,2H),8.05(s,1H),7.97(s,1H),7.66-7.57(m,1H),7.32-7.24(m,1H),7.14-7.07(m,1H),2.11(s,3H),1.99(s,3H),1.73(s,3H),1.53(s,3H),1.50(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.50(d,2H),8.05(s,1H),7.97(s,1H),7.66-7.57(m,1H),7.32-7.24(m,1H ),7.14-7.07(m,1H),2.11(s,3H),1.99(s,3H),1.73(s,3H),1.53(s,3H),1.50(s,3H).
实施例149-2：MS m/z(ESI):563.2[M+H]+.Example 149-2: MS m/z (ESI): 563.2[M+H] + .
HPLC手性拆分条件：

HPLC chiral separation conditions:

HPLC手性分析方法：
HPLC chiral analysis method:
实施例150Example 150
N-(2-(1-(4-(5-氯-4-((2,4-二氟苯基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H) -yl)-5-methylpyridin-2-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
参照实施例149的合成方法，合成得到目标产物N-(2-(1-(4-(5-氯-4-((2,4-二氟苯基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺150。Referring to the synthesis method of Example 149, the target product N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2- Methyl-6-pyrimidinon-1(6H)-yl)-5-methylpyridin-2-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide 150.
MS m/z(ESI):545.2[M+H]+.MS m/z(ESI):545.2[M+H] + .
实施例150的拆分Splitting of Example 150
(S)-N-(2-(1-(4-(5-氯-4-((2,4-二氟苯基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(4-(5-氯-4-((2,4-二氟苯基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(4-(5-chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinone- 1(6H)-yl)-5-methylpyridin-2-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N-(2-(1-( 4-(5-Chloro-4-((2,4-difluorophenyl)methoxy-d2)-2-methyl-6-pyrimidinon-1(6H)-yl)-5-methylpyridine -2-yl)-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例150(70mg，0.128mmol)经手性拆分(IB柱)得到150-1(21.1mg，R.T＝3.053min)，产率：30.1％；150-2(22.7mg，R.T＝4.670min)，产率：32.4％。Example 150 (70mg, 0.128mmol) was subjected to chiral resolution (IB column) to obtain 150-1 (21.1mg, R.T=3.053min), yield: 30.1%; 150-2 (22.7mg, R.T=4.670min), Yield: 32.4%.
实施例150-1：MS m/z(ESI):545.2[M+H]+；Example 150-1: MS m/z (ESI): 545.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.48(d,1H),8.02(s,1H),7.97(s,1H),7.74-7.63(m,1H),7.40-7.30(m,1H),7.23-7.12(m,1H),6.42(d,1H),2.19(s,3H),2.06(s,3H),1.82(s,3H),1.61(s,3H),1.57(s,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.56(s,1H),8.48(d,1H),8.02(s,1H),7.97(s,1H),7.74-7.63(m,1H), 7.40-7.30(m,1H),7.23-7.12(m,1H),6.42(d,1H),2.19(s,3H),2.06(s,3H),1.82(s,3H),1.61(s, 3H), 1.57(s, 3H).
实施例150-2：MS m/z(ESI):545.2[M+H]+.Example 150-2: MS m/z (ESI): 545.2[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例151Example 151
5-氯-6-((2,4-二氟苯基)甲氧基-d2)-3-(2-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5-甲基吡啶-4-基)-2-甲基嘧啶-4-(3H)-酮
5-Chloro-6-((2,4-difluorophenyl)methoxy-d2)-3-(2-(3-(2-hydroxypropan-2-yl)-1H-pyrazole-1- Base) -5-methylpyridin-4-yl)-2-methylpyrimidin-4-(3H)-one
参照实施例149的合成方法，合成得到目标产物5-氯-6-((2,4-二氟苯基)甲氧基-d2)-3-(2-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5-甲基吡啶-4-基)-2-甲基嘧啶-4-(3H)-酮151。Referring to the synthesis method of Example 149, the target product 5-chloro-6-((2,4-difluorophenyl)methoxy-d2)-3-(2-(3-(2-hydroxypropane- 2-yl)-1H-pyrazol-1-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4-(3H)-one 151.
MS m/z(ESI):504.2[M+H]+.MS m/z(ESI):504.2[M+H] + .
实施例151的拆分Splitting of Example 151
(S)-5-氯-6-((2,4-二氟苯基)甲氧基-d2)-3-(2-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5-甲基吡啶-4-基)-2-甲基嘧啶-4-(3H)-酮和(R)5-氯-6-((2,4-二氟苯基)甲氧基-d2)-3-(2-(3-(2-羟基丙烷-2-基)-1H-吡唑-1-基)-5-甲基吡啶-4-基)-2-甲基嘧啶-4-(3H)-酮
(S)-5-chloro-6-((2,4-difluorophenyl)methoxy-d2)-3-(2-(3-(2-hydroxypropan-2-yl)-1H-pyridine Azol-1-yl)-5-methylpyridin-4-yl)-2-methylpyrimidin-4-(3H)-one and (R)5-chloro-6-((2,4-difluorobenzene Base) methoxy-d2)-3-(2-(3-(2-hydroxypropane-2-yl)-1H-pyrazol-1-yl)-5-methylpyridin-4-yl)-2 -Methylpyrimidin-4-(3H)-one
实施例151(60mg，0.120mmol)经手性拆分(IB柱)得到151-1(17.9mg，R.T＝4.183min)，产率：29.9％；151-2(16.1mg，R.T＝5.350min)，产率：27.8％。Example 151 (60mg, 0.120mmol) was resolved by chiral resolution (IB column) to obtain 151-1 (17.9mg, R.T=4.183min), yield: 29.9%; 151-2 (16.1mg, R.T=5.350min), Yield: 27.8%.
实施例151-1：MS m/z(ESI):504.2[M+H]+；Embodiment 151-1: MS m/z (ESI): 504.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.51(d,1H),8.03(s,1H),7.73-7.64(m,1H),7.39-7.29(m,1H),7.22-7.12(m,1H),6.57(d,1H),5.10(s,1H),2.18(s,3H),2.06(s,3H),1.48(s,6H). 1 H NMR (400MHz,DMSO-d 6 )δ8.56(s,1H),8.51(d,1H),8.03(s,1H),7.73-7.64(m,1H),7.39-7.29(m,1H ),7.22-7.12(m,1H),6.57(d,1H),5.10(s,1H),2.18(s,3H),2.06(s,3H),1.48(s,6H).
实施例151-2：MS m/z(ESI):504.2[M+H]+.Example 151-2: MS m/z (ESI): 504.2[M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例152Example 152
N-(2-(1-(4-(5-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1 (6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
参照实施例149的合成方法，合成得到目标产物N-(2-(1-(4-(5-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺152。Referring to the synthetic method of Example 149, the target product N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2) was synthesized. -2-Methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propane-2-yl)B Amide 152.
MS m/z(ESI):564.2[M+H]+。MS m/z (ESI): 564.2 [M+H] + .
实施例152的拆分Splitting of Example 152
(S)-N-(2-(1-(4-(5-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺和(R)-N-(2-(1-(4-(5-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)乙酰胺
(S)-N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6- Pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)-N- (2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1(6H )-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide
实施例152(50mg，0.088mmol)经手性拆分(IB柱)得到152-1(17.0mg，R.T＝3.077min)，产率：34.0％；152-2(17.1mg，R.T＝4.530min)，产率：34.2％。 Example 152 (50 mg, 0.088 mmol) was subjected to chiral resolution (IB column) to obtain 152-1 (17.0 mg, RT = 3.077 min), yield: 34.0%; 152-2 (17.1 mg, RT = 4.530 min), Yield: 34.2%.
实施例152-1：MS m/z(ESI):564.2[M+H]+；Embodiment 152-1: MS m/z (ESI): 564.2[M+H] + ;
1H NMR(400MHz,CDCl3)δ8.44-8.38(m,2H),8.34(d,1H),7.70(s,1H),7.33-7.27(m,1H),6.27(s,1H),2.21(s,3H),2.14(s,3H),2.03(s,3H),1.80(s,3H),1.73(s,3H)。 1 H NMR (400MHz, CDCl 3 )δ8.44-8.38(m,2H),8.34(d,1H),7.70(s,1H),7.33-7.27(m,1H),6.27(s,1H), 2.21(s,3H), 2.14(s,3H), 2.03(s,3H), 1.80(s,3H), 1.73(s,3H).
实施例152-2：MS m/z(ESI):564.2[M+H]+。Example 152-2: MS m/z (ESI): 564.2 [M+H] + .
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：
HPLC chiral analysis method:
实施例153Example 153
N-(2-(1-(4-(5-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)环丙酰胺
N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1 (6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propane-2-yl)cyclopropanamide
参照实施例149的合成方法，合成得到目标产物N-(2-(1-(4-(5-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)环丙酰胺153。Referring to the synthetic method of Example 149, the target product N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2) was synthesized. -2-Methyl-6-pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propane-2-yl)ring Propionamide 153.
MS m/z(ESI):564.2[M+H]+.MS m/z(ESI):564.2[M+H] + .
实施例153的拆分 Splitting of Example 153
(S)-N-(2-(1-(4-(5-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)环丙酰胺和(R)-N-(2-(1-(4-(5-氯-4-((3,5-二氟吡啶-2-基)甲氧基-d2)-2-甲基-6-嘧啶酮-1(6H)-基)-5-甲基吡啶-2-基)-4-氟-1H-吡唑-3-基)丙烷-2-基)环丙酰胺
(S)-N-(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6- Pyrimidinone-1(6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanamide and (R)-N -(2-(1-(4-(5-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-methyl-6-pyrimidinone-1( 6H)-yl)-5-methylpyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)cyclopropanamide
实施例153(45mg，0.076mmol)经手性拆分(IB柱)得到153-1(13.9mg，R.T＝3.013min)，产率：30.9％；153-2(10.5mg，R.T＝4.853min)，产率：23.3％。Example 153 (45mg, 0.076mmol) was subjected to chiral resolution (IB column) to obtain 153-1 (13.9mg, R.T=3.013min), yield: 30.9%; 153-2 (10.5mg, R.T=4.853min), Yield: 23.3%.
实施例153-1：MS m/z(ESI):590.2[M+H]+；Embodiment 153-1: MS m/z (ESI): 590.2[M+H] + ;
实施例153-2：MS m/z(ESI):590.2[M+H]+；Embodiment 153-2: MS m/z (ESI): 590.2[M+H] + ;
1H NMR(400MHz,DMSO-d6)δ8.58(d,1H),8.57-8.55(m,2H),8.31(s,1H),8.09-8.04(m,1H),8.03(s,1H),2.14(s,3H),2.06(s,3H),2.00(q,1H),1.62(s,3H),1.59(s,3H),0.62-0.52(m,4H)。 1 H NMR (400MHz,DMSO-d 6 )δ8.58(d,1H),8.57-8.55(m,2H),8.31(s,1H),8.09-8.04(m,1H),8.03(s,1H ), 2.14(s,3H), 2.06(s,3H), 2.00(q,1H), 1.62(s,3H), 1.59(s,3H), 0.62-0.52(m,4H).
HPLC手性拆分条件：
HPLC chiral separation conditions:
HPLC手性分析方法：

















HPLC chiral analysis method:

















实施例测试评价Example test evaluation
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The following further describes and explains the present invention in combination with test examples, but these examples are not meant to limit the scope of the present invention.
测试例1、本发明化合物对p38α/MK2酶活抑制作用的测定Test Example 1, Determination of the Inhibitory Effect of Compounds of the Present Invention on p38α/MK2 Enzyme Activity
1.实验目的：该测试例的目的是测量化合物对p38α/MK2酶活的抑制能力。1. Experimental purpose: The purpose of this test example is to measure the inhibitory ability of the compound on p38α/MK2 enzyme activity.
2.实验仪器和试剂：2. Experimental instruments and reagents:
2.1仪器：
2.1 Instruments:
2.2试剂：

2.2 Reagents:

3.实验方法：3. Experimental method:
p38/MK2酶活实验方法：在1×酶反应缓冲液(50mM HEPES pH 7.5,1mM EGTA,10mM MgCl2,2mM DTT,0.01％Tween-20)中，孵育0.06nM p38α(Active p38alpha Protein)，1.2nM MK2(Inactive MK2)以及浓度梯度稀释的化合物1小时。加入50nM ULight-CREBtide和25μM ATP(ATP Solution)，室温反应1.5小时。加入等体积检测及终止混合液(含20mM EDTA以及2nM Europium-anti-phospho-CREB的1×LANCE detection buffer)，混匀离心，贴上封板膜，室温反应1小时。用EnVision仪器的TR-FRET程序进行读板，检测各孔665nm/615nm的荧光值。p38/MK2 enzyme activity assay method: Incubate 0.06nM p38α (Active p38alpha Protein) in 1×enzyme reaction buffer (50mM HEPES pH 7.5, 1mM EGTA, 10mM MgCl 2 , 2mM DTT, 0.01% Tween-20), 1.2 nM MK2 (Inactive MK2) and compound diluted in a concentration gradient for 1 hour. Add 50 nM ULight-CREBtide and 25 μM ATP (ATP Solution), and react at room temperature for 1.5 hours. Add an equal volume of detection and termination mixture solution (1×LANCE detection buffer containing 20mM EDTA and 2nM Europium-anti-phospho-CREB), mix well and centrifuge, attach a sealing film, and react at room temperature for 1 hour. Read the plate with the TR-FRET program of the EnVision instrument, and detect the fluorescence value of each well at 665nm/615nm.
p38酶活实验方法：在1×酶反应缓冲液(50mM HEPES pH 7.5,1mM EGTA,10mM MgCl2,2mM DTT,0.01％Tween-20)中，孵育3nM p38α(Active p38 alpha Protein)，以及浓度梯度稀释的化合物1小时。加入50nM ULight-MBP和50μM ATP(ATP 10mM Solution)，室温反应1.5小时。加入等体积检测及终止混合液(含20mM EDTA以及2nM Europium-anti-P-MBP的1×LANCE detection buffer)，混匀离心，贴上封板膜，室温反应1小时。用EnVision仪器的TR-FRET程序进行读板，检测各孔665nm/615nm的荧光值。p38 enzyme activity assay method: Incubate 3nM p38α (Active p38 alpha Protein) in 1× enzyme reaction buffer (50mM HEPES pH 7.5, 1mM EGTA, 10mM MgCl 2 , 2mM DTT, 0.01% Tween-20), and the concentration gradient Dilute compound for 1 hr. Add 50nM ULight-MBP and 50μM ATP (ATP 10mM Solution), react at room temperature for 1.5 hours. Add an equal volume of detection and termination mixture (1×LANCE detection buffer containing 20mM EDTA and 2nM Europium-anti-P-MBP), mix well and centrifuge, attach a sealing film, and react at room temperature for 1 hour. Read the plate with the TR-FRET program of the EnVision instrument, and detect the fluorescence value of each well at 665nm/615nm.
4.实验数据处理方法：4. Experimental data processing method:
将原始数据(665nm/615nm读值比率)按照以下公式进行计算，得到抑制率。抑制率％＝[(阳性对照孔平均值–样品孔值)/(阳性对照孔平均值–阴性对照孔平均值)]×100，其中阳性对照孔为无化合物酶反应孔，阴性对照孔为不加酶的反应孔。 Calculate the raw data (665nm/615nm reading value ratio) according to the following formula to obtain the inhibition rate. Inhibition rate% = [(average value of positive control wells - value of sample wells) / (average value of positive control wells - average value of negative control wells)] × 100, where the positive control wells are the enzyme reaction wells without compound, and the negative control wells are the wells without compound. Enzyme wells.
使用GraphPad Prism 6中的log(inhibitor)vs.response--Variable slope(four parameters)对化合物浓度及对应的抑制率进行拟合方程分析，拟合曲线并得出化合物IC50值。Use the log(inhibitor)vs.response--Variable slope(four parameters) in GraphPad Prism 6 to analyze the compound concentration and the corresponding inhibition rate by fitting the equation, fit the curve and obtain the compound IC 50 value.
拟合计算方程为Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))The fitting calculation equation is Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
5.实验结果：

5. Experimental results:

6.实验结论：6. Experimental conclusion:
以上数据显示，本发明实施例化合物对p38α/MK2酶活具有较强的抑制能力，同时具有很好的选择性。The above data show that the compounds of the examples of the present invention have strong inhibitory ability to p38α/MK2 enzymatic activity, and have good selectivity at the same time.
测试例2、本发明化合物对U937细胞p-Hsp27抑制作用的测定Test example 2, the assay of compound of the present invention to U937 cell p-Hsp27 inhibition
1.实验目的：该测试例的目的是测试本发明化合物对U937细胞p-Hsp27的抑制能力。1. Purpose of the experiment: the purpose of this test example is to test the inhibitory ability of the compound of the present invention to p-Hsp27 in U937 cells.
2.实验仪器和试剂：2. Experimental instruments and reagents:
2.1仪器：
2.1 Instruments:
2.2试剂：
2.2 Reagents:
3.实验方法：3. Experimental method:
20ng/ml PMA处理U937分化过夜，换新鲜培养液，U937静息过夜。分化后的U937消化计数，按照每孔25,000细胞种于96孔板中至细胞贴壁。配置化合物浓度梯度，化合物预处理细胞1小时(化合物终浓度最高浓度1μM，3倍浓度梯度稀释)，加入10ng/ml LPS(Lipopolysaccharides from Escherichia coli O111:B4)刺激0.5小时。用PBS清洗细胞后，裂解液裂解细胞。使用Phospho-HSP27(S78/S82)DuoSet IC ELISA试剂盒进行细胞裂解液中p-Hsp27检测，具体步骤参照试剂盒厂商提供的标准步骤。Treat U937 with 20ng/ml PMA to differentiate overnight, replace with fresh culture medium, and U937 rest overnight. After differentiation, U937 digestion counts, and 25,000 cells per well are seeded in a 96-well plate until the cells adhere to the wall. Concentration gradient of the compound was configured, the cells were pretreated with the compound for 1 hour (the final concentration of the compound was 1 μM, and the concentration was diluted 3 times), and 10 ng/ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) was added to stimulate the cells for 0.5 hours. After washing the cells with PBS, the lysis solution lyses the cells. Use the Phospho-HSP27(S78/S82) DuoSet IC ELISA kit to detect p-Hsp27 in the cell lysate, and refer to the standard steps provided by the kit manufacturer for specific steps.
4.实验数据处理方法：4. Experimental data processing method:
计算p-Hsp27抑制率：抑制率百分比＝[(阳性对照孔p-Hsp27平均值–样品孔p-Hsp27平均值)/(阳性对照孔p-Hsp27平均值–阴性对照孔p-Hsp27平均值)]×100％，其中阳性对照孔为无化合物孔(DMSO处理孔)，阴性对照孔为无LPS刺激孔。Calculate p-Hsp27 inhibition rate: Inhibition rate percentage = [(average value of p-Hsp27 in positive control wells – average value of p-Hsp27 in sample wells)/(average value of p-Hsp27 in positive control wells – average value of p-Hsp27 in negative control wells) ] × 100%, wherein the positive control wells were no compound wells (DMSO-treated wells), and the negative control wells were no LPS-stimulated wells.
剂量响应曲线拟合：使用GraphPad Prism 6中的log(inhibitor)vs.response--Variable slope(four parameters)对化合物浓度及对应的抑制率进行拟合方程分析，拟合曲线并得出化合物IC50值。Dose-response curve fitting: use log(inhibitor)vs.response--Variable slope(four parameters) in GraphPad Prism 6 to analyze the fitting equation of the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 value.
拟合计算方程为Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))The fitting calculation equation is Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
5.实验结果：

5. Experimental results:

6.实验结论：6. Experimental conclusion:
以上数据显示，本发明实施例化合物对U937细胞p-Hsp27具有较强的抑制能力。The above data show that the compounds of the examples of the present invention have strong inhibitory ability to p-Hsp27 in U937 cells.
测试例3、本发明化合物对U937细胞TNF-α表达水平的抑制作用的测定Test Example 3, Determination of the inhibitory effect of the compounds of the present invention on the expression level of TNF-α in U937 cells
1.实验目的：该测试例的目的是测量本发明化合物对U937细胞TNF-α表达水平的抑制能力。1. Purpose of the experiment: the purpose of this test example is to measure the inhibitory ability of the compound of the present invention to the expression level of TNF-α in U937 cells.
2.实验仪器和试剂：2. Experimental instruments and reagents:
2.1仪器：
2.1 Instruments:
2.2试剂：
2.2 Reagents:
3.实验方法：3. Experimental method:
20ng/ml PMA处理U937分化过夜，换新鲜培养液，U937静息过夜。分化后的U937消化计数，按照每孔50,000细胞种于96孔板中至细胞贴壁。配置化合物浓度梯度，化合物预处理细胞1小时(化合物终浓度最高浓度1μM，3倍浓度梯度稀释)，加入10ng/ml LPS(Lipopolysaccharides from Escherichia coli O111:B4)刺激4小时后离心收集培养上清，用于后续ELISA检测上清中TNF-α浓度。TNF-α浓度检测依据ELISA试剂盒厂商提供的标准步骤进行。Treat U937 with 20ng/ml PMA to differentiate overnight, replace with fresh culture medium, and U937 rest overnight. After differentiation, U937 was digested and counted, and 50,000 cells per well were seeded in a 96-well plate until the cells adhered to the wall. The compound concentration gradient was configured, the compound pretreated the cells for 1 hour (the highest concentration of the compound was 1 μM, and the concentration was diluted 3 times), and 10 ng/ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) was added to stimulate the cells for 4 hours, and then the culture supernatant was collected by centrifugation. Used for subsequent ELISA detection of TNF-α concentration in the supernatant. The detection of TNF-α concentration was carried out according to the standard procedure provided by the ELISA kit manufacturer.
4.实验数据处理方法：4. Experimental data processing method:
TNF-α标准品通过线性回归方法绘制标准曲线，依据标准曲线换算样品TNF-α浓度。The standard curve of TNF-α was drawn by linear regression method, and the concentration of TNF-α in samples was converted according to the standard curve.
计算抑制率：抑制率百分比＝[(阳性对照孔TNF-α浓度平均值–样品孔TNF-α浓度平均值)/(阳性对照孔TNF-α浓度平均值–阴性对照孔TNF-α浓度平均值)]×100％，其中阳性对照孔为无化合物孔(DMSO处理孔)，阴性对照孔为培养基孔。Calculation of inhibition rate: Inhibition rate percentage = [(average value of TNF-α concentration in positive control wells – average value of TNF-α concentration in sample wells)/(average value of TNF-α concentration in positive control wells – average value of TNF-α concentration in negative control wells )] × 100%, where the positive control wells were no compound wells (DMSO treated wells), and the negative control wells were medium wells.
剂量响应曲线拟合：使用GraphPad Prism 6中的log(inhibitor)vs.response–Variable slope(four parameters)对化合物浓度及对应的抑制率进行拟合方程分析，拟合曲线并得出化合物IC50值。拟合计算方程为Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))。Dose-response curve fitting: use log(inhibitor)vs.response–Variable slope(four parameters) in GraphPad Prism 6 to analyze the fitting equation of the compound concentration and the corresponding inhibition rate, fit the curve and obtain the IC 50 value of the compound . The fitting calculation equation is Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope)).
5.实验结果：

5. Experimental results:

6.实验结论：6. Experimental conclusion:
以上数据显示，本发明实施例化合物对U937细胞TNF-α表达水平具有较强的抑制能力。The above data show that the compounds of the examples of the present invention have strong inhibitory ability to the expression level of TNF-α in U937 cells.
测试例4、本发明化合物在人肝微粒体中的体外代谢稳定性考察Test example 4, investigation of the in vitro metabolic stability of the compound of the present invention in human liver microsomes
1.实验目的：1. Purpose of the experiment:
本试验目的是评价化合物在人肝微粒体中的I相及部分II相代谢稳定性情况。The purpose of this test is to evaluate the phase I and part II metabolic stability of the compound in human liver microsomes.
2.实验方案2. Experimental protocol
2.1试验药品：2.1 Test drugs:
本发明化合物，自制。The compound of the present invention is self-made.
Alamethicin(Abcam)、7-Hydroxycoumarin(Sigma)、肝微粒体(XenoTech，上海权阳生物科技有限公司)、磷酸缓冲液(Gibco，Lot#SLBS7904和Lot#SLBR3106V，pH 7.4)、NADPH(还原型烟酰胺腺嘌呤二核苷酸磷酸，上海毕得医药科技股份有限公司)、UDPGA(Sigma)，Alamethicin(Abcam)、甲醇(Merck)、乙腈(Merck)。Alamethicin (Abcam), 7-Hydroxycoumarin (Sigma), liver microsomes (XenoTech, Shanghai Quanyang Biotechnology Co., Ltd.), phosphate buffer (Gibco, Lot#SLBS7904 and Lot#SLBR3106V, pH 7.4), NADPH (reduced tobacco Amide adenine dinucleotide phosphate (Shanghai Pide Pharmaceutical Technology Co., Ltd.), UDPGA (Sigma), Alamethicin (Abcam), methanol (Merck), acetonitrile (Merck).
2.2药物配制2.2 Drug preparation
本发明化合物用DMSO(或其它适合的溶液)配置为10mM储备液，于-20℃冰箱保存待用。The compound of the present invention was prepared as a 10 mM stock solution in DMSO (or other suitable solution), and stored in a -20° C. refrigerator until use.
对照化合物：7-Hydroxycoumarin配制为10mM储备液待用。 Control compound: 7-Hydroxycoumarin was prepared as a 10 mM stock solution for use.
2.3实验步骤2.3 Experimental steps
1)配制缓冲液：1) Prepare buffer:
取1M的K2HPO4·3H2O(AR级)4.01mL和1M的KH2PO4(AR级)0.99mL，超纯水溶解并定容至50mL，配制终浓度为100mM的磷酸缓冲液。Take 4.01mL of 1M K 2 HPO 4 ·3H 2 O (AR grade) and 0.99mL of 1M KH 2 PO 4 (AR grade), dissolve them in ultrapure water and dilute to 50mL, and prepare a phosphate buffer solution with a final concentration of 100mM .
2)配制化合物工作液2) Prepare compound working solution
化合物的工作液配制：将2μL化合物储备溶液加入998μL磷酸缓冲液，终浓度为20μM。根据化合物性质，可适当调整配置比例，调整最终浓度。Compound working solution preparation: 2 μL compound stock solution was added to 998 μL phosphate buffer solution, with a final concentration of 20 μM. According to the nature of the compound, the configuration ratio can be adjusted appropriately, and the final concentration can be adjusted.
对照化合物的工作液配制：同化合物的配制过程保持一致。Preparation of the working solution of the reference compound: keep consistent with the preparation process of the compound.
3)配制肝微粒体工作液3) Preparation of liver microsome working solution
156.3μL 20mg/mL微粒体，用100mM磷酸缓冲液稀释到5mL，混匀，终浓度为0.625mg/mL。156.3μL 20mg/mL microsomes, diluted to 5mL with 100mM phosphate buffer solution, mixed well, the final concentration was 0.625mg/mL.
4)准备NADPH和UDPGA4) Prepare NADPH and UDPGA
称取33.3mg的NADPH和25.8mg的UDPGA，加入2mL的100mM磷酸缓冲液，终浓度均为20mM。Weigh 33.3mg of NADPH and 25.8mg of UDPGA, add 2mL of 100mM phosphate buffer, the final concentration is 20mM.
5)准备打孔剂(Alamethicin)5) Prepare punching agent (Alamethicin)
称取1mg Alamethicin加入200μL甲醇，配制成5mg/mL的溶液。再从该溶液中取出10μL，加入990μL磷酸缓冲液中(pH 7.4)，终浓度为50μg/mL。Weigh 1 mg of Alamethicin and add 200 μL of methanol to prepare a 5 mg/mL solution. Then take 10 μL from this solution and add it into 990 μL phosphate buffer (pH 7.4) to a final concentration of 50 μg/mL.
6)配制反应终止液6) Preparation of reaction termination solution
用乙腈(或其他合适的溶液)稀释内标做终止液，储存在2-8℃冰箱。Dilute the internal standard with acetonitrile (or other suitable solution) as a stop solution, and store in a refrigerator at 2-8°C.
7)孵育流程7) Incubation process
在96孔板中依次加入400μL配制好的肝微粒体、25μL化合物工作液(10μM)和25μL Alamethicin(50μg/mL)，于37℃预孵育10min。随后加入50μL配制好的NADPH/UDPGA启动反应，37℃孵育，反应体系的总体积为500μL，各成分最终含量如下：
400 μL of prepared liver microsomes, 25 μL of compound working solution (10 μM) and 25 μL of alamethicin (50 μg/mL) were sequentially added to a 96-well plate, and pre-incubated at 37° C. for 10 min. Then add 50 μL of prepared NADPH/UDPGA to start the reaction, incubate at 37°C, the total volume of the reaction system is 500 μL, and the final content of each component is as follows:
分别在0,5,15,30,60和120min时间点取出50μL，加入200μL含有内标的冷终止液终止样品反应，3500rpm离心10min，取上清液进LC-MS/MS分析。Take out 50 μL at 0, 5, 15, 30, 60 and 120 min time points respectively, add 200 μL cold stop solution containing internal standard to stop the sample reaction, centrifuge at 3500 rpm for 10 min, and take the supernatant for LC-MS/MS analysis.
2.4色谱分析2.4 Chromatographic analysis
1)色谱条件1) Chromatographic conditions
仪器:岛津LC-20 AD； Instrument: Shimadzu LC-20 AD;
色谱柱：PhenomenexC18(50*4.6mm，5μm粒径)；Column: Phenomenex C18 (50*4.6mm, 5μm particle size);
流动相：A：0.1％甲酸水溶液，B:乙腈；Mobile phase: A: 0.1% formic acid aqueous solution, B: acetonitrile;
冲洗梯度：0.2～1.6min 5％A到95％A，3.0～3.1min 95％A到5％A；Washing gradient: 0.2～1.6min 5%A to 95%A, 3.0～3.1min 95%A to 5%A;
流速：1.0ml/min；Flow rate: 1.0ml/min;
运行时间：4.0min；Running time: 4.0min;
进样体积：5μL。Injection volume: 5 μL.
2)质谱条件2) Mass spectrometry conditions
仪器:API4000型液相色谱质谱联用仪，AB Sciex公司；Instrument: API4000 type liquid chromatography mass spectrometry, AB Sciex company;
离子源：电喷雾离子化源(ESI)；Ion source: electrospray ionization source (ESI);
干燥气体：N2，温度500℃；Drying gas: N2, temperature 500°C;
电喷雾电压：5000V；Electrospray voltage: 5000V;
检测方式：正离子检测；Detection method: positive ion detection;
扫描方式：反应监测(MRM)方式；Scanning method: reaction monitoring (MRM) method;
扫描时间：0.8401s。Sweep time: 0.8401s.
3.实验结果及数据处理3. Experimental results and data processing
T1/2＝0.693/Ke，其中Ke表示消除速率常数。
T 1/2 =0.693/Ke, where Ke represents the elimination rate constant.
4.实验结论4. Experimental conclusion
以上数据显示，本发明实施例化合物在人肝微粒体中表现出很好的代谢稳定性。The above data show that the compounds of the examples of the present invention exhibit good metabolic stability in human liver microsomes.
测试例5、SD大鼠药代动力学测定Test example 5, SD rat pharmacokinetic determination
1.实验目的：1. Purpose of the experiment:
以SD大鼠为受试动物，研究本发明化合物，在5mg/kg剂量下口服和1mg/kg剂量下静脉注射给药在大鼠体内(血浆)的药代动力学行为。Taking SD rats as experimental animals, the pharmacokinetic behavior of the compound of the present invention in rats (plasma) was studied by oral administration at a dose of 5 mg/kg and intravenous injection at a dose of 1 mg/kg.
2.实验方案2. Experimental protocol
2.1试验药品：2.1 Test drugs:
本发明的化合物，自制。The compound of the present invention is self-made.
2.2试验动物： 2.2 Test animals:
SD大鼠每组3只，雄性，上海杰思捷实验动物有限公司，动物生产许可证号(SCXK(沪)2013-0006N0.311620400001794)。Three SD rats per group, male, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
2.3药物配制：2.3 Drug preparation:
PO，10％solutol HS15，超声溶解，配制为澄清溶液或均一混悬液。PO, 10% solutol HS15, sonicated, prepared as a clear solution or a homogeneous suspension.
IV，5％DMSO+10％Solutol HS15+85％PBS，超声溶解，配制为澄清溶液。IV, 5% DMSO+10% Solutol HS15+85% PBS, ultrasonically dissolved, and prepared as a clear solution.
2.4给药方案：2.4 Dosing regimen:
SD大鼠每组3只，雄性；禁食一夜后分别p.o.，剂量为5mg/kg，给药体积10mL/kg；i.v.，剂量为1mg/kg，给药体积5mL/kg。Three SD rats in each group, male; after fasting overnight, p.o., the dose was 5 mg/kg, and the administration volume was 10 mL/kg; i.v., the dose was 1 mg/kg, and the administration volume was 5 mL/kg.
2.5样品采集：2.5 Sample collection:
大鼠口服给药后，在0.25、0.5、1、2、4、6、8和24小时；大鼠静脉注射给药后，在0.083、0.25、0.5、1、2、4、6、8和24小时；颈静脉采血0.2mL，置于EDTA-K2试管中，4℃6000rpm离心6min分离血浆，于-80℃保存。After oral administration to rats, at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours; after intravenous administration to rats, at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours; 0.2 mL of blood was collected from the jugular vein, placed in an EDTA-K 2 test tube, centrifuged at 6000 rpm at 4°C for 6 minutes to separate the plasma, and stored at -80°C.
2.6样品处理：2.6 Sample handling:
1)血浆样品20uL加入100uL乙腈沉淀，混合后3500×g离心5～20分钟。1) Add 20uL of plasma sample to 100uL of acetonitrile for precipitation, after mixing, centrifuge at 3500×g for 5-20 minutes.
2)取处理后上清溶液进行LC/MS/MS分析待测化合物的浓度，LC/MS/MS分析仪器：AB Sciex API 4000Qtrap。2) Take the treated supernatant solution and analyze the concentration of the test compound by LC/MS/MS, LC/MS/MS analysis instrument: AB Sciex API 4000Qtrap.
2.7液相分析：2.7 Liquid phase analysis:
●液相条件：Shimadzu LC-20AD泵●Liquid phase conditions: Shimadzu LC-20AD pump
●色谱柱：Waters Xbridge C18 5μm,4.6X 50mm移动相：A液为0.1％甲酸水溶液，B液为甲醇Chromatographic column: Waters Xbridge C18 5μm, 4.6X 50mm Mobile phase: A liquid is 0.1% formic acid aqueous solution, B liquid is methanol
●流速：1.0mL/min●Flow rate: 1.0mL/min
●洗脱时间：0-4.0分钟，洗脱液如下：
●Elution time: 0-4.0 minutes, the eluent is as follows:
3.试验结果及数据处理：3. Test results and data processing:
药代动力学主要参数用WinNonlin 6.1计算得到。

The main pharmacokinetic parameters were calculated with WinNonlin 6.1.

4.试验结论：4. Test conclusion:
SD大鼠药代动力学测定结果显示，本发明化合物呈现好较好地PK优势，同时本发明化合物也测定了小鼠及比格犬药代动力学，结果显示本发明化合物PK种属差异小。SD rat pharmacokinetic measurement results show that the compound of the present invention presents a better PK advantage, and the compound of the present invention has also measured the pharmacokinetics of mice and Beagle dogs, and the results show that the compound of the present invention has little difference in PK species .
测试例6、SD大鼠药代动力学测定Test example 6, SD rat pharmacokinetic determination
1.实验目的：1. Purpose of the experiment:
以SD大鼠为受试动物，研究本发明化合物，在5mg/kg剂量下口服给药在大鼠体内(血浆和脑)的药代动力学行为。Taking SD rats as experimental animals, the pharmacokinetic behavior of the compound of the present invention in rats (plasma and brain) after oral administration at a dose of 5 mg/kg was studied.
2.实验方案2. Experimental protocol
2.1试验药品：2.1 Test drugs:
本发明化合物，自制。The compound of the present invention is self-made.
2.2试验动物：2.2 Test animals:
SD大鼠每组12只，雄性，北京维通利华实验动物技术有限公司。12 SD rats per group, male, Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
2.3药物配制：2.3 Drug preparation:
PO，10％solutol HS15，超声溶解，配制为澄清溶液或均一混悬液。PO, 10% solutol HS15, sonicated, prepared as a clear solution or a homogeneous suspension.
2.4给药方案：2.4 Dosing regimen:
SD大鼠每组12只，雄性；禁食一夜后p.o.，剂量为5mg/kg，给药体积10mL/kg。There are 12 SD rats in each group, male; p.o. after overnight fasting, the dose is 5 mg/kg, and the administration volume is 10 mL/kg.
2.5样品采集：2.5 Sample collection:
大鼠口服给药后，在0.5、1、2小时，采集血浆和脑组织；颈静脉采血0.25mL，肝素钠抗凝，血液样本采集后置于冰上，并于1小时之内离心分离血浆(离心条件：6000g，3分钟，2-8℃)。血浆样本在分析前存放于-80℃冰箱内。After oral administration to rats, collect plasma and brain tissue at 0.5, 1, and 2 hours; collect 0.25 mL of blood from the jugular vein, anticoagulate with sodium heparin, put the blood sample on ice after collection, and centrifuge to separate the plasma within 1 hour (Centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma samples were stored in a -80°C freezer until analysis.
2.6样品处理：2.6 Sample handling:
1)血浆样品50uL加入500uL含内标(100ng/mL)50％甲醇乙腈溶液，混合后在4000rpm、4℃条件下离心10分钟，交由LC-MS/MS分析。1) 50uL plasma sample was added to 500uL 50% methanol-acetonitrile solution containing internal standard (100ng/mL), mixed, centrifuged at 4000rpm, 4°C for 10 minutes, and analyzed by LC-MS/MS.
2)所有样品完全融化后，称取定量的脑组织，加入4倍体积的50％甲醇/水，匀浆。移取匀浆后脑组织样品50uL至96孔板中，加入500uL含内标(100 ng/mL)50％甲醇乙腈溶液。将样品涡旋5分钟后，在4000rpm、4℃条件下离心10分钟，交由LC-MS/MS分析。2) After all the samples are completely melted, weigh a quantitative amount of brain tissue, add 4 times the volume of 50% methanol/water, and homogenize. Pipette 50uL of the homogenized brain tissue sample into a 96-well plate, add 500uL containing internal standard (100 ng/mL) 50% methanol in acetonitrile solution. After the sample was vortexed for 5 minutes, it was centrifuged at 4000 rpm and 4°C for 10 minutes, and then analyzed by LC-MS/MS.
3)移取80uL上清加入到80uL的水中，混合均匀进行LC/MS/MS分析待测化合物的浓度，LC/MS/MS分析仪器：AB Sciex Triple Quad 5500+。3) Pipette 80uL supernatant into 80uL water, mix well and analyze the concentration of the test compound by LC/MS/MS, LC/MS/MS analysis instrument: AB Sciex Triple Quad 5500+.
2.7液相分析：2.7 Liquid phase analysis:
●色谱柱：Synergi 4μm Fusion-RP 80ALC Column 50*2mm移动相：A液为0.1％甲酸水溶液，B液为乙腈Chromatographic column: Synergi 4μm Fusion-RP 80ALC Column 50*2mm Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is acetonitrile
●流速：0.8mL/min●Flow rate: 0.8mL/min
●洗脱时间：0-2.2分钟，洗脱液如下：
●Elution time: 0-2.2 minutes, the eluent is as follows:
3.实验结果及数据处理：3. Experimental results and data processing:
药代动力学主要参数用WinNonlin 6.1计算得到。
The main pharmacokinetic parameters were calculated with WinNonlin 6.1.
4.实验结论4. Experimental conclusion
SD大鼠药代动力学测定结果显示，本发明化合物在脑中具有极低的药物浓度，低的脑血比说明本发明化合物入脑能力差，带来的头疼等副作用可能更低。The results of pharmacokinetic measurement in SD rats show that the compound of the present invention has extremely low drug concentration in the brain, and the low brain-to-blood ratio indicates that the compound of the present invention has poor ability to enter the brain, and the side effects such as headaches may be lower.
测试例7、Wistar大鼠急性炎症模型PD测试 Test Example 7, Wistar Rat Acute Inflammation Model PD Test
1.实验目的：1. Purpose of the experiment:
以6-8周的Wistar大鼠为受试动物，研究本发明化合物在不同剂量不同时间点下口服给药在大鼠体内(血清)的药效学行为。Wistar rats of 6-8 weeks were used as experimental animals to study the pharmacodynamic behavior of the compound of the present invention administered orally in rats (serum) at different doses and at different time points.
2.实验方案2. Experimental protocol
2.1试验样品：2.1 Test sample:
本发明化合物，自制。The compound of the present invention is self-made.
Wistar大鼠，维通利华公司。Wistar rats, Victoria River Corporation.
2.2药物配制：2.2 Drug preparation:
称取适量化合物，加入对应溶剂10％Solutol HS15，通过超声、涡旋、搅拌得到终浓度为0.2mg/mL的悬浊液。Weigh an appropriate amount of compound, add the corresponding solvent 10% Solutol HS15, and obtain a suspension with a final concentration of 0.2 mg/mL by ultrasonication, vortexing, and stirring.
2.3给药方案：2.3 Dosing regimen:
Wistar大鼠每组8只，雄性；禁食一夜后p.o.给药，剂量为1mg/kg，给药体积5mL/kg。8 Wistar rats in each group, male; administered p.o. after overnight fasting, the dose was 1mg/kg, and the administration volume was 5mL/kg.
大鼠体重在200-230g后，开始进行实验。给造模剂LPS前1h、5h、11h、17h、23h给Vehicle或给药。尾静脉注射造模剂LPS或PBS后1h采样。The experiment was started after the rats weighed 200-230 g. Vehicle or administration was given 1h, 5h, 11h, 17h, 23h before the modeling agent LPS was given. Samples were taken 1 hour after injection of modeling agent LPS or PBS into the tail vein.
2.4样品采集：2.4 Sample collection:
大鼠颈静脉采血，将采集的血液加入离心管中，在室温放置60min，8000转/分，离心5分钟。离心后的血清取50μL转移至新的标记好的离心管中，取2份，干冰速冻后置于-80℃冰箱保存，用于检测。Blood was collected from the jugular vein of the rat, and the collected blood was added to a centrifuge tube, left at room temperature for 60 minutes, and centrifuged at 8000 rpm for 5 minutes. Take 50 μL of the centrifuged serum and transfer it to a new labeled centrifuge tube, take 2 aliquots, freeze them on dry ice and store them in a -80°C refrigerator for detection.
2.5样品处理：2.5 Sample handling:
血清样品：融化后，正常组与给药6h组进行1.5倍稀释，即取80.0μL样品加入40.0μL 1x reagent diluent buffer(R&D试剂盒配制)；造模组和给药18h组进行3倍稀释，即取40.0μL样品加入80.0μL 1x reagent diluent buffer。Serum samples: After thawing, the normal group and the 6h administration group were diluted 1.5 times, that is, 80.0 μL samples were added to 40.0 μL 1x reagent diluent buffer (prepared by R&D kit); the modeling group and the 18h administration group were diluted 3 times, Take 40.0μL sample and add 80.0μL 1x reagent diluent buffer.
2.6实验过程2.6 Experimental process
TNF-α测试(试剂盒DY510)：TNF-α test (kit DY510):
1)提前一天包被检测板：取适当包被抗体加入PBS中，得到浓度约4.00μg/mL的包被抗体溶液，将其加入检测板中，每孔100.0μL，放置于24℃恒温箱孵育过夜。1) Coating the detection plate one day in advance: Take appropriate coating antibody and add it to PBS to obtain a coating antibody solution with a concentration of about 4.00 μg/mL, add it to the detection plate, 100.0 μL per well, and place it in a 24°C incubator for incubation overnight.
2)洗板：弃去检测板中的包被液，每孔加入wash buffer 300.0ul，重复洗3次，每次除尽检测板中残留液体。2) Plate washing: Discard the coating solution in the test plate, add 300.0ul of wash buffer to each well, repeat the wash 3 times, and remove the residual liquid in the test plate each time.
3)封闭：每孔加入300.0μL的1×blocking buffer进行封闭，24℃至少孵育1h。3) Blocking: Add 300.0 μL of 1×blocking buffer to each well for blocking, and incubate at 24°C for at least 1 hour.
4)制备标准品：先将其Rat TNFa标准品稀释成1000pg/ml，取4.17μL标准品加入495.83μL1xreagent dilute，再用1xRegent dilute对其进行两倍稀释，制备具有8个浓度的标准品。4) Preparation of standard substance: firstly dilute its Rat TNFa standard substance to 1000pg/ml, take 4.17μL standard substance and add 495.83μL 1xreagent dilute, then dilute it twice with 1xRegent dilute to prepare 8 concentrations of standard substance.
5)封闭后的检测板取出，洗板。 5) Take out the sealed detection plate and wash the plate.
6)样品孵育：取稀释后的样品或标准品100.0μL到ELISA检测板对应的测试孔中，粘结带封闭并放入24℃培养箱孵育2h。6) Sample incubation: Take 100.0 μL of the diluted sample or standard product into the corresponding test well of the ELISA detection plate, seal the adhesive tape and place it in a 24°C incubator for 2 hours.
7)洗板。7) Wash the plate.
8)检测抗体孵育：配制检测抗体工作液：取适当检测抗体到1xRegent Dilute中，得到检测抗体溶液。每孔加入100.0μL检测抗体工作液，用新的粘合带封闭，24℃培养箱孵育2小时。8) Detection antibody incubation: preparation of detection antibody working solution: take appropriate detection antibody into 1xRegent Dilute to obtain detection antibody solution. Add 100.0 μL detection antibody working solution to each well, seal with a new adhesive tape, and incubate in a 24°C incubator for 2 hours.
9)洗板。9) Wash the plate.
10)二抗HRP孵育避光：取适当40xStreptavidin-HRP到1xRegent Dilute中稀释成1x。每孔加入100.0μL，24℃培养箱孵育约20min。10) Incubate the secondary antibody HRP in the dark: take an appropriate amount of 40xStreptavidin-HRP and dilute it into 1xRegent Dilute to 1x. Add 100.0 μL to each well and incubate for about 20 minutes in a 24°C incubator.
11)洗板，重复步骤2。11) Wash the plate and repeat step 2.
12)显色避光:将color reagent A和B等体积混匀配制成Substrate solution，每孔加入100.0ul，室温孵育约20min。12) Color development and light protection: Mix equal volumes of color reagent A and B to prepare Substrate solution, add 100.0ul to each well, and incubate at room temperature for about 20min.
13)终止：等到显色合适，每孔加入50.0μL STOP solution。13) Termination: Wait until the color develops properly, add 50.0 μL STOP solution to each well.
IL-6检测(试剂盒K15059D-2)：IL-6 detection (kit K15059D-2):
1)试剂准备：准备工作，从冰箱中取出试剂盒，室温平衡30min1) Reagent preparation: for preparation, take out the kit from the refrigerator and equilibrate at room temperature for 30 minutes
2)准备标准品：稀释液42加1ml到标准品中，充分振荡，室温放置15-20min，作为最高的浓度点，依次做4倍稀释，7个标准品+1个Blank。2) Prepare the standard: Add 1ml of diluent 42 to the standard, shake fully, and place it at room temperature for 15-20min. As the highest concentration point, make 4-fold dilutions sequentially, 7 standard + 1 Blank.
3)准备样品：大鼠血清进行适当稀释3) Prepare samples: appropriate dilution of rat serum
4)准备检测抗体稀释液：吸取检测抗体，并用稀释液40补足体积。4) Prepare the detection antibody diluent: pipette the detection antibody and make up the volume with diluent 40.
5)准备清洗液：配置1*的PBS(0.05％吐温-20)待用。5) Prepare washing solution: prepare 1* PBS (0.05% Tween-20) for use.
6)准备读板液：配置2*的读板液。(抗体孵育结束前10min时配置)6) Prepare plate reading solution: configure 2* plate reading solution. (Configure 10 minutes before the end of antibody incubation)
7)将复温后的MSD板及Blocker H取出，每孔加入150ul Block H室温800rpm震荡孵育1h。7) Take out the rewarmed MSD plate and Blocker H, add 150ul Block H to each well and incubate at room temperature for 1h with shaking at 800rpm.
8)清洗MSD板3次，每次150ul的清洗液。8) Wash the MSD plate 3 times, each time with 150ul of washing solution.
9)每孔加入50ul稀释好的样本和标准品，并用封口膜封上，室温振荡2h。9) Add 50ul diluted samples and standards to each well, seal with parafilm, and shake at room temperature for 2h.
10)清洗MSD板3次，每次150ul的清洗液。10) Wash the MSD plate 3 times, each time with 150ul of cleaning solution.
11)每孔加入配置好的25ul检测抗体，并用封口膜封上，室温振荡2h。11) Add 25ul of prepared detection antibody to each well, seal with parafilm, shake at room temperature for 2h.
12)清洗MSD板3次，每次150ul的清洗液。12) Wash the MSD plate 3 times, each time with 150ul of cleaning solution.
13)每孔加入150ul配置好的读板液，上机检测。13) Add 150ul of prepared plate reading solution to each well, and test on the machine.
3实验结果及及结论：3 Experimental results and conclusions:
利用Graph pad中进行数据处理。Use the Graph pad for data processing.
Wistar大鼠急性炎症模型PD实验结果显示，本发明化合物显示出优异的PD效应，对TNF-α、IL-6均具有较高的抑制率。 The results of the PD experiment on the acute inflammation model of Wistar rats show that the compound of the present invention exhibits excellent PD effects, and has a high inhibitory rate on both TNF-α and IL-6.

Claims (21)

  1. 一种通式(I-2)所示的化合物、其立体异构体或其药学上可接受盐：

    其中：    A compound represented by general formula (I-2), its stereoisomer or its pharmaceutically acceptable salt:

    in:
    环C选自苯基、噻唑基、吡唑基、嘧啶基或吡啶基；Ring C is selected from phenyl, thiazolyl, pyrazolyl, pyrimidinyl or pyridyl;
    L1选自键或-(CH2)nO(CRaaRbb)n1-；L 1 is selected from a bond or -(CH 2 ) n O(CR aa R bb ) n1 -;
    Raa和Rbb各自独立地选自氢、氘、卤素、C1-8烷基或C1-8氘代烷基，所述的C1-8烷基或C1-8氘代烷基，任选地可以进一步被取代；R aa and R bb are each independently selected from hydrogen, deuterium, halogen, C 1-8 alkyl or C 1-8 deuterated alkyl, said C 1-8 alkyl or C 1-8 deuterated alkyl , optionally can be further substituted;
    M5选自CR5、N、NR5、O或S；M 5 is selected from CR 5 , N, NR 5 , O or S;
    M6选自CR6、N、NR6、O或S；M 6 is selected from CR 6 , N, NR 6 , O or S;
    M7选自CR7或NR7；M 7 is selected from CR 7 or NR 7 ;
    M8选自CR8、N、NR8、O或S；M 8 is selected from CR 8 , N, NR 8 , O or S;
    M9选自C或N； M9 is selected from C or N;
    R5、R6和R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8羟烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-8 alkyl, C 1- 8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano group, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterium Substituted alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or Substituted by one or more substituents in the 5-14 membered heteroaryl;
    优选地，R5、R6和R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一 步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基中的一个或多个取代基所取代；Preferably, R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally further Step by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl , C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 -One or more substituents in 8-membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl;
    R7选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、桥环烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基、5-14元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；所述的氨基、C1-8烷基、桥环烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8羟烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基中的一个或多个取代基所取代； R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, bridged cycloalkyl, C 1-8 deuterated alkyl, C 1-8 haloalkane C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ; said amino, C 1-8 alkyl, bridged cycloalkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1- 8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl , C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1- 8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2- One or more substituents in 8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl replace;
    优选氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基中的一个或多个取代基所取代；Preferably hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkane Base, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C( O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ; said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered hetero Aryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3 One or more substituents in -8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl;
    Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基；R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkanes C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy , C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
    优选地，Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；Preferably, R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    或者，R5、R6、R7和R8任意两个相邻或不相邻的取代基链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一 步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, any two adjacent or non-adjacent substituents of R 5 , R 6 , R 7 and R 8 are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclic radical, aryl and heteroaryl, optionally further Step by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C One or more substituents in 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
    优选地，任意两个相邻或不相邻的取代基链接形成C3-8环烷基、含1-3个N、O、或S原子的3-8元杂环基、C6-10芳基或含1-3个N、O、或S原子的5-10元杂芳基，所述C3-8环烷基、含1-3个N、O、或S原子的3-8元杂环基、C6-10芳基或含1-3个N、O、或S原子的5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-4烷基、C1-4氘代烷基、C1-4卤代烷基、C1-4羟烷基、C1-4烷氧基、C1-4氘代烷氧基、C1-4卤代烷氧基、C2-3烯基、C2-3炔基、C5-8环烷基、5-8元杂环基、C6-8芳基和5-8元杂芳基中的一个或多个取代基所取代；更优选地，任意两个相邻或不相邻的取代基链接形成 任选地可进一步被氘、氟、氯、溴、羟基、巯基、氰基、氧代基、硫代基、羧基、甲基、乙基、丙基、丁基、氘代甲基、氘代乙基、氘代丙基、氘代丁基、羟甲基、羟乙基、羟丙基或羟丁基中的一个或多个所取代；Preferably, any two adjacent or non-adjacent substituents are linked to form a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group containing 1-3 N, O, or S atoms, a C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O, or S atoms, the C 3-8 cycloalkyl, 3-8 containing 1-3 N, O, or S atoms Membered heterocyclic group, C 6-10 aryl group or 5-10 membered heteroaryl group containing 1-3 N, O, or S atoms, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, Cyano, amino, oxo, thio, carboxyl, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 Alkoxy, C 1-4 deuterated alkoxy, C 1-4 haloalkoxy, C 2-3 alkenyl, C 2-3 alkynyl, C 5-8 cycloalkyl, 5-8 membered heterocycle One or more substituents in radical, C 6-8 aryl and 5-8 membered heteroaryl; more preferably, any two adjacent or non-adjacent substituents link to form Optionally can be further substituted by deuterium, fluorine, chlorine, bromine, hydroxyl, mercapto, cyano, oxo, thio, carboxyl, methyl, ethyl, propyl, butyl, deuteromethyl, deuterium One or more of ethyl, deuterated propyl, deuterated butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl;
    x为0～6的整数；x is an integer from 0 to 6;
    y为0～6的整数；y is an integer from 0 to 6;
    z为0～6的整数；z is an integer from 0 to 6;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    n1为0、1、2或3；n1 is 0, 1, 2 or 3;
    n4为0、1、2、3或4。n4 is 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(VI)、(X)或(XI)所示：

    其中：    The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, said compound is further shown in general formula (VI), (X) or (XI):

    in:
    M5选自CR5、N、NR5、O或S；M 5 is selected from CR 5 , N, NR 5 , O or S;
    M6选自CR6、N、NR6、O或S；M 6 is selected from CR 6 , N, NR 6 , O or S;
    M7选自CR7或NR7；M 7 is selected from CR 7 or NR 7 ;
    M8选自CR8、N、NR8、O或S；M 8 is selected from CR 8 , N, NR 8 , O or S;
    M9选自C或N； M9 is selected from C or N;
    R5、R6和R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8羟烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基中的一个或多个取代基所取代；R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-8 alkyl, C 1- 8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano group, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterium Substituted alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or Substituted by one or more substituents in the 5-14 membered heteroaryl;
    优选地，R5、R6和R8各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基中的一个或多个取代基所取代；Preferably, R 5 , R 6 and R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1 -6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substituents in aryl or 5-10 membered heteroaryl;
    R7选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基、5-14 元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；所述的氨基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8羟烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基中的一个或多个取代基所取代； R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 ring Alkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 Member heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C(O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ; the amino, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1 -8 deuterated alkoxy, C 1-8 haloalkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl are substituted;
    优选氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基、5-10元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4C(O)NRhhRgg或-(CReeRff)n4S(O)2NRhhRgg；所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基中的一个或多个取代基所取代；Preferably hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkane Base, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C( O)R gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 C(O)NR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg ; said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered hetero Aryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3 One or more substituents in -8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl;
    Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-8烷基、C1-8氘代烷基、C1-8卤代烷基、C1-8羟烷基、C1-8烷氧基、C1-8氘代烷氧基、C1-8卤代烷氧基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基；R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-8 alkyl, C 1-8 deuterated alkanes C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 deuterated alkoxy, C 1-8 haloalkoxy , C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
    优选地，Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基；Preferably, R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    n4为0、1、2、3或4；n4 is 0, 1, 2, 3 or 4;
    L1选自键、取代或未取代的亚烯基、取代或未取代的亚炔基、-(CH2)n-、-(CH2)nC(O)(CRaaRbb)n1-、-(CH2)nC(O)NRcc(CH2)n1-、-(CH2)n(CRaaRbb)n1-、-(CRaaRbb)nO(CH2)n1-、-(CH2)nO(CRaaRbb)n1-、-(CRaaRbb)nS(CH2)n1-、-(CH2)nS(CRaaRbb)n1-、-(CRaaRbb)n(CH2)n1NRcc-、-(CH2)nNRcc(CRaaRbb)n1-、-(CH2)nNRccC(O)-、-(CH2)nP(O)pRaa-、-(CH2)nS(O)m-、-(CH2)nS(O)mNRcc-和-(CH2)nNRccS(O)m-；L 1 is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)(CR aa R bb ) n1 - , -(CH 2 ) n C(O)NR cc (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH 2 ) n1 - , -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n S(CH 2 ) n1 -, -(CH 2 ) n S(CR aa R bb ) n1 -, - (CR aa R bb ) n (CH 2 ) n1 NR cc -, -(CH 2 ) n NR cc (CR aa R bb ) n1 -, -(CH 2 ) n NR cc C(O)-, -(CH 2 ) n P(O) p R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S(O) m NR cc -and-(CH 2 ) n NR cc S( O) m -;
    Raa、Rbb和Rcc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、 氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkane group, hydroxyalkyl group, alkoxy group, Deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl , alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
    或者，Raa、Rbb和Rcc中的任意两个链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选地可以进一步被取代；Alternatively, any two of R aa , R bb and R cc are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally can be further replaced;
    Ra各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；R a is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
    或者，任意两个相邻或不相邻的Ra链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选地可以进一步被取代；Alternatively, any two adjacent or non-adjacent R a links to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, the cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further replaced;
    或者，L1与Ra链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基任选地可以进一步被取代；Alternatively, L is linked with Ra to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted;
    Rb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；R b are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
    或者，任意两个相邻或不相邻的Rb链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, any two adjacent or non-adjacent R b link to form cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally can be further replaced;
    或者，L1与Rb链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, L and R are linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, which may optionally be further substituted;
    或者，Ra与Rb链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, R a is linked with R b to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl can optionally be further substituted;
    Rc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、烷基、氘代烷基、卤代烷基、羟烷基、烷氧基、氘代烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基或杂芳基，所述的氨基、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；R c are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, Alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, deuterated alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
    或者，任意两个相邻或不相邻的Rc链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, any two adjacent or non-adjacent R c link to form cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally can be further replaced;
    或者，Rb与Rc链接形成环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、芳基和杂芳基，任选地可以进一步被取代；Alternatively, R b is linked with R c to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl may optionally be further substituted;
    x为0～6的整数；x is an integer from 0 to 6;
    y为0～6的整数； y is an integer from 0 to 6;
    z为0～6的整数；z is an integer from 0 to 6;
    n为0、1、2、或3；n is 0, 1, 2, or 3;
    n1为0、1、2、或3；n1 is 0, 1, 2, or 3;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    p为0、1、2或3。p is 0, 1, 2 or 3.
  3. 根据权利要求2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(VI-1)、(VI-2)、(XI-1)或(XI-2)所示：
    The compound according to claim 2, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, said compound is further such as general formula (VI-1), (VI-2), (XI-1) or (XI-2):
  4. 根据权利要求2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(VIII)所示：
    The compound according to claim 2, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, the compound is further shown in general formula (VIII):
  5. 根据权利要求4所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(VIII-1)或(VIII-2)所示：
    The compound according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is further shown in general formula (VIII-1) or (VIII-2):
  6. 根据权利要求2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(IX)所示：
    The compound according to claim 2, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, the compound is further shown in general formula (IX):
  7. 根据权利要求6所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，所述化合物进一步如通式(IX-1)或(IX-2)所示：
    The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is further shown in general formula (IX-1) or (IX-2):
  8. 根据权利要求2所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，化合物进一步如通式(VI-3)或(XI-3)所示：

    其中：    The compound according to claim 2, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, the compound is further shown in general formula (VI-3) or (XI-3):

    in:
    Raa和Rbb各自独立地选自氢、氘、卤素、C1-8烷基或C1-8氘代烷基，所述的C1-8烷基或C1-8氘代烷基，任选地可以进一步被取代。R aa and R bb are each independently selected from hydrogen, deuterium, halogen, C 1-8 alkyl or C 1-8 deuterated alkyl, said C 1-8 alkyl or C 1-8 deuterated alkyl , optionally can be further substituted.
  9. 根据权利要求1-2任一所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，化合物进一步如通式(XII-D)所示：

    其中：    According to the compound described in any one of claims 1-2, its stereoisomer or pharmaceutically acceptable salt thereof, it is characterized in that the compound is further shown in the general formula (XII-D):

    in:
    X1选自N或者CRa5；X 1 is selected from N or CR a5 ;
    X3选自N或者CRb1；X 3 is selected from N or CR b1 ;
    Ra1、Ra2、Ra3、Ra4或Ra5各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R a1 , R a2 , R a3 , R a4 or R a5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, all Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can Further deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C One or more substituents in 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
    或者，任意两个相邻或不相邻的Ra1、Ra2、Ra3、Ra4和Ra5链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂 环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Or, any two adjacent or non-adjacent R a1 , R a2 , R a3 , R a4 and R a5 link to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl Or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heteroaryl Cyclic, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1 -6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl Replaced by one or more substituents in;
    Raa或Rbb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R aa or R bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- Substituted by one or more substituents in 12-membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group;
    或者，Raa和Rbb链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R aa and R bb are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated Alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5 -One or more substituents in the 14-membered heteroaryl;
    Rb1、Rb2或Rb3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R b1 , R b2 or R b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
    或者，Rb1和Rb2取代基链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6 氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R b1 and R b2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and one or more substituents in the 5-14 membered heteroaryl;
    Rc1、Rc2或Rc3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R c1 , R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
    或者，Rc1和Rc2取代基链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R c1 and R c2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and Substituted by one or more substituents in the 5-14 membered heteroaryl;
    或者，Rc1和Rb2取代基链接形成3-12元杂环基或5-14元杂芳基，所述3-12元杂环基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, the R c1 and R b2 substituents are linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, and the 3-12 membered heterocyclic group and the 5-14 membered heteroaryl group can optionally be further replaced by Deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- Substituted by one or more substituents in 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
    Rda、Rdb、R’da或R’db各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R da , R db , R' da or R' db are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 Alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkane Oxygen, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally further By deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
    或者，任意两个相邻的或者不相邻的Rda、Rdb、R’da和R’db链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元 杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Or, any two adjacent or non-adjacent R da , R db , R' da and R' db link to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl Or 5-14 yuan heteroaryl, the C 3-12 cycloalkyl, 3-12 yuan Heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered hetero One or more substituents in the aryl group are substituted;
    R6或R8各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R 6 or R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- Substituted by one or more substituents in 12-membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group;
    或者，R6和R8链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R 6 and R 8 are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio group, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkane Oxygen, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5- Substituted by one or more substituents in the 14-membered heteroaryl;
    n7为0、1、2或3；n7 is 0, 1, 2 or 3;
    优选地，所述的不为 Preferably, the not for
  10. 根据权利要求1-2任一所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，化合物进一步如通式(XIII-B)或(XIII-B’)所示：

    其中：    The compound according to any one of claims 1-2, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that the compound is further shown in the general formula (XIII-B) or (XIII-B'):

    in:
    X1选自N或者CRa5；X 1 is selected from N or CR a5 ;
    Ra1、Ra2、Ra3、Ra4或Ra5各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R a1 , R a2 , R a3 , R a4 or R a5 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, all Amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can Further deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C One or more substituents in 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
    或者，任意两个相邻或不相邻的Ra1、Ra2、Ra3、Ra4和Ra5链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Or, any two adjacent or non-adjacent R a1 , R a2 , R a3 , R a4 and R a5 link to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl Or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen , nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkane One or more substituents in radical, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
    Raa或Rbb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R aa or R bb are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- Substituted by one or more substituents in 12-membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group;
    或者，Raa和Rbb链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代； Alternatively, R aa and R bb are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated Alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5 -One or more substituents in the 14-membered heteroaryl;
    Rb1、Rb2或Rb3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R b1 , R b2 or R b3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
    Rc1、Rc2或Rc3各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R c1 , R c2 or R c3 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
    或者，Rc1和Rc2取代基链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, R c1 and R c2 substituents are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkane Base, 3-12 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, Thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and Substituted by one or more substituents in the 5-14 membered heteroaryl;
    或者，Rc1和Rb2取代基链接形成3-12元杂环基或5-14元杂芳基，所述3-12元杂环基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, the R c1 and R b2 substituents are linked to form a 3-12 membered heterocyclic group or a 5-14 membered heteroaryl group, and the 3-12 membered heterocyclic group and the 5-14 membered heteroaryl group can optionally be further replaced by Deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- Substituted by one or more substituents in 12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
    R7选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6桥环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、 3-12元杂环基、C6-14芳基、5-14元杂芳基、-(CReeRff)n4C(O)Rgg、-(CReeRff)n4NRhhC(O)Rgg、-(CReeRff)n4NRhhORgg、-(CReeRff)n4S(O)2Rgg、-(CReeRff)n4S(O)Rgg、-(CReeRff)n4SRgg、-(CReeRff)n4C(O)NRhhRgg、-(CReeRff)n4S(O)NRhhRgg、-(CReeRff)n4SNRhhRgg或-(CReeRff)n4S(O)2NRhhRgg，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6桥环烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代； R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1 -6 bridged cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CR ee R ff ) n4 C(O)R gg , -(CR ee R ff ) n4 NR hh C( O)R gg , -(CR ee R ff ) n4 NR hh OR gg , -(CR ee R ff ) n4 S(O) 2 R gg , -(CR ee R ff ) n4 S(O)R gg , - (CR ee R ff ) n4 SR gg , -(CR ee R ff ) n4 C(O)NR hh R gg , -(CR ee R ff ) n4 S(O)NR hh R gg , -(CR ee R ff ) n4 SNR hh R gg or -(CR ee R ff ) n4 S(O) 2 NR hh R gg , the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 Bridged cycloalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen , nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkane One or more substituents in radical, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl;
    Ree、Rff、Rgg和Rhh各自独立的选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基；R ee , R ff , R gg and Rhh are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkanes C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl;
    或者Ree、Rff链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Or R ee and R ff link to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio , carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 One or more substituents in the heteroaryl group are substituted;
    R6或R8各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R 6 or R 8 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterium Substituted alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkene radical, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkane C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3- Substituted by one or more substituents in 12-membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl group;
    或者，任意两个相邻或不相邻的R6、R7和R8链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、 C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；Alternatively, any two adjacent or non-adjacent R 6 , R 7 and R 8 are linked to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heterocyclic group Aryl, the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, Mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1 -6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
    n4为0、1、2、3或4。n4 is 0, 1, 2, 3 or 4.
  11. 根据权利要求9-10任一所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，化合物进一步如通式(XII-D-1)、(XII-D-2)、(XIII-B-1)、(XIII-B-2)、(XIII-B’-1)或(XIII-B’-2)所示：
    According to the compound described in any one of claims 9-10, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that, the compound is further as general formula (XII-D-1), (XII-D-2) , (XIII-B-1), (XIII-B-2), (XIII-B'-1) or (XIII-B'-2):
  12. 根据权利要求1-6任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，L1选自键、取代或未取代的亚烯基、取代或未取代的亚炔基、-(CH2)n-、-(CH2)nC(O)(CRaaRbb)n1-、-(CH2)nC(O)NRcc(CH2)n1-、-(CH2)n(CRaaRbb)n1-、-(CRaaRbb)nO(CH2)n1-、-(CH2)nO(CRaaRbb)n1-、-(CRaaRbb)nS(CH2)n1-、-(CH2)nS(CRaaRbb)n1-、-(CRaaRbb)n(CH2)n1NRcc-、-(CH2)nNRcc(CRaaRbb)n1-、 -(CH2)nNRccC(O)-、-(CH2)nP(O)pRaa-、-(CH2)nS(O)m-、-(CH2)nS(O)mNRcc-和-(CH2)nNRccS(O)m-；The compound according to any one of claims 1-6, its stereoisomer or pharmaceutically acceptable salt thereof, wherein L is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted Alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR cc (CH 2 ) n1 - , -(CH 2 ) n (CR aa R bb ) n1 -, -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -( CR aa R bb ) n S(CH 2 ) n1 -, -(CH 2 ) n S(CR aa R bb ) n1 -, -(CR aa R bb ) n (CH 2 ) n1 NR cc -, -(CH 2 ) n NR cc (CR aa R bb ) n1 -, -(CH 2 ) n NR cc C(O)-, -(CH 2 ) n P(O) p R aa -, -(CH 2 ) n S(O) m -, -(CH 2 ) n S( O) m NR cc - and - (CH 2 ) n NR cc S(O) m -;
    优选地，L1选自键、取代或未取代的亚烯基、取代或未取代的亚炔基、-(CH2)n-、-(CH2)nC(O)-、-(CRaaRbb)nO-、-O(CRaaRbb)n1-、-(CRaaRbb)nS-、-S(CRaaRbb)n1-、-(CH2)n1NRcc-、-NRcc(CRaaRbb)n1-或-NRccC(O)-；Preferably, L 1 is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, -(CH 2 ) n -, -(CH 2 ) n C(O)-, -(CR aa R bb ) n O-, -O(CR aa R bb ) n1 -, -(CR aa R bb ) n S-, -S(CR aa R bb ) n1 -, -(CH 2 ) n1 NR cc - , -NR cc (CR aa R bb ) n1 -or -NR cc C(O)-;
    更优选地，L1选自键、-CH2-、-OCH2-、-OCD2-、-NH-、-C(O)NH-、-OCH(CH3)-、-OC(CH3)2-、-NH-CH2-或 More preferably, L 1 is selected from a bond, -CH 2 -, -OCH 2 -, -OCD 2 -, -NH-, -C(O)NH-, -OCH(CH 3 )-, -OC(CH 3 ) 2 -, -NH-CH 2 -or
    Raa、Rbb和Rcc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1 -6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1 -6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, Nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxy Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl are substituted by one or more substituents;
    优选地，Raa、Rbb和Rcc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；Preferably, R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further deuterized , halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1 -3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are substituted by one or more substituents;
    或者，Raa、Rbb和Rcc中的任意两个链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基和C1-6卤代烷氧基中的一个或多个取代基所取代；Alternatively, any two of R aa , R bb and R cc are linked to form C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, Amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy , C 1-6 deuterated alkoxy and C 1-6 haloalkoxy replaced by one or more substituents;
    优选地，Raa、Rbb和Rcc中的任意两个链接形成C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代 基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基和C1-3卤代烷氧基中的一个或多个取代基所取代。Preferably, any two of R aa , R bb and R cc are linked to form C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, so The C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl can optionally be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano , amino, oxo group, thiol group, carboxyl group, C 1-3 alkyl group, C 1-3 deuterated alkyl group, C 1-3 haloalkyl group, C 1-3 hydroxyalkyl group, C 1-3 alkoxy group, C 1-3 alkoxy group, C 1-3 3 deuterated alkoxy and C 1-3 haloalkoxy substituents in one or more substituents.
  13. 根据权利要求1-8任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，Ra各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；According to the compound described in any one of claims 1-8, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that R a is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto , cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered hetero Cyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl Replaced by one or more substituents;
    优选地，Ra各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代。Preferably, each R a is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- One or more substituents in 8-membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group.
  14. 根据权利要求1-8任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，Rb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代； The compound according to any one of claims 1-8, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R b are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto , cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered hetero Cyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl Replaced by one or more substituents;
    优选地，Rb各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代。Preferably, each R b is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- One or more substituents in 8-membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group.
  15. 根据权利要求1-8任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，Rc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；According to the compound described in any one of claims 1-8, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that R c is each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto , cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered hetero Cyclic group, C 6-14 aryl or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 Haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl Replaced by one or more substituents;
    优选地，Rc各自独立地选自氢、氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基或5-10元杂芳基，所述的氨基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基、C1-3羟烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-3烷基、C1-3氘代烷基、C1-3卤代烷基、C1-3羟烷基、C1-3烷氧基、C1-3氘代烷氧基、C1-3卤代烷氧基、C2-4烯基、C2-4炔基、C3-8环烷基、3-8元杂环基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；Preferably, each Rc is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkene radical, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl, the amino, C 1-3 alkane C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy , C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, Hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3- One or more substituents in 8-membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group;
    或者，Rb与Rc链接形成C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘 代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代。Alternatively, R b is linked with R c to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-14 aryl group or a 5-14 membered heteroaryl group, and the C 3-12 cycloalkyl group, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, sulfur Substitute, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterium Substituted alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and One or more substituents in the 5-14 membered heteroaryl are substituted.
  16. 根据权利要求1-3或6-11任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，R6选自卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基或5-14元杂芳基，所述的氨基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基，任选地可以进一步被氘、卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环基、C6-14芳基和5-14元杂芳基中的一个或多个取代基所取代；The compound according to any one of claims 1-3 or 6-11, its stereoisomer or pharmaceutically acceptable salt thereof, wherein R is selected from halogen, nitro, hydroxyl, mercapto, cyano , amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy Base, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, the amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 14 aryl and 5-14 membered heteroaryl, optionally can be further replaced by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy , C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl replaced by a substituent;
    优选地，R6选自卤素、硝基、羟基、巯基、氰基、氨基、氧代基、硫代基、羧基、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟烷基、C1-6烷氧基、C1-6氘代烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基；Preferably, R is selected from halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, thio, carboxyl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
    更优选地，R6选自氟。More preferably, R6 is selected from fluorine.
  17. 根据权利要求确认1-16任一项所述的化合物、其立体异构体或其药学上可接受盐，其特征在于，化合物的结构如下所示：












    Confirm the compound described in any one of 1-16 according to the claim, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that the structure of the compound is as follows:












  18. 一种制备权利要求9所述的通式(XII-D)化合物或其立体异构体及其药学上可接受的盐的方法，其特征在于，包含如下步骤：
    A method for preparing the compound of general formula (XII-D) or its stereoisomers and pharmaceutically acceptable salts thereof according to claim 9, characterized in that it comprises the following steps:
    通式(M-1)与通式(M-2)反应，得到通式(XII-D)所示的目标化合物；The general formula (M-1) reacts with the general formula (M-2) to obtain the target compound shown in the general formula (XII-D);
    所述X1、X3、Ra1、Ra2、Ra3、Ra4、Raa、Rbb、Rb2、Rb3、Rc1、Rc2、Rc3、Rda、Rdb、R’da、R’db、R6、R8、n7如权利要求9所述。Said X 1 , X 3 , R a1 , R a2 , R a3 , R a4 , R aa , R bb , R b2 , R b3 , R c1 , R c2 , R c3 , R da , R db , R' da , R' db , R 6 , R 8 , and n7 are as described in claim 9.
  19. 一种药物组合物，其包括治疗有效剂量的权利要求1～17任一项所述化合物、其立体异构体或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluent or excipient.
  20. 根据权利要求1～17任一项所述化合物、其立体异构体或其药学上可接受的盐，或权利要求19所述的药物组合物在制备治疗p38激酶介导的疾病药物中的应用。Application of the compound according to any one of claims 1 to 17, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 19 in the preparation of medicines for treating diseases mediated by p38 kinase .
  21. 根据权利要求1～17任一项所述化合物、其立体异构体或其药学上可接受的盐，或权利要求19所述的药物组合物在制备治疗自身免疫疾病、慢性炎性疾病、急性炎症性病症、自身炎性疾病、动脉粥样硬化、糖尿病、纤维变性疾病、代谢疾病、癌症、肿瘤、白血病和淋巴瘤的药物中的应用。 According to any one of claims 1 to 17, the compound, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19 is used in the preparation and treatment of autoimmune diseases, chronic inflammatory diseases, acute Applications in the medicine of inflammatory disorders, autoinflammatory diseases, atherosclerosis, diabetes, fibrotic diseases, metabolic diseases, cancer, tumors, leukemias and lymphomas.
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