WO2023134765A1 - Dérivés contenant un cycle à cinq chaînons, leur procédé de préparation et leurs utilisations - Google Patents

Dérivés contenant un cycle à cinq chaînons, leur procédé de préparation et leurs utilisations 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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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/fr

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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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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
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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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    • C—CHEMISTRY; METALLURGY
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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
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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

La présente invention concerne des dérivés contenant un cycle à cinq chaînons, leur procédé de préparation et leurs utilisations. En particulier, la présente invention concerne des composés représentés par une formule générale, leur procédé de préparation, une composition pharmaceutique contenant les composés, et des utilisations des composés en tant que régulateurs biologiques dans la préparation de médicaments pour le traitement de maladies auto-immunes, de maladies inflammatoires chroniques, de maladies inflammatoires aiguës, de maladies auto-inflammatoires, de l'athérosclérose, du diabète, de maladies fibreuses, de maladies métaboliques, de cancers, de tumeurs, de la leucémie et du lymphome, chaque substituant dans la formule générale étant identique à celui défini dans la description.
PCT/CN2023/072393 2022-01-14 2023-01-16 Dérivés contenant un cycle à cinq chaînons, leur procédé de préparation et leurs utilisations WO2023134765A1 (fr)

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US20050176775A1 (en) * 2003-08-13 2005-08-11 Balekudru Devadas Substituted pyridinones
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