WO2022166796A1 - Inhibiteur du récepteur de l'adénosine hétérocyclique de type pyrimidine ou pyridine, son procédé de préparation et son utilisation - Google Patents

Inhibiteur du récepteur de l'adénosine hétérocyclique de type pyrimidine ou pyridine, son procédé de préparation et son utilisation Download PDF

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WO2022166796A1
WO2022166796A1 PCT/CN2022/074495 CN2022074495W WO2022166796A1 WO 2022166796 A1 WO2022166796 A1 WO 2022166796A1 CN 2022074495 W CN2022074495 W CN 2022074495W WO 2022166796 A1 WO2022166796 A1 WO 2022166796A1
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mmol
pharmaceutically acceptable
solvate
acceptable salt
methyl
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PCT/CN2022/074495
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English (en)
Chinese (zh)
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潘建峰
孙大庆
闫琪
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上海齐鲁制药研究中心有限公司
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Priority to CN202280012721.7A priority Critical patent/CN116981669B/zh
Publication of WO2022166796A1 publication Critical patent/WO2022166796A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicinal chemistry, in particular to a new class of pyrimidine/pyrido heterocyclic compounds, which can be used as A2a or/and A2b adenosine receptor inhibitors for the treatment of diseases related to A2a or/and A2b receptors .
  • Adenosine as a neurotransmitter and regulator, is widely distributed in nervous system, cardiovascular system, kidney, gastrointestinal tract and other tissues, and regulates various important physiological functions.
  • ADO participates in the pathophysiological process of various diseases by binding to its specific receptors A1R, A2aR, A2bR and A3R.
  • A1R, A2aR, A2bR and A3R the specific receptors of ADO.
  • A1R A2aR
  • A2bR A3R
  • the distribution and quantity of A1R and A2aR in the brain are significantly more than the other two receptors, and the affinity with ADO is also stronger.
  • Adenosine receptors are present on the surface of most tissue cells in the body, and A1 receptors are mainly present in brain tissue, spinal cord and heart. A1 receptors in the heart are distributed on the surface of atrial, ventricular, sinoatrial node and atrioventricular node cells.
  • Adenosine and its analogs inhibit adenylate cyclase (AC), G protein and catecholamine by exciting A1 receptors, and promote outward potassium ion current to produce negative chronotropic, inotropic and negative conduction effects;
  • Post-in vivo signal transduction mechanism namely activation of G protein, which in turn activates phospholipase C (PLC), PLC activates the phosphatidylinositol system to generate inositol triphosphate (IP3) and diglyceride (DG), and DG activates the corresponding protein kinase C (PKC), and then activate ATP-sensitive potassium channel (KATP) ion flow to produce ischemic preconditioning (PC) in the myocardium; activate nitric oxide synthase in sinoatrial node and atrioventricular node cells to synthesize nitric oxide Increase, inhibit the inward calcium ion influx of slow response autonomic cells to produce negative chronotropic, negative conduction effect on
  • A2a receptors are mainly distributed in dopamine-enriched areas in brain tissue, followed by renal papilla, endothelial cells of blood vessels (aorta and coronary arteries, etc.), platelets and polymorphonuclear leukocyte membranes.
  • A2b receptors are mainly distributed in the digestive system. When adenosine and its analogs bind to A2 receptors, they can activate AC and increase the formation of cyclic adenosine monophosphate (cAMP), thereby expanding vascular smooth muscle and inhibiting the toxic effects of neutrophils.
  • cAMP cyclic adenosine monophosphate
  • Adenosine A3 receptors are widely distributed in the spleen, heart, kidney and other organs of rats, rabbits, dogs, sheep and humans, as well as different regions of the brain and the surface of inflammatory cells.
  • the binding of A3 receptor to its radioligand has the effect of inhibiting AC to increase cAMP and producing PC; meanwhile, PLC is activated by pertussis toxin-sensitive G protein to generate IP3 and DG, which in turn activates PKC and also produces PC; adenosine excites A3 Post-receptor can promote mast cell degranulation and increase the release of allergenic mediators from mast cells.
  • A2a antagonists have been suggested for the management and treatment of eg Parkinson's disease and cancer; modulation of A2b has been suggested for the management and treatment of eg chronic lung diseases including asthma; modulation of A3 has been suggested for For the management and treatment of eg asthma and chronic obstructive pulmonary disease, glaucoma, cancer and stroke.
  • Adenosine receptor inhibitors are receiving increasing attention. Some potential inhibitors of A2a or/and A2b have been discovered one after another. However, obtaining A2a and/or A2b inhibitors with stronger inhibitory effect and better selectivity, especially A2a/A2b dual inhibitors, still has important significance and development value.
  • the present invention provides a compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof:
  • R 2 is H, CN, halogen atom, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, N(Re)(Rf) or Ar; preferably, R 2 is NH 2 or Ar;
  • Re and Rf are independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkyl-CO-, C 1-4 haloalkyl-CO-, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or Re and Rf together with the attached N atom form a 4-6 membered ring, optionally by one or more selected from CN, OH, C 1- 4 alkyl, C 1-4 haloalkyl and substituent substitution of halogen atoms; preferably, the 4-6 membered ring is a 4-6 membered heterocycloalkyl; preferably, N(Re)(Rf) is NH 2. Tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl;
  • Ar is aryl or heteroaryl; the aryl is preferably phenyl or naphthyl, more preferably phenyl; the heteroaryl is preferably a 5-6 membered heteroaromatic ring, more preferably pyridyl, pyrimidinyl , pyridazinyl, pyrazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazolyl, more preferably pyridyl, furanyl, pyrazolyl, thienyl, more Preferably pyridyl; said aryl and said heteroaryl are optionally independently substituted with one or more Rc; preferably, Ar is substituted with 1, 2, 3 or 4 Rc; Rc is independently H, C1 -4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, CN or halogen
  • Ar can be selected from any of the following structures:
  • Ar is a compound having more specifically, More specifically, Ar is a compound having more specifically, Ar.
  • R 2 is NH 2 ; in other embodiments, R 2 is Ar, preferably
  • X 1 is N or C-Ra; preferably, X 1 is N or CH; more preferably, X 1 is CH;
  • the directly connected atoms together form a five-membered heteroaromatic ring substituted by 1, 2 or 3 Ra, the five-membered heteroaromatic ring is preferably pyrrolyl, furanyl, thienyl, imidazolyl, isoxazolyl, iso Thiazolyl, pyrazolyl, oxazolyl, thiazolyl;
  • Z 1 is N or CH
  • Y 1 , Y 2 , Y 3 are independently N and C-Rb; preferably, Y 1 is C-Rb, Y 2 is N, and Y 3 is N; more preferably, Y 1 is CH, and Y 2 is N , Y 3 is N;
  • Ra is independently H, CN, NH 2 CO-, halogen atom, C 1-4 alkyl, C 1-4 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl or 5-6 membered heteroaryl; preferably, Ra is independently H, CN, halogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, Cyclohexyl, azetidine, phenyl, pyrazolyl, furanyl or imidazolyl; Ra is optionally selected from one or more halogen atoms, CN, C 1-4 alkyl and C 1-4 haloalkanes Substituent substitution of radicals; more preferably, Ra is independently H, Br, Cl, F, CN, CHF2 , CF3 , NH2CO- , methyl, pyrazolyl,
  • Rb is independently H, CN, C1-4 alkyl, C1-4 haloalkyl or halogen atom; preferably, Rb is independently H, Cl, F, CN, methyl, ethyl, isopropyl or tris fluoromethyl; more preferably, Rb is independently H, Cl, methyl or trifluoromethyl;
  • L is -( CH2 )n-, -(CD2)n-, -NH-( CH2 )n-, -O-( CH2 )n- or -S-( CH2 ) n-; preferably , L is CH 2 or CD 2 ; more preferably, L is CH 2 ; the D refers to deuterium;
  • aryl or 5-6 membered heteroaryl preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, furyl, thienyl, More preferably phenyl, pyridyl;
  • R 1 is independently H, CN, halogen atom, NH 2 , aminocarbonyl-C 1-4 alkyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, C 1-4 alkyl , C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl-OC 1-4 alkyl, 3-7 membered cycloalkyl, 3-7 membered Heterocycloalkyl, 5-13-membered spirocyclic group, 5-13-membered heterospirocyclic group, 6-12-membered bridged ring group, 6-12-membered heterobridged ring group, phenyl, 5-6-membered heteroaryl, DiC 1-4 alkyl P(O)-, 3-7 membered cycloalkyl-OC 1-4 alkyl, 3-7 membered heterocycloalkyl-OC 1-4 alkyl and
  • R 1 is F, -OCH 3 , CN or Preferably, R 1 is
  • two adjacent R1 can be cyclized together with the atoms connecting them to form a saturated 5-6 membered ring or an unsaturated 5-6 membered ring, the saturated 5-6 membered ring and the unsaturated 5-6 membered ring optionally substituted by one or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy and halogen atoms; preferably, the saturated 5-6 membered ring and unsaturated 5-6 membered Rings are pyrazole ring, oxazole ring, thiazole ring, isothiazole ring, isoxazole ring, pyridine ring, pyrrole ring, thiophene ring, furan ring, imidazole ring, benzene ring, pyrimidine ring, pyrazine ring, pyridazine ring or 1,3-dioxolane; more preferably, the two R 1 and Co-cyclization to the following groups:
  • n 0, 1, 2 or 3; preferably 1 or 2; more preferably 1;
  • n 0, 1, 2 or 3, preferably 1 or 2; more preferably 1;
  • Ar is phenyl and the other variables are as defined in any one of the embodiments of the present invention.
  • Ar is pyridyl and the other variables are as defined in any one of the embodiments of the present invention.
  • Z1 is C and the other variables are as defined in any one of the embodiments of the present invention.
  • X2 is S and the other variables are as defined in any one of the embodiments of the present invention.
  • X2 is S
  • X3 and X4 are independently N or C-Ra, and other variables are as defined in any one of the embodiments of the present invention.
  • X2 is S
  • X3 is CH
  • X4 is C-Ra
  • other variables are as defined in any one of the embodiments of the present invention.
  • X2 is S
  • X3 is CH
  • X4 is C-Br
  • other variables are as defined in any one of the embodiments of the present invention.
  • X2 is S
  • X3 is N
  • X4 is C-Ra
  • other variables are as defined in any of the embodiments of the present invention.
  • X4 is S and the other variables are as defined in any one of the embodiments of the present invention.
  • X4 is S
  • X2 and X3 are independently N or C-Ra, and other variables are as defined in any one of the embodiments of the present invention.
  • X4 is S
  • X2 is C - Ra
  • X3 is N
  • other variables are as defined in any one of the embodiments of the present invention.
  • X2 is O
  • X3 and X4 are independently N or C-Ra, and other variables are as defined in any one of the embodiments of the present invention.
  • X2 is N-Ra
  • X3 and X4 are independently N or C-Ra
  • other variables are as defined in any one of the embodiments of the present invention.
  • X2, X3 , and X4 are independently C-Ra, N, or N-Ra, and other variables are as defined in any one of the embodiments of the present invention.
  • X2 is N and the other variables are as defined in any one of the embodiments of the present invention.
  • X2 is N
  • X3 is CH
  • other variables are as defined in any one of the embodiments of the present invention.
  • X2 and X3 are connected by a double bond, and other variables are as defined in any one of the embodiments of the present invention.
  • X 2 and X 3 are connected by a double bond, X 2 and X 3 are independently N or C-Ra, and other variables are as defined in any one of the embodiments of the present invention.
  • X 2 and X 3 are connected by a single bond, and other variables are as defined in any one of the embodiments of the present invention.
  • the structural unit choose from any of the following structures: preferably more preferably
  • the structural unit choose from any of the following structures: preferably
  • Y 1 , Y 2 , and Y 3 are all N, and other variables are as defined in any one of the embodiments of the present invention.
  • Y 1 is CH
  • Y 2 is CH
  • Y 3 is N
  • other variables are as defined in any one of the embodiments of the present invention.
  • Y 1 is CH
  • Y 2 is N
  • other variables are as defined in any one of the embodiments of the present invention.
  • Y3 is N, and the other variables are as defined in any one of the embodiments of the present invention.
  • L is CH2 and the other variables are as defined in any one of the embodiments of the present invention.
  • L is CD2 and the other variables are as defined in any of the embodiments of the invention.
  • R 2 is NH 2 and other variables are as defined in any one of the embodiments of the present invention.
  • R 1 is Other variables are as defined in any aspect of the present invention.
  • the compound shown in formula II has the structure shown in formula II-a:
  • X 2 , X 3 , X 4 , Y 1 , Y 2 , L, R 1 , m as defined in any aspect of the present invention
  • Y 1 is CH
  • Y 2 is N
  • other variables are as defined in any one of the embodiments of the present invention.
  • X5 is CH and the other variables are as defined in any of the embodiments of the invention.
  • X5 is N and the other variables are as defined in any one of the embodiments of the present invention.
  • L is CH2 and the other variables are as defined in any of the embodiments of the invention.
  • L is CD2 and the other variables are as defined in any of the embodiments of the invention.
  • R 1 is Other variables are as defined in any aspect of the present invention.
  • X2 is S and the other variables are as defined in any one of the embodiments of the present invention.
  • X2 is S
  • X3 and X4 are independently N or C-Ra, and other variables are as defined in any one of the embodiments of the present invention.
  • X 2 is S
  • X 3 is CH
  • X 4 is C-Ra
  • other variables are as defined in any one of the embodiments of the present invention.
  • X2 is S
  • X3 is CH
  • X4 is C-Br
  • other variables are as defined in any one of the embodiments of the present invention.
  • X 2 is S
  • X 3 is N
  • X 4 is C-Ra
  • other variables are as defined in any one of the embodiments of the present invention.
  • X4 is S and the other variables are as defined in any one of the embodiments of the present invention.
  • X4 is S
  • X2 and X3 are independently N or C-Ra
  • other variables are as defined in any one of the embodiments of the present invention.
  • X4 is S
  • X2 is C - Ra
  • X3 is N
  • other variables are as defined in any one of the embodiments of the present invention.
  • X 2 is O
  • X 3 and X 4 are independently N or C-Ra, and other variables are as defined in any one of the embodiments of the present invention.
  • X 2 is N-Ra
  • X 3 and X 4 are independently N or C-Ra
  • other variables are as defined in any one of the embodiments of the present invention.
  • X2, X3 and X4 are independently C-Ra, N or N-Ra, and other variables are as defined in any one of the embodiments of the present invention.
  • the compound shown in formula II has the structure shown in formula II-b:
  • X 2 , X 3 , X 4 , Y 1 , Y 2 , L, R 1 , m as defined in any aspect of the present invention
  • X6 and X7 are selected from N, O, S, NH, CH and CH2 .
  • X6 is NH and X7 is N.
  • the compound shown in formula II has the structure shown in formula II-c:
  • Ra and R 1 are as defined in any one of the embodiments of the present invention.
  • R 1 is
  • Ra is selected from methyl, Br, Cl, CN, CHF2 , CF3 , and cyclopropyl.
  • the compound shown in formula II has the structure shown in formula I',
  • each group is as defined in any one of the embodiments of the present invention.
  • the compound shown in formula II has the structure shown in formula I'-a,
  • X 4-1 and X 5-1 are independently N or CH;
  • p 0, 1, 2, 3, or 4;
  • X 1 is CH and the other variables are as defined in any one of the embodiments of the present invention.
  • X3 is CH and the other variables are as defined in any one of the embodiments of the present invention.
  • X 4-1 is N, and other variables are as defined in any one of the embodiments of the present invention.
  • X 5-1 is CH, and other variables are as defined in any one of the embodiments of the present invention.
  • Y 1 is CH
  • Y 2 is N
  • other variables are as defined in any one of the embodiments of the present invention.
  • the compound shown in formula II has the structure shown in formula I'-b,
  • R 3 , R 4 and R 5 are independently Rc;
  • R 6 is Rb
  • R 1 , Rb, Rc, X 1 , X 2 , X 3 As defined in any aspect of the present invention.
  • R 3 is H, CH 3 , CH 3 O or Cl, and other variables are as defined in any one of the embodiments of the present invention.
  • R 4 is H, CH 3 , Cl, CH 3 O, F or CN, and other variables are as defined in any one of the embodiments of the present invention.
  • R 5 is H or a halogen atom; preferably H or F, and other variables are as defined in any one of the embodiments of the present invention.
  • R 6 is H, C 1-4 alkyl or C 1-4 haloalkyl; preferably H or CH 3 , other variables such as any of the present invention defined by a program.
  • R 3 is CH 3
  • R 4 is CN
  • R 5 is H
  • R 6 is H
  • other variables are as defined in any one of the embodiments of the present invention.
  • X 1 is CH and other variables are as defined in any one of the embodiments of the present invention.
  • X 1 is N, and other variables are as defined in any one of the embodiments of the present invention.
  • X2 is N, and other variables are as defined in any one of the embodiments of the present invention.
  • X3 is CH and the other variables are as defined in any one of the embodiments of the present invention.
  • R 1 is Other variables are as defined in any aspect of the present invention.
  • the compound shown in formula II has the structure shown in formula I-c, formula I-d or formula I-e,
  • X 1 , X 2 , X 3 , R 1 , R 3 , R 5 , and R 6 are as defined in any one of the embodiments of the present invention.
  • the present invention provides a compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof:
  • R 2 is H, CN, halogen atom, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, N(Re)(Rf) or Ar; preferably, R 2 is NH 2 or Ar;
  • Re and Rf are independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkyl-CO-, C 1-4 haloalkyl-CO-, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; or Re and Rf together with the attached N atom form a 4-6 membered ring, optionally by one or more selected from CN, OH, C 1- 4 alkyl, C 1-4 haloalkyl and substituent substitution of halogen atoms; preferably, the 4-6 membered ring is a 4-6 membered heterocycloalkyl; preferably, N(Re)(Rf) is NH 2. Tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl;
  • Ar is aryl or heteroaryl; the aryl is preferably phenyl or naphthyl, more preferably phenyl; the heteroaryl is preferably a 5-6 membered heteroaromatic ring, more preferably pyridyl, pyrimidinyl , pyridazinyl, pyrazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazolyl, more preferably pyridyl, furanyl, pyrazolyl, thienyl, more preferably Preferably pyridyl; said aryl and said heteroaryl are optionally independently substituted with one or more Rc; preferably, Ar is substituted with 1, 2, 3 or 4 Rc; Rc is independently H, C1 -4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, CN or
  • Ar can be selected from any of the following structures:
  • Ar is a compound having more specifically, More specifically, Ar is a compound having more specifically, Ar.
  • Ra is independently H, CN, NH 2 CO-, halogen atom, C 1-4 alkyl, C 1-4 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, aryl or 5-6 membered heteroaryl; preferably, Ra is independently H, CN, halogen, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, Cyclohexyl, azetidine, phenyl, pyrazolyl, furanyl or imidazolyl; Ra is optionally selected from one or more halogen atoms, CN, C 1-4 alkyl and C 1-4 haloalkanes Substituent substitution of radicals; more preferably, Ra is independently H, Br, Cl, F, CN, CHF2 , CF3 , NH2CO- , methyl, pyrazolyl,
  • R 2 is NH 2 ; in other embodiments, R 2 is Ar, preferably
  • X 1 is N or C-Ra; preferably, X 1 is N or CH; more preferably, X 1 is CH;
  • the atoms directly connected together form a five-membered heteroaromatic ring substituted by 1-3 Ra, the five-membered heteroaromatic ring is preferably pyrrolyl, furanyl, thienyl, imidazolyl, isoxazolyl, isothiazolyl , pyrazolyl, oxazolyl, thiazolyl;
  • Z 1 is N or CH
  • Y 1 , Y 2 , Y 3 are independently N or C-Rb; preferably, Y 1 is C-Rb, Y 2 is N, and Y 3 is N; more preferably, Y 1 is CH, and Y 2 is N , Y 3 is N;
  • Rb is independently H, CN, C 1-4 alkyl, C 1-4 haloalkyl or halogen atom; preferably, Rb is independently H, Cl, F, CN, methyl, ethyl, isopropyl or trifluoromethyl; more preferably, Rb is independently H, Cl, methyl or trifluoromethyl;
  • L is -(CH 2 )n-, -(CD 2 )n-, -NH-(CH 2 )n-, -O-(CH 2 )n- or -S-(CH 2 )n-; preferably , L is CH 2 or CD 2 ; more preferably, L is CH 2 ; the D refers to deuterium;
  • aryl or 5-6 membered heteroaryl preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, More preferably phenyl, pyridyl;
  • R 1 is independently H, halogen atom, NH 2 , aminocarbonyl-C 1-4 alkyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl-OC 1-4 alkyl, 3-7 membered cycloalkyl, 3-7 membered heterocycle Alkyl, 5-13-membered spirocyclic group, 5-13-membered heterospirocyclic group, 6-12-membered bridged ring group, 6-12-membered heterobridged ring group, phenyl, 5-6-membered heteroaryl group, di-C 1-4 alkyl P(O)-, 3-7 membered cycloalkyl-OC 1-4 alkyl, 3-7 membered heterocycloalkyl-OC 1-4 alkyl or phenoxy-C
  • R 1 is F, -OCH 3 , Preferably, R 1 is
  • two adjacent R 1 can be cyclized into saturated 5-6 membered rings or unsaturated 5-6 membered rings, and these rings can be optionally separated by a or more substituents selected from C 1-4 alkyl, C 1-4 alkoxy and halogen atoms; preferably, two adjacent R 1 can be cyclized into pyrazole ring, oxazole ring, thiazole ring Ring, isothiazole ring, isoxazole ring, pyridine ring, pyrrole ring, thiophene ring, furan ring, imidazole ring, benzene ring, pyrimidine ring, pyrazine ring, pyridazine ring, 1,3-dioxolane;
  • the two R 1 and Co-cyclization to the following groups:
  • n 0, 1, 2 or 3; preferably 1 or 2; more preferably 1;
  • n 0, 1, 2 or 3; preferably 1 or 2; more preferably 1.
  • R 1 is independently H, NH 2 , aminocarbonyl-C 1-4 alkyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl-OC 1-4 alkyl, 3-7 membered cycloalkane base, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclyl, 5-13 membered heterospirocyclyl, 6-12 membered bridged ring, 6-12 membered heterobridged ring, phenyl, 5- 6-membered heteroaryl, di-C 1-4 alkyl P(O)-, 3-7 membered cycloalkyl-OC 1-4 alkyl, 3-7 membered heterocycloalkyl-OC 1-4 alkyl or Phenoxy-C
  • R1 is
  • the structural unit choose from any of the following structures: preferably more preferably
  • R 1 is independently H, NH 2 , aminocarbonyl-C 1-4 alkyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl-OC 1-4 alkyl, 3-7 membered cycloalkane base, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclyl, 5-13 membered heterospirocyclyl, 6-12 membered bridged ring, 6-12 membered heterobridged ring, phenyl, 5- 6-membered heteroaryl, di-C 1-4 alkyl P(O)-, 3-7 membered cycloalkyl-OC 1-4 alkyl, 3-7 membered heterocycloalkyl-OC 1-4 alkyl or Phenoxy-C
  • R1 is
  • the present invention provides a kind of compound shown in formula I, its pharmaceutically acceptable salt:
  • X 1 is N or C-Ra; Ra is independently H, CN, C 1-4 alkyl, C 1-4 haloalkyl or halogen atom; preferably, Ra is independently H, Cl, F, CN , methyl, ethyl, isopropyl or trifluoromethyl; more preferably, Ra is independently H, Cl, methyl or trifluoromethyl; preferably, X 1 is CH;
  • Y 1 , Y 2 , Y 3 are independently N and C-Rb;
  • Rb is independently H, CN, C 1-4 alkyl, C 1-4 haloalkyl or halogen atom; preferably, Rb is independently H , Cl, F, CN, methyl, ethyl, isopropyl or trifluoromethyl; more preferably, Rb is independently H, Cl, methyl or trifluoromethyl;
  • L is -( CH2 )n-, -(CD2)n-, -NH-( CH2 )n-, -O-( CH2 )n- or -S-( CH2 ) n-; preferably , L is CH 2 or CD 2 ; more preferably, L is CH 2 ; the D refers to deuterium;
  • Ar is an aryl group or a heteroaryl group; the aryl group is preferably a phenyl group and a naphthyl group, more preferably a phenyl group; the heteroaryl group is preferably a 5-6 membered heteroaromatic ring, more preferably a pyridyl group, a pyrimidinyl group, and a pyridazinyl group , pyrazinyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazole, thiazolyl, more preferably pyridyl, furanyl, pyrazolyl, thienyl, more preferably pyridyl;
  • the aryl and the heteroaryl are optionally independently substituted with one or more Rc;
  • Rc is independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4
  • Ar can be selected from any of the following structures:
  • Ar is a compound having more specifically, More specifically, Ar is a compound having more specifically, Ar.
  • aryl or 5-6 membered heteroaryl preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, furyl, thienyl, More preferably phenyl, pyridyl;
  • R 1 is independently H, CN, halogen atom, NH 2 , aminocarbonyl-C 1-4 alkyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, C 1-4 alkyl , C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl-OC 1-4 alkyl, 3-7 membered cycloalkyl, 3-7 membered Heterocycloalkyl, 5-13-membered spirocyclic group, 5-13-membered heterospirocyclic group, 6-12-membered bridged ring group, 6-12-membered heterobridged ring group, phenyl, 5-6-membered heteroaryl, DiC 1-4 alkyl P(O)-, 3-7 membered cycloalkyl-OC 1-4 alkyl, 3-7 membered heterocycloalkyl-OC 1-4 alkyl or
  • R 1 is independently F, CN, Preferably, R 1 is independently
  • two adjacent R 1 may be cyclized into a saturated 5-6 membered ring or an unsaturated 5-6 membered ring, and these rings may be optionally selected by one or more Substituents from C 1-4 alkyl, C 1-4 alkoxy and halogen atoms; preferably, two adjacent R 1 can be cyclized into pyrazole ring, oxazole ring, thiazole ring, isothiazole ring, isoxazole ring, pyridine ring, pyrrole ring, thiophene ring, furan ring, imidazole ring, benzene ring, pyrimidine ring, pyrazine ring, pyridazine ring, 1,3-dioxolane ring; preferably, two adjacent R 1 with Co-cyclization to the following groups:
  • n 0, 1, 2 or 3; preferably 1 or 2; more preferably 1;
  • n 0, 1, 2 or 3; preferably 1 or 2; more preferably 1.
  • the structural unit Choose from any of the following structures:
  • X 1 , X 2 , X 3 , Y 1 , Y 2 , R 1 , Rc are as defined in any one of the schemes in the present invention.
  • X4 and X5 are independently N or CH;
  • p 0, 1, 2, 3 or 4.
  • X1 is CH and the other variables are as defined in any one of the embodiments of the present invention.
  • X2 and X3 are connected by a double bond, and other variables are as defined in any one of the embodiments of the present invention.
  • X2 and X3 are connected by a single bond, and other variables are as defined in any one of the embodiments of the present invention.
  • X3 is CH and the other variables are as defined in any of the embodiments of the invention.
  • X4 is N, and the other variables are as defined in any one of the embodiments of the present invention.
  • X5 is CH and the other variables are as defined in any one of the embodiments of the present invention.
  • Y 1 is CH
  • Y 2 is N
  • other variables are as defined above.
  • R 1 , X 1 , X 2 , X 3 are as defined in formula Ia;
  • X 2 and X 3 are connected with a double bond; or X 2 and X 3 are connected with a single bond;
  • R 3 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen atom or CN; preferably, R 3 is selected from H, CH 3. CH 3 O or Cl;
  • R 4 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, halogen atom or CN; preferably, R 4 is selected from H, CH 3. Cl, CH 3 O, F or CN;
  • R 5 is H or a halogen atom; preferably, R 5 is H or F;
  • R 6 is H, C 1-4 alkyl or C 1-4 haloalkyl; preferably, R 6 is H, or R 6 is CH 3 .
  • R3 is CH3
  • R4 is CN
  • R5 is H
  • R6 is H
  • other variables are as defined in any one of the embodiments of the present invention.
  • X1 is CH and the other variables are as defined in any one of the embodiments of the present invention.
  • X1 is N, and other variables are as defined in any one of the embodiments of the present invention.
  • X2 is N, and the other variables are as defined in any one of the embodiments of the present invention.
  • X3 is CH and the other variables are as defined in any of the embodiments of the invention.
  • R 1 is Other variables are as defined in any aspect of the present invention.
  • the compound is represented by Formula I-c, Formula I-d, or Formula I-e,
  • X 1 , X 2 , X 3 , R 1 , R 3 , R 5 and R 6 are as defined in any one of the embodiments of the present invention.
  • Ar can be selected from any of the following structures:
  • R 1 is independently H, NH 2 , aminocarbonyl-C 1-4 alkyl, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkyl-OC 1-4 alkyl, 3-7 membered cycloalkane base, 3-7 membered heterocycloalkyl, 5-13 membered spirocyclyl, 5-13 membered heterospirocyclyl, 6-12 membered bridged ring, 6-12 membered heterobridged ring, phenyl, 5- 6-membered heteroaryl, di-C 1-4 alkyl P(O)-, 3-7 membered cycloalkyl-OC 1-4 alkyl, 3-7 membered heterocycloalkyl-OC 1-4 alkyl or Phenoxy-C
  • R1 is
  • R 1 is
  • the compound is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound as described above, a pharmaceutically acceptable salt thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof A solvate, and optionally one or more pharmaceutically acceptable carriers or excipients.
  • the present invention provides a compound as described above, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof for use in the preparation of treatment or/and prevention Use in the medicament of a disease or disorder associated with A2a and/or A2b receptors in mammals, including humans.
  • the present invention provides the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for the treatment or/and prevention of diseases or conditions associated with A2a and/or A2b receptors in mammals (including humans). .
  • the present invention provides a method for treating and/or preventing a disease or disorder associated with the A2a and/or A2b receptor in a mammal (including a human) in need thereof, the method comprising administering to the needy A compound as described above, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, are administered to a mammal, preferably in a therapeutically effective amount.
  • the present invention provides a method for treating and/or preventing a disease or disorder associated with the A2a and/or A2b receptor in a mammal (including a human) in need thereof, the method comprising administering to the needy
  • the mammal is administered (preferably a therapeutically effective amount) of the pharmaceutical composition as described above.
  • the disease or disorder associated with the A2a and/or A2b receptor is cancer, which may be a solid tumor or a non-solid tumor.
  • selected or optional substituents can be attached to the modified group at any attachable position of the substituent.
  • the di-C 1-4 alkylphosphoroxy group refers to two C 1-4 alkyl groups directly connected to the phosphorus atom.
  • the halogen atoms refer to fluorine, chlorine, bromine, and iodine; the "halogenated” refers to the formation of one or more hydrogen atoms in the substituents replaced by halogen atoms. the group.
  • alkyl refers to straight or branched chain hydrocarbon groups linked by single bonds between carbon atoms, and between carbon atoms and hydrogen atoms.
  • the alkyl group is preferably a C 1-4 or C 1-6 alkyl group; "C 1-4 alkyl” means an alkyl group having 1-4 carbon atoms, and "C 1-6 alkyl” means an alkyl group having 1-6 carbon atoms An alkyl group of atoms.
  • alkyl groups include, but are limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl .
  • cycloalkyl refers to a saturated hydrocarbon group in which atoms are linked by single bonds to form a ring.
  • C 3-7 cycloalkyl refers to a cycloalkyl group containing 3 to 7 carbon atoms.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.
  • spirocycle refers to a polycyclic hydrocarbon group in which a single carbon atom is shared between the single rings; the spirocycloalkyl is preferably a C5-13 , C6-12 , or C7-11 spirocycloalkyl ; the spirocycloalkyl Examples include, but are not limited to, spiro[2.2]pentane, spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.4]octane, spiro[4.4]nonane, spiro[4.5]decane, spiro[4.5]decane, 5.5]Undecane, spiro[5.6]dodecane, spiro[6.6]tridecane, spiro[6.7]tetradecane.
  • bridged ring refers to a polycyclic hydrocarbon group that shares two or more carbon atoms.
  • the bridged ring group is preferably a 4-13-membered bridged ring group, a 5-12-membered bridged ring group, a 6-12-membered bridged ring group, a 6-11-membered bridged ring group, and a 7-11-membered bridged ring group.
  • bridged cyclyl groups include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.1.0]heptyl, bicyclo[4.1.0]heptyl, Cyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, bicyclo[3.2.1]octyl.
  • alkoxy refers to an alkyl group attached through an oxygen bridge, ie, a group obtained by replacing a hydrogen atom in a hydroxyl group with an alkyl group.
  • the alkoxy group is preferably C1-4 or C1-6 alkoxy; examples of alkoxy include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy Oxy, tert-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms.
  • the haloalkyl group is preferably a C 1-6 or C 1-4 haloalkyl group.
  • Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl.
  • haloalkoxy refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms.
  • haloalkoxy include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy.
  • heterocycloalkyl refers to a cycloalkyl group in which one or more carbon atoms in the cyclic backbone structure is replaced by a heteroatom; the heteroatom is generally selected from N, O, S.
  • the heterocycloalkyl group is preferably a 3-6-membered, 3-7-membered, 4-6-membered, 4-7-membered, 5-6-membered, and 5-7-membered heterocycloalkyl group.
  • heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyrazolyl, tetrahydropyranyl, piperidine group, piperazinyl, morpholinyl.
  • heterospirocyclyl refers to a spirocyclyl group in which one or more carbon atoms in the spirocyclic backbone structure are substituted with a heteroatom selected from N, O, S.
  • the heterospirocyclic group is selected from the following spirocyclic groups in which the carbon atoms of the spirocyclic backbone are substituted with 1-3 heteroatoms selected from N, O, S: spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.3]hexyl [2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[ 4.4] Nonyl, spiro[4.5
  • heterospirocyclyl also include 2-oxa-7-azaspiro[5.3]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2 ,6-diazaspiro[3.3]heptane-2-yl, 2,7-diazaspiro[5.3]nonyl, 2,7-dioxaspiro[5.3]nonyl, 3,9-bis Azaspiro[5.5]undecan-3-yl, 1-oxa-4,9-diazaspiro[5.5]undecan-9-yl, 1-oxa-4,8-diaza Spiro[5.4]decan-8-yl, 3-azaspiro[5.5]undecan-3-yl, 7-azaspiro[3.5]decan-7-yl, 1-oxa-4,9 - Diazaspiro[5.5]undecan-4-yl, 6-oxa-2,9-diazaspiro[4.5]
  • nitrogen-containing heterospirocyclic group refers to a heterospirocyclic group containing at least one N atom, which may also contain other heteroatoms, such as N, O, S; preferably, the nitrogen-containing heterospirocyclic group is a group containing A heterospirocycle of 1 N and 1 O; more preferably, the nitrogen-containing heterospirocycle is attached to the substituted structure through its N atom.
  • heterobridged cyclyl refers to a bridged cyclyl group in which one or more carbon atoms constituting the skeleton of the bridged ring are substituted with a heteroatom selected from N, O, S.
  • the heterobridged ring group is selected from the following bridged ring groups in which the carbon atoms of the bridged ring skeleton are substituted with 1-3 heteroatoms selected from N, O, S: bicyclo[3.1.0]hexyl, bicyclo[3.2.
  • heterobridged cyclyl groups include, but are limited to, 1,4-diazabicyclo[4.4.0]decan-4-yl, 1,4-diazabicyclo[4.3.0]-nonane-4 -yl, 8-oxa-1,4-diazabicyclo[4.4.0]decane-4-yl, 1,4-diazabicyclo[4.4.0]decane-4-yl, 4,7-Diazabicyclo[4.3.0]nonan-4-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 3,7-diaza Heterobicyclo[4.3.0]nonan-3-yl, 3,7-diazabicyclo[3.3.0]octan-3-yl, 3,7-diazabicyclo[4.4.0] Decan-3-yl, 3,6-diazabicyclo[4.3.0]nonan-3-yl, 3,6-diazabicyclo[4.4.0]
  • aryl refers to an unsaturated, usually aromatic, hydrocarbon group, which may be a single ring or multiple rings fused together. Examples of aryl groups include, but are not limited to, phenyl, naphthyl.
  • heteroaryl refers to a stable monocyclic or polycyclic aromatic hydrocarbon containing at least 1 heteroatom ring member selected from N, O, S, when the heteroaryl group contains N atom, also includes its nitrogen oxides. Heteroaryl includes 5-6 membered heteroaryl, 8-14 membered condensed heteroaryl.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, iso Cerazolyl, pyridyl, pyrimidinyl, indazolyl, indolyl, isoquinolinyl, quinoxalinyl, benzoxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzene Imidazolyl, quinolinyl, quinazolinyl.
  • substituted refers to the substitution of one or more hydrogen atoms on a specified group with a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified group is normal and the substituted compound is stable.
  • composition as used herein is meant to include a product comprising the specified amounts of each of the specified ingredients, as well as any product that results, directly or indirectly, from combination of the specified amounts of each of the specified ingredients.
  • compositions can vary the actual dosage levels of each active ingredient in the pharmaceutical compositions of the present invention so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected based on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and past medical history of the patient to be treated.
  • the pharmaceutical composition may be specially formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.
  • solvate refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water.
  • pharmaceutically acceptable carrier refers to a medium generally acceptable in the art for delivering biologically active agents to animals, particularly mammals, including, for example, adjuvants, excipients, depending on the mode of administration and the nature of the dosage form or excipients such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfuming agents, antibacterial agents, antifungal agents , lubricants and dispersants.
  • Pharmaceutically acceptable carriers are formulated according to a number of factors within the purview of one of ordinary skill in the art.
  • compositions containing the agent include both aqueous and non-aqueous media and various solid and semisolid dosage forms.
  • such carriers include many different ingredients and additives, which are well known to those of ordinary skill in the art to include such additional ingredients in formulations for a variety of reasons (eg, stabilizing the active agent, binders, etc.). .
  • excipient generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • prophylactically effective or therapeutic amount refers to a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount sufficient to treat the disorder at a reasonable effect/risk ratio suitable for any medical treatment and/or prevention. It should be recognized, however, that the total daily dosage of the compounds of the present invention, or pharmaceutically acceptable salts and compositions thereof, should be determined by the attending physician within the scope of sound medical judgment.
  • the particular therapeutically effective dosage level will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; age, weight, general health, sex, and diet of the patient; time of administration, route of administration, and excretion rate of the particular compound employed; duration of treatment; drugs used in combination or concomitantly with the particular compound employed; and Similar factors well known in the medical field. For example, it is the practice in the art to start with a dose of the compound below that required to obtain the desired therapeutic effect and gradually increase the dose until the desired effect is obtained.
  • the compound of the present invention may be used in combination with other pharmaceutically active ingredients as long as it does not produce other adverse effects, such as allergic reactions.
  • the compounds of the present invention can be used alone as anticancer drugs, or can be used in combination with one or more other antitumor drugs. Combination therapy is accomplished by administering the individual therapeutic components simultaneously, sequentially or separately.
  • salts means, within the scope of sound medical judgment, suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reaction, etc., and with reasonable effect/risk than commensurate salt.
  • Pharmaceutically acceptable salts are well known in the art.
  • the salts can be prepared by reacting the acidic functional groups of the compounds of the present invention with a suitable organic or inorganic base.
  • the compounds of the invention are prepared in situ or separately during the final isolation and purification of the compounds of the invention.
  • the base can be a pharmaceutically acceptable metal cation hydroxide, organic primary amine, secondary amine or tertiary amine and the like.
  • compositions of the present invention include salts of the compounds of the present invention with acids or salts with bases.
  • the ratio "10/1 to 2/1” can also be expressed as (10 to 2):1.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured using Bruker Neo400M or Bruker Ascend 400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and/or deuterated chloroform (CDCl 3 ). Designated as tetramethylsilane (TMS).
  • NMR nuclear magnetic resonance
  • LC-MS liquid chromatography-mass spectrometry
  • the determination of LC-MS was performed with an Agilent 1260-6125B single quadrupole mass spectrometer or a Waters H-Class SQD2 mass spectrometer (the ion source was electrospray ionization).
  • the HPLC assay used Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
  • Preparative high performance liquid chromatography used Waters 2555-2489 (10 ⁇ m, ODS 250cm ⁇ 5cm) or GILSON Trilution LC, and the chromatographic column was Welch XB-C18 column (5um, 21.2*150mm).
  • the thin layer chromatography silica gel plate uses GF254 silica gel plate of Yantai Jiangyou Silica Gel Development Co., Ltd. or GF254 silica gel plate of Rushan Shangbang New Materials Co., Ltd.
  • the 200-300 mesh silica gel used in Cheng Chemical Industry Co., Ltd. is used as the carrier.
  • Embodiment a-1
  • Step 1 Methyl 6-(hydroxymethyl)picolinate (4.5 g, 26.9 mmol) was dissolved in tetrahydrofuran (70 mL), cooled to 0 °C, and a solution of methylmagnesium bromide in tetrahydrofuran (3 mol/L, 54 mL) was added dropwise , 162.0 mmol).
  • the reaction system was naturally warmed to room temperature and stirred for 4 hours. TLC monitoring showed that the reaction was complete, and the reaction solution was quenched by adding saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), and the organic phases were combined.
  • Step 2 Dissolve 2-(6-(hydroxymethyl)pyridin-2-yl)propan-2-ol (1.0 g, 6.0 mmol) in toluene (30 mL), cool to 0 °C, add DPPA (2.0 g, 7.2 mmol) and DBU (1.1 g, 7.2 mmol). The reaction system was naturally warmed to room temperature and stirred overnight. Water (20 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • DPPA 2.0 g, 7.2 mmol
  • DBU 1.1 g, 7.2 mmol
  • Step 4 Dissolve 2-chloro-4-((triisopropylsilyl)acetylene)thieno[3,2-d]pyrimidine (500 mg, 1.4 mmol) in tetrahydrofuran (5 mL), add (4-methyl) at room temperature oxyphenyl)methanamine (3 mL, 23 mmol). The reaction system was warmed to 80°C and stirred overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate (50 mL). Then it was washed with 5% aqueous citric acid solution (20 mL ⁇ 3 times), and the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 5 N-(4-Methoxybenzyl)-4-((triisopropylsilyl)ethyne)thieno[3,2-d]pyrimidin-2-amine (334 mg, 0.74 mmol) was dissolved in Dichloromethane (2 mL), trifluoroacetic acid (15 mL) was added. The reaction system was stirred at room temperature overnight, concentrated under reduced pressure, added with ethyl acetate (50 mL), and washed with saturated aqueous sodium bicarbonate solution (20 mL ⁇ 3 times). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Embodiment a-2
  • Step 1 1H-Pyrazole-4-pinacol boronate (500 mg, 2.6 mmol) and methyl 6-(bromomethyl)picolinate (460 mg, 2.0 mmol) were dissolved in acetonitrile (30 mL), carbonic acid was added Cesium (1.1 g, 3.4 mmol). The reaction system was stirred at room temperature for 3 hours, diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with saturated brine (30 mL ⁇ 2 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 3 The solution of methylmagnesium bromide in tetrahydrofuran (3M, 1.3mL, 3.9mmol) was cooled to -10°C, under nitrogen protection, 6-((4-(2-chlorothieno[3,2- d] A solution of pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl)picolinate (370 mg, 0.96 mmol) in tetrahydrofuran (5 mL). The reaction system was naturally warmed to room temperature and stirred overnight, and a saturated aqueous ammonium chloride solution (40 mL) was added to the reaction solution to quench the reaction.
  • Step 4 Convert 2-(6-((4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl )propan-2-ol (40 mg, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL), and (4-methoxyphenyl)methanamine (0.5 mL, 3.8 mmol) was added at room temperature. The reaction system was warmed to 80°C and stirred overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate (50 mL).
  • Step 5 2-(6-((4-(2-((4-methoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)-1H-pyrazole-1 -yl)methyl)pyridin-2-yl)propan-2-ol (crude) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (1.0 mL) was added.
  • reaction system was stirred at room temperature overnight, concentrated under reduced pressure, added with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL ⁇ 3 times) and saturated brine (20 mL) successively, and the organic phase was dried over anhydrous sodium sulfate , filtered, and finally concentrated under reduced pressure.
  • Embodiment a-3 is a diagrammatic representation of Embodiment a-3.
  • Step 2 Dissolve 2-chloro-4-((triisopropylsilyl)acetylene)thieno[2,3-d]pyrimidine (1.0 g, 2.8 mmol) in tetrahydrofuran (2 mL), add (4- Methoxyphenyl)methanamine (5 mL, 38 mmol). The reaction system was warmed to 80°C and stirred overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate (50 mL). Then it was washed with 5% aqueous citric acid solution (20 mL ⁇ 3 times), and the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 3 N-(4-Methoxybenzyl)-4-((triisopropylsilyl)ethyne)thieno[2,3-d]pyrimidin-2-amine (480 mg, 1.1 mmol) was dissolved in Dichloromethane (2 mL), trifluoroacetic acid (5 mL) was added. The reaction system was stirred at room temperature overnight, concentrated under reduced pressure, added with ethyl acetate (50 mL), and washed with saturated aqueous sodium bicarbonate solution (20 mL ⁇ 3 times). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Embodiment a-4
  • Step 2 6-Chloro-1-methyl-4-((triisopropylsilyl)acetylene)-1H-pyrazolo[3,4-d]pyrimidine (200 mg, 0.57 mmol) was dissolved in tetrahydrofuran (5 mL) ), and (4-methoxyphenyl)methanamine (3 mL, 23 mmol) was added at room temperature. The reaction system was warmed to 80°C and stirred overnight. The reaction solution was cooled to room temperature and diluted with ethyl acetate (50 mL).
  • Step 3 N-(4-Methoxybenzyl)-1-methyl-4-((triisopropylsilyl)ethyne)-1H-pyrazolo[3,4-d]pyrimidine-6-
  • the amine 180 mg, 0.4 mmol
  • TBAF ⁇ 3H2O 156 mg, 0.5 mmol
  • the reaction system was naturally warmed to room temperature, stirred for 1 hour, and diluted with ethyl acetate (50 mL).
  • reaction system was stirred at room temperature overnight, diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL ⁇ 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 5 2-(6-((4-(6-((4-methoxybenzyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4- yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)propan-2-ol (100 mg, 0.21 mmol) was dissolved in dichloromethane (3 mL), triazole was added Fluoroacetic acid (5 mL).
  • the reaction system was stirred at room temperature overnight, diluted with ethyl acetate (50 mL), and washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL ⁇ 2 times) and saturated brine (20 mL ⁇ 2 times) successively.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was dissolved in tetrahydrofuran (20 mL), TBAF ⁇ 3H 2 O (392 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature overnight.
  • Embodiment a-5
  • Embodiment a-6
  • Embodiment a-7
  • Embodiment a-8
  • Embodiment a-9
  • Embodiment a-10
  • Step 1 Thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (5.0 g, 29.8 mmol) was dissolved in glacial acetic acid (200 mL), and liquid bromine (4.5 mL, 82.9 mmol) was added ).
  • Step 2 Dissolve 7-bromothieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (12.0 g, 48.8 mmol) in phosphorus oxychloride (70 mL), add N,N - Diisopropylethylamine (12.5 g, 96.9 mmol). The reaction system was heated to 100°C and stirred for 16 hours.
  • V ethyl acetate /V tetrahydrofuran 1/1, 200 mL
  • Step 4 7-Bromo-2-chloro-4-((triisopropylsilyl)ethyne)thieno[3,2-d]pyrimidine (900 mg, 2.1 mmol) was dissolved in 1,4-dioxane The ring (10 mL) was added (4-methoxyphenyl)methanamine (3.2 g, 23.4 mmol) at room temperature. The reaction system was warmed to 80°C and stirred for 4 hours. The reaction solution was cooled to room temperature and diluted with ethyl acetate (50 mL).
  • Step 5 7-Bromo-N-(4-methoxybenzyl)-4-((triisopropylsilyl)ethyne)thieno[3,2-d]pyrimidin-2-amine (370 mg, 0.7 mmol) was dissolved in tetrahydrofuran (26 mL), cooled to -10°C, and TBAF ⁇ 3H 2 O (298 mg, 0.95 mmol) was added.
  • reaction solution was cooled to room temperature, quenched by adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 7 2-(6-((4-(7-Bromo-2-((4-methoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)-1H- 1,2,3-Triazol-1-yl)methyl)pyridin-2-yl)propan-2-ol (60 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (5 mL) was added .
  • the reaction system was stirred at 40 °C for 5 hours, concentrated under reduced pressure, diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL ⁇ 3 times), the organic phase was dried with anhydrous sodium sulfate, filtered, and finally Concentrate under reduced pressure.
  • Embodiment a-11
  • Embodiment a-12
  • Step 1 2-(6-((4-(7-Bromo-2-((4-methoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)-1H- 1,2,3-Triazol-1-yl)methyl)pyridin-2-yl)propan-2-ol (200 mg, 0.35 mmol) was dissolved in NMP (18 mL) and CuCN (127 mg, 1.4 mmol) was added.
  • the reaction system was heated to 180°C and stirred for 4 hours, cooled to room temperature, diluted with ethyl acetate (100 mL), filtered, the filtrate was washed with water (200 mL ⁇ 3 times), the organic phase was dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure .
  • Step 2 4-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)- 2-((4-Methoxybenzyl)amino)thieno[3,2-d]pyrimidine-7-carbonitrile (60 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (5 mL). The reaction system was stirred at 40 °C for 5 hours, concentrated under reduced pressure, diluted with dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL ⁇ 3 times), the organic phase was dried with anhydrous sodium sulfate, filtered, and finally Concentrate under reduced pressure.
  • Embodiment a-13
  • Step 1 6-Bromo-2-picolinate ethyl ester (0.5 g, 2.2 mmol) and 2-oxo-6-azaspiro[3.3]heptane (0.22 g, 2.2 mmol) were dissolved in DMF (20 mL), Potassium carbonate (1.5 g, 10.9 mmol) was added. The reaction system was warmed to 90°C and stirred overnight. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and diluted with water (60 mL).
  • Step 2 Dissolve ethyl 6-(2-oxo-6-azaspiro[3.3]heptan-6-yl)-2-picolinate (750 mg, 3.0 mmol) in tetrahydrofuran (35 mL) and cool to 0°C , under nitrogen protection, red aluminum toluene solution (3.6M, 1.0 mL, 3.6 mmol) was added dropwise. The reaction system was stirred at 0°C for 2 hours and quenched by the addition of 10% aqueous sodium carbonate solution (70 mL). The mixture was filtered through celite to remove the aluminum salt, and the layers were separated.
  • Step 3 Dissolve (6-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methanol (540 mg, 2.6 mmol) in toluene (15 mL) and cool to 0 At °C, DPPA (860 mg, 3.1 mmol) and DBU (480 mg, 3.1 mmol) were added. The reaction system was naturally warmed to room temperature and stirred overnight. Water (20 mL) was added to the reaction to quench the reaction.
  • Embodiment a-14
  • Step 1 2,4-Dimethoxy-7-(trifluoromethyl)thieno[3,2-d]pyrimidine (2.0 g, 7.6 mmol) was dissolved in glacial acetic acid (10 mL) and iodine was added in portions Sodium chloride (5.6 g, 37.3 mmol).
  • the reaction system was heated to 100 °C, stirred for 2 hours, cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, diluted with ethyl acetate (20 mL), washed with saturated sodium thiosulfate (15 mL), separated from the organic layer, and used for the aqueous phase Extract with ethyl acetate (50 mL ⁇ 3 times), combine the organic phases, wash the organic phase with saturated brine (50 mL ⁇ 3 times), then dry with anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure.
  • Step 2 7-Trifluoromethylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (294 mg, 1.2 mmol) was dissolved in redistilled phosphorous oxychloride (5 mL), N,N-diisopropylethylamine (0.11 mL, 0.9 mmol) was added at room temperature. The reaction system was heated to 80°C and stirred for 16 hours.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of phosphorus oxychloride, diluted with ethyl acetate (20 mL), slowly poured into saturated aqueous sodium bicarbonate solution (30 mL), stirred until no bubbles were generated, and separated The organic layer and the aqueous phase were extracted with ethyl acetate (10 mL ⁇ 3 times), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment a-15
  • Step 2 7-Cyclopropyl-2,4-dimethoxythieno[3,2-d]pyrimidine (161 mg, 0.68 mmol) was dissolved in glacial acetic acid (5 mL), and sodium iodide (510 mg) was added in portions , 3.4 mmol). The reaction system was heated to 110 °C, stirred for 2 hours, cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, diluted with ethyl acetate (10 mL), washed with saturated sodium thiosulfate (10 mL), and the organic phase was separated, first saturated with saturated sodium thiosulfate (10 mL).
  • Step 3 Dissolve 7-cyclopropylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (117 mg, 0.56 mmol) in redistilled phosphorus oxychloride (2 mL), room temperature N,N-diisopropylethylamine (0.053 mL, 0.42 mmol) was added at the bottom. The reaction system was warmed to 80°C and stirred overnight.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of phosphorus oxychloride, diluted with ethyl acetate (10 mL), slowly poured into saturated aqueous sodium bicarbonate solution (15 mL), stirred until no bubbles were formed, and separated The organic layer and the aqueous phase were extracted with ethyl acetate (10 mL ⁇ 3 times), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment a-16
  • Step 3 Dissolve 2,4-dimethoxythieno[3,2-d]pyrimidine-7-carbaldehyde (362 mg, 1.6 mmol) in dry dichloromethane (5 mL), cool down to -20°C, add dropwise DAST (519 mg, 3.2 mmol). The reaction system was naturally warmed to room temperature and stirred for 3 hours. After the reaction, saturated aqueous sodium bicarbonate solution was slowly added until no bubbles were generated. The organic layer was separated, and the aqueous phase was extracted with dichloromethane (5 mL ⁇ 3 times), and the organic phases were combined.
  • Step 4 7-(Difluoromethyl)-2,4-dimethoxythieno[3,2-d]pyrimidine (330 mg, 1.3 mmol) was dissolved in glacial acetic acid (6 mL) and iodine was added in portions Sodium (602 mg, 4.0 mmol). The reaction system was heated to 110°C, stirred for 2 hours, cooled to room temperature, concentrated under reduced pressure to remove most of the solvent, diluted with ethyl acetate (10 mL), washed with saturated sodium thiosulfate (20 mL), and the organic phase was separated.
  • Step 5 7-(Difluoromethyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (100 mg, crude) was dissolved in redistilled phosphorus oxychloride (1 mL) , and N,N-dimethylaniline (44 mg, 0.36 mmol) was added at room temperature. The reaction system was warmed to 80°C and stirred overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove most of phosphorus oxychloride, diluted with ethyl acetate (10 mL), slowly added dropwise saturated sodium bicarbonate solution under ice bath until no air bubbles were released, the organic layer was separated, and the aqueous phase was separated.
  • Embodiment a-17
  • Step 1 (6-Bromopyridin-2-yl)methanol (17.6 g, 94.1 mmol) was dissolved in dichloromethane (200 mL). Under nitrogen protection, cooled to 0°C, imidazole (7.7 g, 113 mmol) and TBSCl (15.7 g, 113 mmol) were added successively. The reaction system was heated to 25°C and stirred for 2 hours, water (100 mL) was added, the layers were separated, the aqueous phase was extracted with dichloromethane (100 mL ⁇ 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (200 mL).
  • Step 2 Dissolve 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (6.0 g, 19.9 mmol) in dry tetrahydrofuran (60 mL), under nitrogen protection, cool down to - At 78°C, n-butyllithium (8.1 mL, 20.3 mmol) was added dropwise, and after stirring for 0.5 hours, cyclobutyl ketone (1.54 g, 22.0 mmol) was added.
  • reaction system was naturally warmed to room temperature, stirred for 2 hours, then cooled to 0° C., TBAF ⁇ 3H 2 O (6.3 g, 20.0 mmol) was added, and stirring was continued at room temperature for 20 hours.
  • Saturated aqueous ammonium chloride solution 50 mL was slowly added, the organic layer was separated, the aqueous phase was extracted with ethyl acetate (100 mL ⁇ 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 3 Dissolve 1-(6-(hydroxymethyl)pyridin-2-yl)cyclobutyl-1-ol (1.0 g, 5.6 mmol) in toluene (20 mL), cool to 0 °C, add DPPA (1.9 g, 6.8 mmol) and DBU (1.0 g, 6.8 mmol). The reaction system was naturally warmed to room temperature and stirred overnight. Water (20 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (30 mL ⁇ 3 times), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • DPPA 1.9 g, 6.8 mmol
  • DBU 1.0 g, 6.8 mmol
  • Step 5 1-(6-((4-(7-Bromo-2-((4-methoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)-1H- 1,2,3-Triazol-1-yl)methyl)pyridin-2-yl)cyclobutyl-1-ol (80 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid ( 5mL).
  • Embodiment a-18
  • Embodiment a-20
  • Embodiment a-21
  • Embodiment a-22
  • Step 1 7-Bromo-4-ethynyl-N-(4-methoxybenzyl)thieno[3,2-d]pyrimidin-2-amine (1.6 g, 4.3 mmol) was dissolved in trifluoroacetic acid (20 mL). The reaction system was heated to 50°C, stirred for 12 hours, concentrated under reduced pressure to remove most of the trifluoroacetic acid, and added 30% aqueous sodium carbonate solution (30 mL). The mixture was extracted with dichloromethane (30 mL ⁇ 3 times).
  • the reaction system was heated to 50° C., stirred for 2 hours, cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (40 mL ⁇ 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure.
  • Embodiment a-28
  • Step 1 Dissolve 2-(3-(hydroxymethyl)phenyl)propan-2-ol (750 mg, 4.5 mmol) in toluene (30 mL), cool to 0 °C, add DPPA (1.2 g, 4.3 mmol) and DBU (653 mg, 4.3 mmol). The reaction system was naturally warmed to room temperature and stirred overnight. Water (20 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • DPPA 1.2 g, 4.3 mmol
  • DBU 653 mg, 4.3 mmol
  • the reaction system was warmed to 50°C and stirred for 2 hours.
  • the reaction solution was cooled to room temperature, quenched by adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment a-29
  • Step 1 Dissolve 3-(6-(hydroxymethyl)pyridin-2-yl)oxetan-3-ol (1.0 g, 5.5 mmol) in toluene (20 ml), cool to 0°C, add DPPA (1.9 g, 6.8 mmol) and DBU (1.0 g, 6.8 mmol). The reaction system was naturally warmed to room temperature and stirred overnight. Water (20 ml) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (30 ml ⁇ 3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • DPPA 1.9 g, 6.8 mmol
  • DBU 1.0 g, 6.8 mmol
  • the reaction system was warmed to 50°C and stirred for 2 hours.
  • the reaction solution was cooled to room temperature, quenched by adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment a-30
  • Step 1 Dissolve 2-methyl-2-(6-methylpyridin-2-yl)propionitrile (800 mg, 5.0 mmol) in carbon tetrachloride (6 mL), and add N-bromobutanedi in sequence at room temperature imide (976 mg, 5.5 mmol) and phthaloyl peroxide (120 mg, 0.5 mmol).
  • the reaction system was heated to 78°C under nitrogen protection, stirred for 16 hours, cooled to room temperature, and slowly added saturated aqueous sodium bicarbonate solution (20 mL) to the reaction solution to quench the reaction.
  • Step 2 Dissolve 2-(6-(bromomethyl)pyridin-2-yl)-2-methylpropionitrile (200 mg, 0.84 mmol) in dimethyl sulfoxide (6 mL), add sodium azide at room temperature (82 mg, 1.3 mmol). The reaction system was heated to 50°C and stirred for 16 hours. Water (20 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (100 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the reaction system was warmed to 50°C and stirred for 3 hours.
  • the reaction solution was cooled to room temperature, quenched by adding water (20 mL), the mixture was extracted with ethyl acetate (100 mL ⁇ 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the residue was purified by stirring crystallization from anhydrous ether to give 2-(6-((4-(2-amino-7-bromothieno[3,2-d]pyrimidin-4-yl)-1H-1,2,3 -Triazol-1-yl)methyl)pyridin-2-yl)-2-methylpropionitrile (20 mg, 43% yield).
  • Embodiment a-31
  • Step 1 Dissolve 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (1.0 g, 3.3 mmol) in DMF (15 mL), add cis-2 at room temperature, 6-Dimethylmorpholine (460 mg, 4.0 mmol), cuprous iodide (63 mg, 0.33 mmol) and potassium carbonate (2.3 g, 16.7 mmol).
  • the reaction system was heated to 95° C. and stirred for 16 hours under nitrogen protection, cooled to room temperature, and water (30 mL) was slowly added to the reaction solution to quench the reaction.
  • Step 2 cis-4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-2,6-dimethylmorpholine (600 mg, 1.8 mmol) Dissolve in tetrahydrofuran (6 ml) and add TBAF.3H2O (560 mg, 2.1 mmol). After the reaction was stirred at room temperature for 16 hours, water (3 mL) was added to quench the reaction.
  • Step 3 Dissolve (6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)methanol (350 mg, 1.6 mmol) in toluene (10 mL), cool to 0 °C, add DPPA (492 mg, 1.8 mmol) and DBU (273 mg, 1.8 mmol). The reaction system was naturally warmed to room temperature and stirred for 5 hours. Water (10 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the reaction system was warmed to 50°C and stirred for 2 hours.
  • the reaction solution was cooled to room temperature, quenched by adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment a-32
  • Step 1 Dissolve 1-(6-(hydroxymethyl)pyridin-2-yl)-4-methylpiperidin-4-ol (397 mg, 1.8 mmol) in toluene (6 mL), cool to 0 °C, add DPPA (492 mg, 1.8 mmol) and DBU (273 mg, 1.8 mmol). The reaction system was naturally warmed to room temperature and stirred for 5 hours. Water (10 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the reaction system was warmed to 50°C and stirred for 2 hours.
  • the reaction solution was cooled to room temperature, quenched by adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 1 Methyl 6-(2-hydroxyprop-2-yl)picolinate (1.0 g, 5.1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0 °C, and deuterated tetrahydroaluminum lithium (430 mg) was added. , 10.2 mmol). The reaction system was naturally warmed to room temperature and stirred for 2 hours. Water (20 mL) was slowly added to the reaction to quench the reaction.
  • Step 2 Dissolve 2-(6-(hydroxymethyl-d2)pyridin-2-yl)propan-2-ol (650 mg, 3.8 mmol) in toluene (10 mL), cool to 0°C, add DPPA (1.0 g) , 3.9 mmol) and DBU (591 mg, 3.9 mmol). The reaction system was naturally warmed to room temperature and stirred for 5 hours. Water (10 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the reaction system was warmed to 50°C and stirred for 2 hours.
  • the reaction solution was cooled to room temperature, quenched by adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 1 1-(6-(Hydroxymethyl)pyridin-2-yl)-3-methylazetidin-3-ol (350 mg, 1.8 mmol) was dissolved in toluene (10 mL) and cooled to 0 At °C, DPPA (492 mg, 1.8 mmol) and DBU (273 mg, 1.8 mmol) were added. The reaction system was naturally warmed to room temperature and stirred for 5 hours. Water (10 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the reaction system was warmed to 50°C and stirred for 2 hours.
  • the reaction solution was cooled to room temperature, quenched by adding water (10 mL), the mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment a-35
  • Step 1 2-Bromo-6-((tert-butyldimethylsilyloxy)methyl)pyridine (1.4 g, 4.7 mmol), 2-(azetidin-3-yl)propane- 2-ol hydrochloride (850 mg, 5.6 mmol), cesium carbonate (3.0 g, 9.3 mmol), palladium acetate (105 mg, 0.47 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine ( 290 mg, 0.47 mmol) was dissolved in toluene (30 mL), replaced with nitrogen three times, heated to 120° C. and stirred under reflux for 2 hours.
  • Step 2 Transfer 2-(1-(6-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)azetidin-3-yl)propan-2-ol ( 600 mg, 1.8 mmol) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (560 mg, 2.1 mmol) was added under ice cooling, and the mixture was warmed to room temperature and stirred for 2 hours. LCMS monitoring showed that the reaction of the raw materials was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (40 mL ⁇ 2 times).
  • Step 3 Dissolve 2-(1-(6-(hydroxymethyl)pyridin-2-yl)azetidin-3-yl)propan-2-ol (350 mg, 1.6 mmol) in a mixture of toluene and tetrahydrofuran
  • the reaction system was naturally warmed to room temperature and stirred for 5 hours. Water (10 mL) was added to the reaction to quench the reaction.
  • Step 1 Dissolve 2-(bromomethyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (800 mg, 2.5 mmol) and 2-fluorophenol (341 mg, 3.0 mmol) To dry DMF (10 mL), potassium carbonate (525 mg, 3.8 mmol) was added, and the reaction system was stirred at 25°C for 20 hours. LCMS monitoring showed that the reaction of the raw materials was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3 times). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 2 Dissolve 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-((2-fluorophenoxy)methyl)pyridine (800 mg, 2.3 mmol) in tetrahydrofuran (10 mL) , tetrabutylammonium fluoride trihydrate (728 mg, 2.3 mmol) was added under ice-cooling, and the mixture was kept at 0°C and stirred for 1 hour. LCMS monitoring showed that the reaction of the raw materials was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (40 mL ⁇ 2 times).
  • Step 3 Dissolve (6-((2-fluorophenoxy)methyl)pyridin-2-yl)methanol (300 mg, 1.3 mmol) in toluene (10 mL), cool to 0-5 °C, add DPPA (425 mg) , 1.5 mmol) and DBU (235 mg, 1.5 mmol). The reaction system was naturally warmed to room temperature and stirred overnight. Water (20 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (20 mL ⁇ 3 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the reaction system was warmed to 50°C and stirred for 3 hours.
  • the reaction solution was cooled to room temperature, quenched by adding water (10 mL), the mixture was extracted with ethyl acetate (50 mL ⁇ 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the resulting residue was purified by beating with ether to give 7-bromo-4-(1-((6-((2-fluorophenoxy)methyl)pyridin-2-yl)methyl)-1H-1,2,3 - Triazol-4-yl)thieno[3,2-d]pyrimidin-2-amine (40 mg, 65% yield).
  • Step 1 Methyl 6-fluoropicolinate (1.0 g, 6.5 mmol) and (R)-pyrrolin-3-ol (562 mg, 6.5 mmol) were dissolved in dry DMF (100 mL), potassium carbonate (4.5 g) was added , 32.2 mmol) and cuprous iodide (124 mg, 0.65 mmol), nitrogen was replaced 3 times, the reaction system was heated to 98° C. and stirred overnight. TLC monitoring showed that the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (20 mL ⁇ 2 times), and the mixture was concentrated under reduced pressure.
  • Step 2 Dissolve (R)-methyl 6-(3-hydroxypyrrolin-1-yl)picolinate (850 mg, 3.8 mmol) and imidazole (785 mg, 11.5 mmol) in dichloromethane (30 mL), ice bath TBSCl (1160 mg, 7.7 mmol) was added under cooling, and the mixture was stirred at room temperature overnight. TLC monitoring showed that the reaction of the raw materials was completed, water (50 mL) was added, the layers were separated, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 3 (R)-Methyl 6-(3-(tert-butyldimethylsilyloxy)pyrrolin-1-yl)picolinate (1.0 g, 3.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) ), cooled to 0°C, and a solution of lithium borohydride in tetrahydrofuran (1 M, 6.6 mL, 6.6 mmol) was added dropwise. The reaction system was naturally warmed to room temperature and stirred for 2 hours. The reaction was quenched by slowly adding cold saturated ammonium chloride solution (50 mL).
  • Step 4 Dissolve (R)-(6-(3-(tert-butyldimethylsilyloxy)pyrrolin-1-yl)pyridin-2-yl)methanol (400 mg, 1.3 mmol) in dry water Tetrahydrofuran (50 mL), cooled to 0-5°C, and DPPA (430 mg, 1.6 mmol) and DBU (240 mg, 1.6 mmol) were added. The reaction system was naturally warmed to room temperature and stirred overnight. Water (50 mL) was added to the reaction to quench the reaction.
  • Step 6 (R)-7-Bromo-4-(1-((6-(3-(tert-butyldimethylsilyloxy)pyrrolin-1-yl)pyridin-2-yl)methyl yl)-1H-1,2,3-triazol-4-yl)thieno[3,2-d]pyrimidin-2-amine (50 mg, 0.085 mmol) was dissolved in tetrahydrofuran (5 mL) under ice cooling Tetrabutylammonium fluoride trihydrate (54 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
  • Step 1 Combine 2-bromo-6-((tert-butyldimethylsilyloxy)methyl)pyridine (2.0 g, 6.6 mmol), 3,3-difluoroazetidine hydrochloride ( 2.1 g, 16.3 mmol), cesium carbonate (3.0 g, 9.3 mmol), palladium acetate (149 mg, 0.66 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (414 mg, 0.66 mmol) were dissolved In toluene (30 mL), nitrogen was replaced three times, the temperature was raised to 120° C. and refluxed and stirred for 2 hours.
  • Step 2 Dissolve 2-((tert-butyldimethylsilyloxy)methyl)-6-(3,3-difluoroazetidin-1-yl)pyridine (700 mg, 2.2 mmol) Tetrabutylammonium fluoride trihydrate (696 mg, 2.2 mmol) was added to tetrahydrofuran (5 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours. LCMS monitoring showed that the reaction of the raw materials was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (40 mL ⁇ 2 times).
  • Step 3 Dissolve (6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)methanol (400 mg, 2.0 mmol) in dichloromethane (5 mL), cool to 0 ⁇ At 5°C, triethylamine (606 mg, 6.0 mmol) was added followed by methanesulfonyl chloride (344 mg, 3.0 mmol). The reaction system was naturally warmed to room temperature and stirred for 2 hours. TLC monitoring showed that the reaction of the raw materials was completed, water (10 mL) was added, and the mixture was extracted with dichloromethane (40 mL ⁇ 2 times).
  • Step 5 7-Bromo-N-(4-methoxybenzyl)-4-(1H-1,2,3-triazol-4-yl)thieno[3,2-d]pyrimidine-2 -amine (800 mg, 1.9 mmol) and methyl (6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)methanesulfonate (500 mg, 1.8 mmol) in dry DMF (3 mL), potassium carbonate (730 mg, 5.3 mmol) and sodium iodide (264 mg, 1.8 mmol) were added, and the reaction system was stirred at 30° C. for 3 hours.
  • Step 6 7-Bromo-4-(1-(((6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)methyl)-1H-1,2 ,3-triazol-4-yl)-N-(4-methoxybenzyl)thieno[3,2-d]pyrimidin-2-amine (100 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (5 mL) ), the reaction system was warmed to 50 ° C and stirred for 12 hours.
  • Embodiment a-40
  • Embodiment a-41
  • Embodiment a-42
  • Embodiment a-43
  • V methanol /V Dimethyl sulfoxide 1/1, 120 mL
  • Step 2 Add methylmagnesium bromide (6.0 mL, 18.2 mmol, 3M in 2-methyltetrahydrofuran) to the flask under nitrogen atmosphere, cool to 0°C, dropwise add 3-(((tert-butyldimethyl A solution of methyl silyl)oxy)methyl)-2-fluorobenzoate (800 mg, 2.7 mmol) in dry tetrahydrofuran (5 mL) was dripped in about 20 minutes, and then warmed to room temperature and stirred for 3 hours. TLC monitoring showed that the starting material disappeared, the reaction solution was quenched with saturated ammonium chloride solution (30 mL) under ice bath, and extracted with ethyl acetate (50 mL ⁇ 2 times).
  • Step 3 Dissolve 2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluorophenyl)propan-2-ol (300 mg, 1.0 mmol) in tetrahydrofuran ( 10 mL), tetrabutylammonium fluoride (316 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 12 hours. TLC monitoring showed the disappearance of the raw material, ethyl acetate (20 mL) was added to the reaction solution to dilute, washed with water (100 mL ⁇ 3 times), and then washed with saturated brine (30 mL ⁇ 2 times).
  • Step 4 Dissolve 2-(2-fluoro-3-(hydroxymethyl)phenyl)propan-2-ol (190 mg, about 1.0 mmol) in dry toluene (7 mL liters), cool to 0-5 °C, and sequentially Diphenylphosphoryl azide (282 mg, 1.0 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (157 mg, 1.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. TLC monitoring showed the disappearance of the starting material. Concentration under reduced pressure gave 2-(3-(azidomethyl)-2-fluorophenyl)propan-2-ol (200 mg, crude product), which was directly used in the next reaction. MS(ESI)M/Z: 210.1[M+H] + .
  • Embodiment a-44
  • Embodiment a-45
  • Step 2 Methyl 5-fluoro-6-styrylpicolinate (800 mg, 3.1 mmol) was dissolved in tetrahydrofuran/water (18/9 mL), followed by 2,6-lutidine (670 mg, 6.2 mmol) , sodium periodate (4 g, 18.6 mmol) and potassium osmate dihydrate (52 mg, 0.16 mmol), and stirred at room temperature for 20 hours. TLC monitoring showed the disappearance of raw materials, the reaction solution was extracted with ethyl acetate (30 mL ⁇ 2 times), the organic layers were combined, washed with saturated brine (30 mL ⁇ 2 times), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 3 Dissolve methyl 5-fluoro-6-formylmethylpicolinate (300 mg, 1.6 mmol) in methanol (10 mL), cool to 0 °C, add sodium borohydride (100 mg, 2.6 mmol), and add 1 liter Stir to room temperature for 3 hours. TLC monitoring showed that the starting material disappeared, the reaction solution was quenched with saturated ammonium chloride solution (20 mL) under ice bath, and then extracted with ethyl acetate (30 mL ⁇ 2 times). The organic layers were combined, washed with saturated brine (30 mL ⁇ 2 times), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Embodiment b-1
  • Step 1 Methyl 6-(hydroxymethyl)picolinate (4.5 g, 26.9 mmol) was dissolved in tetrahydrofuran (70 mL), cooled to 0 °C, and a solution of methylmagnesium bromide in tetrahydrofuran (3 mol/L, 54 mL) was added dropwise , 162.0 mmol).
  • the reaction system was naturally warmed to room temperature and stirred for 4 hours. TLC monitoring showed that the reaction was complete, and the reaction solution was quenched by adding saturated aqueous ammonium chloride solution (50 mL). Ethyl acetate (40 mL ⁇ 3 times) was extracted, and the organic phases were combined.
  • Step 2 Dissolve 2-(6-(hydroxymethyl)pyridin-2-yl)propan-2-ol (1.0 g, 6.0 mmol) in toluene (30 mL), cool to 0 °C, add DPPA (2.0 g, 7.2 mmol) and DBU (1.1 g, 7.2 mmol). The reaction system was naturally warmed to room temperature and stirred overnight. Water (20 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • DPPA 2.0 g, 7.2 mmol
  • DBU 1.1 g, 7.2 mmol
  • Step 4 Dissolve 6-chloro-4-((trimethylsilyl)acetylene)-1H-pyrrolo[2,3-b]pyridine (124 mg, 0.5 mmol) in tetrahydrofuran (10 mL), cool to 0 °C, TBAF.3H2O (189 mg, 0.6 mmol) was added. The reaction system was naturally warmed to room temperature and stirred overnight. To the reaction solution was added saturated aqueous ammonium chloride solution (10 mL) to quench the reaction.
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (10 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • reaction system was warmed to 98°C and stirred overnight.
  • the reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment b-2
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 2 3-(7-Chloro-3H-imidazo[4,5-b]pyridin-5-yl)-2-methylbenzonitrile (110 mg, 0.41 mmol) was dissolved in acetonitrile (10 mL) and added Acetyl chloride (161 mg, 2.1 mmol) and sodium iodide (369 mg, 2.5 mmol). The reaction system was warmed to 90°C and stirred for 20 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined. Dry over anhydrous sodium sulfate, filter, and finally concentrate under reduced pressure.
  • Step 3 Dissolve 3-(7-iodo-3H-imidazo[4,5-b]pyridin-5-yl)-2-methylbenzonitrile (147 mg, 0.41 mmol) in dichloromethane (10 mL) , p-toluenesulfonic acid monohydrate (8 mg, 0.04 mmol) and DHP (53 mg, 0.63 mmol) were added.
  • the reaction system was stirred at room temperature for 4 hours, washed successively with saturated aqueous sodium bicarbonate solution (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 4 3-(7-Iodo-3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-2-methylbenzene
  • CuI 5 mg, 0.03 mmol
  • Pd(PPh 3 ) 2 Cl 2 (9 mg, 0.01 mmol)
  • triisopropylsilylacetylene (273 mg, 1.5 mmol) were added sequentially.
  • the reaction system was warmed to 60°C and stirred overnight.
  • reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step 5 2-Methyl-3-(3-(tetrahydro-2H-pyran-2-yl)-7-((triisopropylsilyl)ethyne)-3H-imidazo[4,5 -b]pyridin-5-yl)benzonitrile (103 mg, 0.21 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and TBAF ⁇ 3H2O (78 mg, 0.25 mmol) was added. The reaction system was stirred at 0°C for 20 minutes. To the reaction solution was added saturated aqueous ammonium chloride solution (10 mL) to quench the reaction.
  • Embodiment b-3
  • Step 2 Dissolve 2-chloro-4-((triisopropylsilyl)acetylene)-7H-pyrrolo[2,3-d]pyrimidine (334 mg, 1.0 mmol) in tetrahydrofuran (10 mL) and cool to 0 At °C, TBAF.3H2O (379 mg, 1.2 mmol) was added. The reaction system was stirred at 0°C for 30 minutes. To the reaction solution was added saturated aqueous ammonium chloride solution (10 mL) to quench the reaction.
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (10 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • reaction system was warmed to 98°C and stirred overnight.
  • the reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment b-4
  • Step 1 4-Bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (1.0 g, 4.8 mmol) was dissolved in diethyl ether (20 mL). Under nitrogen, m-CPBA (1.2 g, 7.0 mmol) was added. The reaction system was stirred at room temperature overnight. TLC monitoring showed that the reaction was complete, the reaction solution was filtered, the filter cake was washed with diethyl ether (20 mL), and dried to obtain 4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (870 mg, yield 81%).
  • Step 2 4-Bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (340 mg, 1.5 mmol) was dissolved in phosphorus oxychloride (10 mL), and the temperature was raised to 110 °C Stir for 24 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, cold water (20 mL) was added to the residue, extracted with ethyl acetate (20 mL ⁇ 2 times), the organic phases were combined, and the organic phase was washed with saturated brine (20 mL), and then with Dry over sodium sulfate, filter, and finally concentrate under reduced pressure.
  • reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step 4 6-Chloro-2-methyl-4-((triisopropylsilyl)acetylene)-1H-pyrrolo[2,3-b]pyridine (290 mg, 0.84 mmol) was dissolved in tetrahydrofuran (10 mL) ), cooled to 0°C, and TBAF ⁇ 3H 2 O (315 mg, 1.0 mmol) was added. The reaction system was naturally warmed to room temperature and stirred for 20 minutes. To the reaction solution was added saturated aqueous ammonium chloride solution (10 mL) to quench the reaction. The mixture was extracted with ethyl acetate (15 mL ⁇ 2 times), and the organic phases were combined.
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the reaction system was warmed to 98°C and stirred for 48 hours.
  • the reaction solution was cooled to room temperature, extracted with ethyl acetate (15 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment b-5
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (20 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 2 3-(4-Chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-methylbenzonitrile (183 mg, 0.68 mmol) was dissolved in acetonitrile (10 mL), Acetyl chloride (267 mg, 3.4 mmol) and sodium iodide (613 mg, 4.1 mmol) were added. The reaction system was warmed to 98°C and stirred overnight.
  • reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Embodiment b-6
  • Step 1 6-Bromo-2-picolinate ethyl ester (0.5 g, 2.2 mmol) and 2-oxo-6-azaspiro[3.3]heptane (0.22 g, 2.2 mmol) were dissolved in DMF (20 mL), Potassium carbonate (1.5 g, 10.9 mmol) was added. The reaction system was warmed to 90°C and stirred overnight. TLC monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature and diluted with water (60 mL).
  • Step 2 Dissolve ethyl 6-(2-oxo-6-azaspiro[3.3]heptan-6-yl)-2-picolinate (750 mg, 3.0 mmol) in tetrahydrofuran (35 mL) and cool to 0°C , under nitrogen protection, red aluminum toluene solution (3.6M, 1.0 mL, 3.6 mmol) was added dropwise. The reaction system was stirred at 0°C for 2 hours and quenched by the addition of 10% aqueous sodium carbonate solution (70 mL). The mixture was filtered through celite to remove the aluminum salt, and the layers were separated.
  • aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3 times), the organic phases were combined, and the organic phases were washed with saturated brine (50 mL), and then dried over anhydrous sodium sulfate. , filtered, and finally concentrated under reduced pressure to obtain (6-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methanol (560 mg, yield 90%).
  • Step 3 Dissolve (6-(2-oxo-6-azaspiro[3.3]heptan-6-yl)pyridin-2-yl)methanol (540 mg, 2.6 mmol) in toluene (15 mL) and cool to 0 At °C, DPPA (860 mg, 3.1 mmol) and DBU (480 mg, 3.1 mmol) were added. The reaction system was naturally warmed to room temperature and stirred overnight. Water (20 mL) was added to the reaction to quench the reaction.
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (10 mL ⁇ 2 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment b-7
  • Example b-6 7-oxo-2-azaspiro[3.5]nonane was used to replace 2-oxo-6-azaspiro[3.3]heptane to obtain the final product 3-(4-( 1-((6-(7-Oxo-2-azaspiro[3.5]nonan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazole-4- yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-methylbenzonitrile (15 mg, 14% yield).
  • Embodiment b-8
  • Step 1 Dissolve 2,6-dichloro-9H-purine (500 mg, 2.7 mmol) in dichloromethane (50 mL), add p-toluenesulfonic acid monohydrate (50 mg, 0.25 mmol) and DHP (400 mg, 4.8 mmol) .
  • reaction system was stirred at room temperature overnight, washed with saturated aqueous sodium bicarbonate solution (30 mL) and saturated brine (30 mL) successively, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 2,6-dichloro-9- (Tetrahydro-2H-pyran-2-yl)-9H-purine (500 mg, yield 69%) was directly used in the next reaction.
  • reaction system was stirred at room temperature overnight, and TLC monitoring showed that the reaction was complete, and 5% aqueous citric acid solution (40 mL) was added to the reaction solution.
  • the mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 4 2-Methyl-3-(9-(tetrahydro-2H-pyran-2-yl)-6-((triisopropylsilyl)ethynyl)-9H-purin-2-yl) Benzonitrile (200 mg, crude) was dissolved in tetrahydrofuran (10 mL) and TBAF.3H2O (125 mg, 0.4 mmol) was added.
  • the reaction system was warmed to 60°C and stirred overnight.
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate (50 mL), and the mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL ⁇ 3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • the obtained residue was purified by preparative high performance liquid chromatography to give the final product 3-(6-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1 ,2,3-Triazol-4-yl)-9H-purin-2-yl)-2-methylbenzonitrile (21 mg, 25% yield).
  • Embodiment b-9
  • Example b-2 use 5,7-dichloro-2-methyl-3H-imidazo[4,5-b]pyridine instead of 5,7-dichloro-3H-imidazo[4, 5-b]pyridine to give 70 mg of final product 3-(7-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3 - Triazol-4-yl)-2-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-2-methylbenzonitrile.
  • Embodiment b-10
  • reaction solution was cooled to room temperature, extracted with ethyl acetate (100 mL ⁇ 3 times), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 2 3-(7-Chloro-3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-2-fluorobenzyl
  • dichloromethane 5 mL
  • hydrogen chloride in ethyl acetate (3.7 M, 1 mL, 3.7 mmol) was added.
  • the reaction system was stirred at room temperature for 2 hours, and a saturated aqueous sodium bicarbonate solution (20 mL) was added, followed by extraction with ethyl acetate (50 mL ⁇ 3 times).
  • Step 3 2-Fluoro-3-(7-iodo-3H-imidazo[4,5-b]pyridin-5-yl)benzonitrile (160 mg, 0.44 mmol) was dissolved in dichloromethane (15 mL), P-toluenesulfonic acid monohydrate (8 mg, 0.04 mmol) and DHP (370 mg, 4.4 mmol) were added. The reaction system was stirred at 30°C for 4 hours, washed successively with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step 5 2-Fluoro-3-(3-(tetrahydro-2H-pyran-2-yl)-7-((triisopropylsilyl)ethyne)-3H-imidazo[4,5- b] Pyridin-5-yl)benzonitrile (90 mg, 0.18 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -10°C, and TBAF ⁇ 3H 2 O (68 mg, 0.22 mmol) was added. The reaction system was stirred at 0°C for 20 minutes. To the reaction solution was added saturated aqueous ammonium chloride solution (10 mL) to quench the reaction.
  • the reaction system was warmed to 60°C and stirred overnight.
  • the reaction was The liquid was cooled to room temperature, extracted with ethyl acetate (50 mL ⁇ 3 times), and the organic phases were combined.
  • the organic phase was washed with saturated brine (50 mL), then dried with anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 7 2-Fluoro-3-(7-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-tris Azazol-4-yl)-3-(tetrahydro-2H-pyran-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)benzonitrile (40 mg, 0.074 mmol) was dissolved in in dichloromethane (2 mL). Under nitrogen, hydrogen chloride in ethyl acetate (3.7M, 0.03 mL, 0.10 mmol) was added.
  • reaction system was stirred at room temperature for 2 hours, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL ⁇ 3 times), the organic phases were combined, and the organic phase was first washed with saturated brine (30 mL). ), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment b-11
  • Embodiment b-12
  • 3-cyanophenylboronic acid was used instead of 3-cyano-2-fluorophenylboronic acid to obtain the final product 3-(7-(1-((6-(2-hydroxypropyl) -2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)benzyl Nitrile (10 mg, white solid).
  • Embodiment b-13
  • Example b-10 3,5-difluorophenylboronic acid was used instead of 3-cyano-2-fluorophenylboronic acid to obtain the final product 2-(6-((4-(5-(3,5 -Difluorophenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)propane -2-ol (22 mg).
  • Example b-10 replace 2-(6-(azido)pyridine with (S)-2-(azidomethyl)-6-(((tetrahydrofuran-3-yl)oxo)methyl)pyridine Nitromethyl)pyridin-2-yl)propan-2-ol to give the final product (S)-2-methyl-3-(7-(1-((6-(((tetrahydrofuran-3-yl)oxy) substituted)methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)benzyl Nitrile (80 mg).
  • Embodiment b-15
  • Example b-10 replace 2-(6-(azido)pyridine with (R)-2-(azidomethyl)-6-(((tetrahydrofuran-3-yl)oxo)methyl)pyridine Nitromethyl)pyridin-2-yl)propan-2-ol to give the final product (R)-2-methyl-3-(7-(1-((6-(((tetrahydrofuran-3-yl)oxy) substituted)methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)benzyl Nitrile (30 mg).
  • Example b-10 Referring to the similar preparation procedure of Example b-10, substituting 1-(6-(azidomethyl)pyridin-2-yl)cyclobutan-1-ol for 2-(6-(azidomethyl)pyridin-2 -yl)propan-2-ol to give the final product 3-(7-(1-((6-(1-hydroxycyclobutyl)pyridin-2-yl)yl)-1H-1,2,3-tris Azazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-2-methylbenzonitrile (20 mg).
  • Embodiment b-21
  • Step 1 Methyl 6-(2-hydroxyprop-2-yl)picolinate (1.0 g, 5.1 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0 °C, and deuterated tetrahydroaluminum lithium (430 mg) was added. , 10.2 mmol). The reaction system was naturally warmed to room temperature and stirred for 2 hours. Water (20 mL) was slowly added to the reaction to quench the reaction.
  • Step 2 Dissolve 2-(6-(hydroxymethyl-d2)pyridin-2-yl)propan-2-ol (650 mg, 3.8 mmol) in toluene (10 mL), cool to 0°C, add DPPA (1.0 g) , 3.9 mmol) and DBU (591 mg, 3.9 mmol). The reaction system was naturally warmed to room temperature and stirred for 5 hours. Water (10 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Step 3 Referring to the relevant preparation steps of Example b-10, using 2-(6-(azidomethyl-d2)pyridin-2-yl)propan-2-ol as a raw material, the final product 3-(7- (1-((6-(2-Hydroxypropyl-2-yl)pyridin-2-yl)methyl-d2)-1H-1,2,3-triazol-4-yl)-3H-imidazole [4,5-b]pyridin-5-yl)-2-methylbenzonitrile (40 mg).
  • Embodiment b-22
  • Embodiment b-23
  • Step 1 Dissolve 2-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)pyridine (1.0 g, 3.3 mmol) in DMF (15 mL), add cis-2 at room temperature, 6-Dimethylmorpholine (460 mg, 4.0 mmol), cuprous iodide (63 mg, 0.33 mmol) and potassium carbonate (2.3 g, 16.7 mmol).
  • the reaction system was heated to 95°C and stirred for 16 hours under nitrogen protection, cooled to room temperature, and water (30 mL) was slowly added to the reaction solution to quench the reaction.
  • Step 2 cis-4-(6-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-2,6-dimethylmorpholine (600 mg, 1.8 mmol) Dissolve in tetrahydrofuran (6 mL) and add TBAF.3H2O (560 mg, 2.1 mmol). After the reaction was stirred at room temperature for 16 hours, water (3 mL) was added to quench the reaction.
  • Step 3 Dissolve (6-(cis-2,6-dimethylmorpholino)pyridin-2-yl)methanol (350 mg, 1.6 mmol) in toluene (10 mL), cool to 0 °C, add DPPA (492 mg, 1.8 mmol) and DBU (273 mg, 1.8 mmol). The reaction system was naturally warmed to room temperature and stirred for 5 hours. Water (10 mL) was added to the reaction to quench the reaction. The mixture was extracted with ethyl acetate (40 mL ⁇ 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.
  • Embodiment b-24

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Sont divulgués un nouvel inhibiteur du récepteur de l'adénosine hétérocyclique de type pyrimidine/pyridine, son procédé de préparation et son utilisation. Le nouvel inhibiteur du récepteur de l'adénosine hétérocyclique de type pyrimidine/pyridine est un composé représenté par la formule II, un sel pharmaceutiquement acceptable de celui-ci, un solvate de celui-ci, ou un solvate du sel pharmaceutiquement acceptable de celui-ci. Les données d'activité de médicament montrent que les composés ont un meilleur effet inhibiteur sur A2a et/ou A2b, et certains composés présentent une meilleure sélectivité, et peuvent être utilisés pour traiter des maladies associées à des récepteurs A2a et/ou A2b.
PCT/CN2022/074495 2021-02-05 2022-01-28 Inhibiteur du récepteur de l'adénosine hétérocyclique de type pyrimidine ou pyridine, son procédé de préparation et son utilisation WO2022166796A1 (fr)

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