[go: up one dir, main page]

WO2025040167A1 - Phosphoinositide 3-kinase allosteric inhibitor for treating disease related to pi3k regulation - Google Patents

Phosphoinositide 3-kinase allosteric inhibitor for treating disease related to pi3k regulation Download PDF

Info

Publication number
WO2025040167A1
WO2025040167A1 PCT/CN2024/114185 CN2024114185W WO2025040167A1 WO 2025040167 A1 WO2025040167 A1 WO 2025040167A1 CN 2024114185 W CN2024114185 W CN 2024114185W WO 2025040167 A1 WO2025040167 A1 WO 2025040167A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
independently
membered
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/114185
Other languages
French (fr)
Chinese (zh)
Inventor
匡荣仁
陶瑞衡
吴振
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Allist Pharmaceuticals Inc
Original Assignee
Shanghai Allist Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Allist Pharmaceuticals Inc filed Critical Shanghai Allist Pharmaceuticals Inc
Publication of WO2025040167A1 publication Critical patent/WO2025040167A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a phosphoinositide 3-kinase allosteric inhibitor for treating diseases associated with PI3K regulation.
  • Phosphoinositide 3-kinase is an intracellular phosphatidylinositol kinase that plays a regulatory role in key cellular processes such as cell growth, proliferation, differentiation, and intracellular trafficking.
  • PI3K can be divided into three categories (I, II, and III), of which the most widely studied is class I PI3K, which can be divided into class IA and IB based on signaling pathways and regulatory proteins.
  • Class IA PI3K (PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ ) is located downstream of receptor tyrosine kinase (RTK) and is a heterodimeric complex composed of the catalytic subunit p110 (p110 ⁇ , p110 ⁇ , and p110 ⁇ , respectively) and the regulatory subunit p85 (e.g., p85 ⁇ , p85 ⁇ , p55 ⁇ , p55 ⁇ , and p50 ⁇ ); class IB PI3K (PI3K ⁇ ) is located downstream of G protein-coupled receptors (GPCRs) and is a heterodimer composed of the catalytic subunit p110 ⁇ and the regulatory subunit p101 or p84.
  • GPCRs G protein-coupled receptors
  • Mutations in the PI3K ⁇ encoding gene or mutations that cause PI3K ⁇ upregulation occur in many human cancers, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer.
  • Mutations in the PI3K ⁇ encoding gene are point mutations clustered within several hotspots in the helical and kinase domains, such as E542K, E545K, and H1047R. Most of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high mutation rate of PI3K ⁇ , targeting this pathway may provide valuable therapeutic opportunities.
  • PI3K ⁇ inhibition in patients often results in hyperglycemia and/or hyperinsulinemia.
  • High levels of circulating insulin may have mitogenic and/or anti-apoptotic effects on cancer cells, thereby counteracting the anti-proliferative effects of PI3K inhibitors.
  • one approach to overcome the problem of compensatory production of insulin and/or glucose following systemic PI3K ⁇ inhibition is to develop inhibitors that are more selective for mutant PI3K ⁇ than wild-type PI3K ⁇ , thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target.
  • the various PI3K inhibitors that have been developed are all small molecule compounds that competitively bind to the ATP binding site to block the phosphorylation of PIP2 and the formation of PIP3.
  • This type of inhibitor will inhibit a variety of IA PI3K subtypes.
  • the type is called a "pan-PI3K” inhibitor.
  • Pan-PI3K inhibitors have certain target-related toxicities, including diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors depends on their subtype selectivity.
  • PI3K ⁇ inhibitors such as Alpelisib
  • small molecule compounds also bind to the ATP binding site of PI3K, are almost equivalent to wild-type and mutant PI3K ⁇ , and have toxic side effects such as hyperglycemia.
  • PI3K ⁇ selective inhibitors that abandon binding to the ATP binding site of PI3K, allosterically target and inhibit PI3K ⁇ mutants (such as PI3K ⁇ H1047R mutations), treat related diseases (such as cancer), and avoid dose-limiting toxicity.
  • the technical problem to be solved by the present invention is the defect of the single structure of PI3K inhibitors in the prior art, and a phosphoinositide 3-kinase allosteric inhibitor for treating and/or preventing diseases or disorders related to PI3K regulation is provided.
  • the phosphoinositide 3-kinase allosteric inhibitor of the present invention can effectively allosterically target and inhibit PI3K ⁇ mutations, especially PI3K ⁇ H1047R mutations, has good selectivity, and is expected to treat and/or prevent related diseases or disorders.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,
  • Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each
  • X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;
  • Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12
  • each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)
  • Each R 4-a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl ,
  • each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)
  • Each R 4-b is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • each R 10 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a ;
  • Each R 10a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 11 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 11a ;
  • Each R 11a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)OR 13 -N(R
  • each of R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, —C(O)NH 2 , —O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or —OC 1-6 alkyl substituted by one or more R 5b′ ;
  • R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;
  • each R 12 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a ;
  • Each R 12a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a ;
  • Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally
  • Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;
  • heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;
  • heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;
  • R 1 is hydrogen, hydroxyl, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 1a ;
  • Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each
  • Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;
  • R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 7a ;
  • Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted
  • Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12
  • each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)
  • Each R 4-a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl ,
  • each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)
  • Each R 4-b is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • each R 10 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a ;
  • Each R 11a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each of R 5-a , R 5-b , R 5-c , R 5 -d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;
  • Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 4-b is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 11 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl R 11a, R 11a, R 11b , R 11c, R 11d ...
  • Each R 11a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a ;
  • Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally
  • Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;
  • heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;
  • heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.
  • R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ;
  • Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ;
  • Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;
  • R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ;
  • Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;
  • Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ;
  • each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ;
  • each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • Each R 11 is independently hydrogen or C 1-6 alkyl
  • each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, —C(O)NH 2 , —O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or —OC 1-6 alkyl substituted by one or more R 5b′ ;
  • Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.
  • Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ;
  • Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;
  • R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ;
  • R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;
  • Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ;
  • each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ;
  • each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • Each R 11 is independently hydrogen or C 1-6 alkyl
  • each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • Each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;
  • each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ;
  • Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.
  • R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ;
  • Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ;
  • Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;
  • R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ;
  • Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;
  • Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ;
  • each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ;
  • each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • Each R 11 is independently hydrogen or C 1-6 alkyl
  • each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5-c , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or substituted by one or more R 5-k substitute
  • R 5-a , R 5-b , R 5-c , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 13 is independently hydrogen or C 1-6 alkyl
  • each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ;
  • Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl;
  • X is NR 7 , N, O or S, and Y is CR 8 ;
  • R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ;
  • Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 8 is hydrogen, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;
  • Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl;
  • R 4B is hydrogen, C 1-6 alkyl or -N(R 9 ) 2 , wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ;
  • Each R 4b is independently deuterium, halogen, cyano, -NH 2 or hydroxyl;
  • each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R
  • each of R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;
  • R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;
  • Each R 13 is independently hydrogen or C 1-6 alkyl
  • Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl.
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl;
  • X is NR 7 , N, O or S, and Y is CR 8 ;
  • R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ;
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl;
  • R 4B is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ;
  • Each R 4b is independently deuterium, halogen, -NH 2 or hydroxy;
  • each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R
  • R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;
  • Each R 13 is independently hydrogen or C 1-6 alkyl
  • Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl.
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl;
  • X is NR 7 , N, O or S, and Y is CR 8 ;
  • R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ;
  • Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;
  • R 8 is hydrogen, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;
  • Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl;
  • R 4B is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ;
  • Each R 4b is independently deuterium, halogen, -NH 2 or hydroxy;
  • each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;
  • R 5-a , R 5-b , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 13 is independently hydrogen or C 1-6 alkyl
  • Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl.
  • R 1 is hydrogen or C 1-6 alkyl
  • X is NR 7 , N, O or S, and Y is CR 8 ;
  • R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen;
  • R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is hydrogen, -NH 2 or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;
  • each R 4b is deuterium or cyano
  • Each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 1 is hydrogen or C 1-6 alkyl
  • R2 and R3 are each independently hydrogen or C1-6 alkyl
  • X is NR 7 , N, O or S, and Y is CR 8 ;
  • R 7 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen;
  • R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is hydrogen or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;
  • each R 4b is deuterium
  • Each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;
  • R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;
  • Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy.
  • R2 and R3 are each independently hydrogen or C1-6 alkyl
  • X is NR 7 , N, O or S, and Y is CR 8 ;
  • R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen;
  • R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;
  • R 4A and R 4B are each independently hydrogen or C 1-6 alkyl
  • Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;
  • R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy.
  • R 1 is hydrogen
  • R2 and R3 are each independently hydrogen or C1-6 alkyl
  • X is S, Y is CR 8 ;
  • R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is hydrogen, -NH 2 or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;
  • each R 4b is deuterium or cyano
  • Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;
  • each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;
  • R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R2 and R3 are each independently hydrogen or C1-6 alkyl
  • X is S, Y is CR 8 ;
  • R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is hydrogen or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;
  • each R 4b is deuterium
  • Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;
  • R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R2 and R3 are each independently hydrogen or C1-6 alkyl
  • X is S, Y is CR 8 ;
  • R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;
  • R 4A and R 4B are each independently hydrogen or C 1-6 alkyl
  • Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j or 5-10 membered heteroaryl substituted by one or more R 5-k ;
  • Each R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R 2 and R 3 one is hydrogen and the other is C 1-6 alkyl;
  • X is S, Y is CR 8 ;
  • R8 is C1-6 alkyl
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is -NH 2 or C 1-6 alkyl; the C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium or cyano;
  • Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;
  • each R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;
  • R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R 2 and R 3 one is hydrogen and the other is C 1-6 alkyl;
  • X is S, Y is CR 8 ;
  • R8 is C1-6 alkyl
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium;
  • Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;
  • R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R 2 and R 3 one is hydrogen and the other is C 1-6 alkyl;
  • X is S, Y is CR 8 ;
  • R8 is C1-6 alkyl
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is C 1-6 alkyl
  • Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl or substituted by one or more R 5-k substituted 5-10 membered heteroaryl;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R 2 and R 3 one is hydrogen and the other is C 1-6 alkyl;
  • X is S, Y is CR 8 ;
  • R8 is C1-6 alkyl
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium;
  • Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;
  • Each R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl, -OC 1-6 alkyl, or -OC 1-6 alkyl substituted with one or more R 5b' ;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R 2 and R 3 one is hydrogen and the other is C 1-6 alkyl;
  • X is S, Y is CR 8 ;
  • R8 is C1-6 alkyl
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium;
  • R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R 2 and R 3 one is hydrogen and the other is C 1-6 alkyl;
  • R8 is C1-6 alkyl
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium;
  • Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5a , R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;
  • Each R 5-k and R 5-j is independently C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen
  • R 2 and R 3 one is hydrogen and the other is C 1-6 alkyl;
  • X is S, Y is CR 8 ;
  • R8 is C1-6 alkyl
  • R 4A is hydrogen or C 1-6 alkyl
  • R 4B is C 1-6 alkyl
  • Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl substituted by one or more R 5-k ;
  • Each R 5-k is independently C 1-6 alkyl
  • Each R 6 is independently hydrogen or halogen.
  • R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ;
  • Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.
  • R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ;
  • Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.
  • R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein the C 1-6 alkyl and -OC 1-6 alkyl The groups are each independently optionally substituted with one or more R 7a ;
  • Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.
  • R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;
  • Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.
  • R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ;
  • Each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; each R 11 is independently hydrogen or C 1-6 alkyl.
  • R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ;
  • each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;
  • Each R 11 is independently hydrogen or C 1-6 alkyl.
  • each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)OR 13 -N(R
  • Each of R 5-a , R 5-b , R 5-c , R 5 -d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;
  • each R 12 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a ;
  • Each R 12a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl R 13a, R 13b, R 14c , R 15d, R 16d, R 17d, R 18d, R 19d, R 20d, R 21d, R 22d, R 23d, R 24d, R 25d, R 26d, R 27d, R 28d, R 29d, R 30d, R 31d, R 32d, R 33d, R 34d, R 35d, R 36d, R 37d
  • R 5-a , R 5-b , R 5-c , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;
  • Each R 13 is independently hydrogen or C 1-6 alkyl.
  • R2 and R3 are each independently hydrogen or C1-6 alkyl.
  • X is S and Y is CR 8 .
  • R 4B is C 1-6 alkyl.
  • R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl substituted by one or more R 5-k ;
  • each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5 -c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 2-6 alkyny
  • each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or substituted by one or more R 5f A 5-10 membered heteroaryl group;
  • each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R
  • each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, —OC 1-6 alkyl, cyano, —N(C 1-6 alkyl) 2 , —C(O)—C 1-6 alkyl or deuterated C 1-6 alkyl.
  • R 4B is hydrogen or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;
  • each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;
  • R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, —OC 1-6 alkyl, cyano, —N(C 1-6 alkyl) 2 , —C(O)—C 1-6 alkyl or deuterated C 1-6 alkyl.
  • each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;
  • R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl or -OC 1-6 alkyl.
  • each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;
  • R 5a , R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;
  • R 5-k and R 5-j is independently C 1-6 alkyl or -OC 1-6 alkyl.
  • the compound as shown in formula I is a compound shown in any one of the following formulas (IA) to (ID):
  • the compound shown in formula I is a compound shown in any one of the following formulas (IE) to (IH):
  • each of the "C 1-6 alkyl groups” is independently a C 1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
  • each of the "C 2-6 alkynyl” is independently a C 2-4 alkynyl, such as ethynyl, propynyl or propargyl, preferably ethynyl.
  • each of the "C 2-6 alkenyl groups” is independently vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl or pent-1,4-dienyl.
  • each of the "C 3-12 cycloalkyl” is independently a C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • each of the "C 3-12 cycloalkyl” is independently a C 3-6 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or a C 4-10 bridged ring cycloalkyl (e.g., ).
  • each of the "C 3-12 cycloalkyl” is independently a C 3-6 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclo pentyl or cyclohexyl) or C 4-10 bridged ring cycloalkyl (e.g. Another example ).
  • each of the "C 3-12 cycloalkenyl groups” is independently a C 3-6 cycloalkenyl group, such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
  • each of the "3-12 membered heterocycloalkyl” is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, and for example ) or 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example For example ).
  • the heteroatom species is independently selected from one, two or more of N, O and S
  • the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic hetero
  • each of the "3-12 membered heterocycloalkyl” is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, and for example ) or 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example For example ).
  • the heteroatom species is independently selected from one, two or more of N, O and S
  • the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic hetero
  • each of the "3-12 membered heterocycloalkyl” is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, and for example ), 7-10 membered spirocyclic heterocycloalkyl (e.g.
  • each of the "3-12 membered heterocycloalkyl” is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, and for example ), 7-10 membered spirocyclic heterocycloalkyl (e.g.
  • each of the "3-12 membered heterocycloalkenyl” is independently a 3-12 membered heterocycloalkenyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heterocycloalkenyl group, for example (1,2,3,6-tetrahydropyridinyl), for example
  • each of the "C 6-10 aryl groups” is independently phenyl or naphthyl, preferably phenyl.
  • each of the "5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl or pyrrolyl, for example ) or a 9-10 membered heteroaryl ring (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl or 1,2,3,4-tetrahydroisoquinolinyl, for example For example ).
  • the heteroatom species is independently selected from one, two or more of N, O and S,
  • each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl or pyrrolyl, for example ) or a 9-10 membered heteroaryl ring (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[
  • each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group whose heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group (e.g., 1H-tetrazolyl, 2H-tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or pyrrolyl, for example ) or a 9-10 membered heteroaryl ring (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyri
  • each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group whose heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or pyrrolyl, for example ) or 9-10 membered heteroaryl (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,
  • each of the "halogen" is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • each of the "deuterated C 1-6 alkyl” is independently deuterated methane or deuterated ethane, for example -CD 3 .
  • each of the "-OC 1-6 alkyl" is independently -OC 1-4 alkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy, more preferably methoxy.
  • the compound as shown in Formula I is not the following compound:
  • R2 and R3 one is H and the other is methyl.
  • X is S
  • Y is CCH 3 or CCF 3 .
  • R 4A is hydrogen or methyl.
  • R 4B is methyl, amino, -CH 2 CN or -CD 3 .
  • R 4B is methyl or -CD 3 .
  • R 4B is methyl
  • each R 5 is independently phenyl
  • each R 5 is independently phenyl
  • each R 5 is independently phenyl
  • each R 5 is independently phenyl
  • Cy 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Cy 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Cy 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Cy 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Cy 2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound as shown in formula I is any of the following compounds:
  • the compound as shown in Formula I contains or does not contain a chiral center.
  • the compound as shown in Formula I is a stereoisomer or a mixture thereof.
  • the compound as shown in Formula I is an R configuration, an S configuration, or an R, S configuration racemate.
  • the compound as shown in Formula I is any of the following compounds:
  • the compound as shown in Formula I is any of the following compounds:
  • the present invention also provides a method for preparing the compound as shown in Formula I, which is any of the following routes:
  • Step 1 Under alkaline or neutral conditions, a condensation reaction is carried out in the presence of a condensation reagent.
  • the operating conditions of the condensation reaction may be conventional operations and conditions for such reactions in the art.
  • the condensation reagent may be 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI);
  • Step 2 performing a transposition reaction in the presence of a base, wherein the operating conditions of the transposition reaction may be conventional operations and conditions of such reactions in the art, and the base may be sodium hydrogen or lithium bis(trimethylsilyl)amide (LiHMDS);
  • Step 3 performing a ring-closing reaction in the presence of an acid, wherein the operating conditions of the ring-closing reaction may be conventional operations and conditions of such reactions in the art, and the acid may be sulfuric acid or hydrobromic acid;
  • Step 4 a coupling reaction in the presence of a palladium catalyst, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium catalyst may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;
  • Step 5 Carry out carbonyl reduction reaction in the presence of a reducing agent.
  • the operating conditions of the reduction reaction may be conventional conditions for such reactions in the art.
  • the reducing agent may be sodium borohydride or sodium cyanoborohydride;
  • Step 6 performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;
  • Step 7 performing nucleophilic substitution in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art, and the base may be diisopropylethylamine (DIPEA) or sodium carbonate;
  • DIPEA diisopropylethylamine
  • Step 8 performing an ester hydrolysis reaction in the presence of a base.
  • the operating conditions of the ester hydrolysis reaction may be conventional operations and conditions of this type of reaction in the art.
  • the base may be sodium hydroxide or lithium hydroxide.
  • Step 1 performing an aldol reaction in the presence of a base, wherein the operating conditions of the aldol reaction may be conventional operations and conditions of such reactions in the art, and the base may be potassium hydroxide or lithium diisopropylamide (LDA);
  • the base may be potassium hydroxide or lithium diisopropylamide (LDA);
  • Step 2 performing a hydroxyl oxidation reaction in the presence of an oxidant, wherein the operating conditions of the oxidation reaction may be conventional operations and conditions of such reactions in the art, and the oxidant may be a Dess-Martin oxidant or manganese dioxide;
  • Step 3 performing demethylation and ring-closing reactions in the presence of an acid, wherein the operating conditions of the reaction may be conventional operations and conditions of such reactions in the art, and the acid may be a hydrobromic acid acetic acid solution or a hydrobromic acid aqueous solution;
  • Step 4 performing a coupling reaction in the presence of a palladium reagent, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;
  • Step 5 performing a carbonyl reduction reaction in the presence of a reducing agent, wherein the operating conditions of the reduction reaction may be conventional operations and conditions of such reactions in the art, and the reducing agent may be sodium borohydride or sodium cyanoborohydride;
  • Step 6 performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;
  • Step 7 performing nucleophilic substitution in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or sodium carbonate;
  • Step 8 performing an ester hydrolysis reaction in the presence of a base, wherein the operating conditions of the hydrolysis reaction may be conventional operations and conditions of such reactions in the art, and the base may be sodium hydroxide or lithium hydroxide;
  • P 1 is a hydroxyl protecting group, such as Boc, PMB, Bn or Cbz;
  • Step 1 performing a nucleophilic substitution reaction in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be potassium carbonate or sodium carbonate;
  • Step 2 performing an ester hydrolysis reaction in the presence of a base, wherein the operating conditions of the hydrolysis reaction may be conventional operations and conditions of such reactions in the art, and the base may be sodium hydroxide or lithium hydroxide;
  • Step 3 carrying out an acid-amine condensation reaction in the presence of a condensing agent, wherein the operating conditions of the condensation reaction may be conventional operations and conditions of such reactions in the art, and the condensing agent may be HATU or EDCI;
  • Step 4 performing a nucleophilic substitution reaction in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be LDA or LiHMDS;
  • Step 5 performing a deprotection reaction in the presence of a deprotection reagent, wherein the operating conditions of the deprotection reaction may be conventional operations and conditions of such reactions in the art, and the deprotection reagent may be trifluoroacetic acid or hydrogen chloride;
  • Step 6 performing a cyclization reaction in the presence of a cyclization reagent, wherein the operating conditions of the cyclization reaction may be conventional operations and conditions of such reactions in the art, and the cyclization reagent may be trifluoromethanesulfonic anhydride or methanesulfonic anhydride;
  • Step 7 performing a coupling reaction in the presence of a palladium reagent, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;
  • Step 8 performing a carbonyl reduction reaction in the presence of a reducing agent, wherein the operating conditions of the reduction reaction may be conventional operations and conditions of such reactions in the art, and the reducing agent may be sodium borohydride or sodium cyanoborohydride;
  • Step 9 performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;
  • Step 10 performing a nucleophilic substitution reaction in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or sodium carbonate;
  • Step 11 Carry out ester hydrolysis reaction in the presence of a base.
  • the operating conditions of the hydrolysis reaction can be conventional operations of this type of reaction in the art. and conditions, the base can be sodium hydroxide or lithium hydroxide;
  • Step 1 performing a halogenation reaction in the presence of a halogenation reagent, wherein the operating conditions of the halogenation reaction may be conventional operations and conditions of such reactions in the art, and the halogenation reagent may be liquid bromine or N-bromosuccinimide (NBS);
  • Step 2 performing a urea synthesis reaction in the presence of a base, wherein the operating conditions of the urea synthesis reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or potassium carbonate;
  • Step 3 performing a ring-closing reaction in the presence of a base, wherein the operating conditions of the ring-closing reaction may be conventional operations and conditions of such reactions in the art, and the base may be sodium methoxide or potassium tert-butoxide;
  • Step 4 carrying out a nucleophilic substitution reaction in the presence of a condensing agent, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the condensing agent may be tripyrrolidinophosphonium bromide hexafluorophosphate (Pybrop) or 1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (Pybop);
  • Step 5 performing a coupling reaction in the presence of a palladium reagent, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;
  • Step 6 performing a carbonyl reduction reaction in the presence of a reducing agent, wherein the operating conditions of the reduction reaction may be conventional operations and conditions of such reactions in the art, and the reducing agent may be sodium borohydride or sodium cyanoborohydride;
  • Step 7 performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;
  • Step 8 performing a nucleophilic substitution reaction in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or potassium carbonate;
  • Step 9 performing an ester hydrolysis reaction in the presence of a base.
  • the operating conditions of the hydrolysis reaction may be conventional operations and conditions for such reactions in the art.
  • the base may be sodium hydroxide or lithium hydroxide.
  • Step 1 performing an ester hydrolysis reaction in the presence of a hydrolysis agent, wherein the operating conditions of the ester hydrolysis reaction may be conventional operations and conditions of such reactions in the art, and the hydrolysis agent may be sodium hydroxide or lithium hydroxide;
  • Step 2 carrying out an acid-amine condensation reaction in the presence of a condensing agent, wherein the operating conditions of the acid-amine condensation reaction may be conventional operations and conditions of such reactions in the art, and the condensing agent may be HATU or EDCI;
  • Step 3 performing a cyclization reaction in the presence of an oxidant, wherein the operating conditions of the cyclization reaction may be conventional operations and conditions for such reactions in the art, and the oxidant may be iodine or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ);
  • the oxidant may be iodine or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ);
  • Step 4 performing a coupling reaction in the presence of a palladium reagent, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;
  • Step 5 performing a carbonyl reduction reaction in the presence of a reducing agent, wherein the operating conditions of the reduction reaction may be conventional operations and conditions of such reactions in the art, and the reducing agent may be sodium borohydride or sodium cyanoborohydride;
  • Step 6 performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;
  • Step 7 performing nucleophilic substitution in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or potassium carbonate;
  • Step 8 Carry out ester hydrolysis reaction in the presence of a base.
  • the operating conditions of the hydrolysis reaction may be conventional operations and conditions for such reactions in the art.
  • the base may be sodium hydroxide or lithium hydroxide.
  • the present invention also provides a compound represented by any one of the following formulas (I-1) to (I-4):
  • R 4A , R 4B , X, and Y are as defined above;
  • the compound as shown in formula I-1 is The compound shown in formula I-2 is The compound shown in formula I-3 is The compound shown in formula I-4 is
  • the present invention also provides a method for preparing the compound shown in formula I-2.
  • the steps include:
  • X is a halogen atom (such as Cl, Br or I),
  • Step 1 performing an addition reaction in the presence of an addition reagent, wherein the operating conditions of the addition reaction may be conventional operations and conditions of such reactions in the art, and the addition reagent may be liquid bromine or chlorine gas;
  • Step 2 performing a cyclization reaction in the presence of a base.
  • the operating conditions of the cyclization reaction may be conventional operations and conditions of such reactions in the art.
  • the base may be sodium methoxide or sodium ethoxide;
  • Step 3 performing an electrophilic halogenation reaction in the presence of a halogenating agent, wherein the operating conditions of the electrophilic halogenation reaction may be conventional operations and conditions of such reactions in the art, and the halogenating agent may be liquid bromine or NBS;
  • Step 4 performing a methylation reaction in the presence of a methylating agent, wherein the operating conditions of the methylation reaction may be conventional operations and conditions of such reactions in the art, and the methylating agent may be methyl iodide or dimethyl sulfate;
  • Step 5 Carry out ester reduction reaction in the presence of a reducing agent.
  • the operating conditions of the ester reduction reaction can be the conventional conditions for such reactions in the art.
  • Standard operation and conditions the reducing agent can be lithium aluminum tetrahydride or borane;
  • Step 6 performing a hydroxyl oxidation reaction in the presence of an oxidant, wherein the operating conditions of the oxidation reaction may be conventional operations and conditions of such reactions in the art, and the oxidant may be a Dess-Martin oxidant or manganese dioxide;
  • Step 7 performing a nucleophilic substitution reaction in the presence of a nucleophilic reagent, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the nucleophilic reagent may be a Grignard reagent, a lithium reagent or a zinc reagent;
  • Step 8 performing a hydroxyl group oxidation reaction in the presence of an oxidant, wherein the operating conditions of the oxidation reaction may be conventional operations and conditions of such reactions in the art, and the oxidant may be a Dess-Martin oxidant or manganese dioxide;
  • Step 9 carrying out a demethylation reaction in the presence of a demethylation agent.
  • the operating conditions of the demethylation reaction may be conventional operations and conditions for such reactions in the art.
  • the demethylation agent may be an aqueous solution of hydrobromic acid, a hydrobromic acid-acetic acid solution or boron tribromide.
  • the present invention also provides a pharmaceutical composition, which comprises a substance A and a pharmaceutical excipient (or a pharmaceutically acceptable carrier); the substance A is the compound shown in the above formula I or a pharmaceutically acceptable salt thereof.
  • the substance A can be in a therapeutically effective amount.
  • the present invention also provides an application of a substance A or the above-mentioned pharmaceutical composition in the preparation of a PI3K ⁇ inhibitor, wherein the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof.
  • the PI3K ⁇ inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or a control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting PI3K ⁇ .
  • the present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent diseases or disorders related to PI3K ⁇ regulation;
  • the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount;
  • the disease or disorder related to PI3K ⁇ regulation is preferably cancer, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.
  • the present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent diseases or disorders related to PI3K ⁇ regulation;
  • the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount;
  • the disease or disorder related to PI3K ⁇ regulation is preferably CLOVES syndrome (for example, manifested as congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3K ⁇ -related overgrowth syndrome (PROS).
  • CLOVES syndrome for example, manifested as congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis, bone or spinal syndrome
  • PROS PI3K ⁇ -related overgrowth syndrome
  • the present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent cancer;
  • the cancer is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer;
  • the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount.
  • the present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent CLOVES syndrome (for example, manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3K ⁇ -related overgrowth syndrome (PROS);
  • CLOVES syndrome for example, manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome
  • PROS PI3K ⁇ -related overgrowth syndrome
  • the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount.
  • the present invention also provides a method for inhibiting PI3K ⁇ , which comprises administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for treating and/or preventing a disease or disorder associated with PI3K ⁇ regulation, comprising administering to a patient A therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the disease or disorder related to PI3K ⁇ regulation is preferably cancer, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.
  • cancer such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.
  • the present invention also provides a method for treating and/or preventing a disease or disorder associated with PI3K ⁇ regulation, comprising administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient;
  • the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof;
  • the disease or disorder associated with PI3K ⁇ regulation is preferably CLOVES syndrome (e.g., manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3K ⁇ -related overgrowth syndrome (PROS).
  • CLOVES syndrome e.g., manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome
  • PROS PI3K ⁇ -related overgrowth syndrome
  • the present invention also provides a method for treating and/or preventing cancer, comprising administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient;
  • the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof;
  • the cancer is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.
  • the present invention also provides a method for treating and/or preventing CLOVES syndrome (e.g., manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3K ⁇ -related overgrowth syndrome (PROS), which comprises administering to the patient a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof.
  • CLOVES syndrome e.g., manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome
  • PROS PI3K ⁇ -related overgrowth syndrome
  • the PI3K ⁇ as described above is a PI3K ⁇ mutation, preferably a PI3K ⁇ H1047R mutation or a PI3K ⁇ E545K mutation, and more preferably a PI3K ⁇ H1047R mutation.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts ...
  • an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • the pharmaceutically acceptable acid includes an inorganic acid and an organic acid.
  • pharmaceutical composition refers to a preparation comprising a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • pharmaceutically acceptable refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.
  • pharmaceutical excipients or “pharmaceutically acceptable carriers” refers to excipients and additives used in the production of drugs and the preparation of prescriptions. They are all substances contained in pharmaceutical preparations except the active ingredients. Please refer to Part IV of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredients at the desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredients after the subject receives the composition.
  • the pharmaceutical excipients may be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients of the composition.
  • the pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
  • treatment refers to therapeutic treatment or palliative measures.
  • treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.
  • Treatment may also mean prolonging survival as compared to expected survival if not receiving treatment.
  • prevent refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient.”
  • Therapeutically effective amount will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.
  • patient refers to any animal that is about to or has been administered the compound or composition according to embodiments of the present invention, preferably a mammal, and most preferably a human.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • the term "substituted" or “substituent” means that the hydrogen atom in a group is replaced by a specified group.
  • substitution position is not specified, the substitution can be in any position, but only a stable or chemically feasible chemical is formed. Examples are as follows: The structure indicates that the hydrogen atoms on ring A are replaced by p R 4.
  • the substituent can be attached to the rest of the molecule through any permissible attachment site; for example, 6-azaspiro[2.5]octanyl means that it can be attached to the rest of the molecule through any permissible ring atom on any ring, for example, the attachment site can be on a ring containing a heteroatom (e.g. ), or on a ring containing no heteroatoms (e.g. ).
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with at least one R, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • alkyl refers to a saturated linear or branched monovalent hydrocarbon group.
  • C1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, preferably a C1-4 alkyl group having 1 to 4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the term "-OC 1-6 alkyl” refers to an alkoxy group, wherein “C 1-6 alkyl” is as defined above. Preferably, it is an alkoxy group having 1 to 4 carbon atoms, such as methoxy or ethoxy.
  • deuterated C 1-6 alkyl refers to a C 1-6 alkyl group in which one or more hydrogen atoms are replaced by a deuterium atom, such as -CD 3 .
  • C 1-6 alkyl in the term "-C(O)-C 1-6 alkyl” is as defined above, for example, -C(O)-CH 3 , -C(O)-CH 2 CH 3 .
  • C 2-6 alkynyl refers to a C 2 to C 6 , linear or branched, unsaturated, monovalent hydrocarbon group having one or more (e.g., 1, 2 or 3) carbon-carbon sp 3 triple bonds, preferably a C 2-4 alkynyl group.
  • Alkyl groups include, but are not limited to, ethynyl, wait.
  • C 2-6 alkenyl refers to a linear or branched, unsaturated, monovalent hydrocarbon group with a carbon number of C 2 to C 6 , which has one or more (e.g., 1, 2 or 3) carbon-carbon sp 2 double bonds, preferably a C 2-4 alkenyl group.
  • Alkenyl groups include, but are not limited to, vinyl, wait.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) carbocyclic substituent, and it can be connected to the rest of the molecule through a single bond via any suitable carbon atom.
  • the cycloalkyl group is preferably a 3-12-membered cycloalkyl group having 3 to 12 carbon atoms, more preferably a 3-7-membered monocyclic cycloalkyl group having 3 to 7 carbon atoms (most preferably a 3-6-membered monocyclic cycloalkyl group having 3 to 6 carbon atoms) or a 4-10-membered bridged ring cycloalkyl group having 4 to 10 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc., for example
  • any ring carbon atom in the cycloalkyl group may be substituted with oxygen.
  • cycloalkenyl means a partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) non-aromatic carbocyclic substituent having at least one double bond (e.g., carbon-carbon double bond), and which can be connected to the rest of the molecule by a single bond via any suitable carbon atom; such as a 3-12-membered cycloalkenyl having 3 to 12 carbon atoms, more preferably a 3-7-membered cycloalkenyl having 3 to 7 carbon atoms, and most preferably a 3-6-membered cycloalkenyl having 3 to 6 carbon atoms.
  • cycloalkenyl examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g., ), cyclopentadienyl (e.g. ), cyclohexenyl (e.g. ), cycloheptenyl, cyclohexadienyl, etc.
  • any suitable ring carbon atom in the cycloalkenyl group may be substituted with oxygen.
  • heterocycloalkyl refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3-12, 4-6, 7-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified heteroatom type (one or more of N, O and S), a monocyclic or polycyclic (e.g., a bicyclic, tricyclic or more cyclic bridged ring, a fused ring or a spirocyclic system), which is connected to the rest of the molecule through any suitable carbon atom or heteroatom.
  • ring atoms e.g., 3-12, 4-6, 7-10
  • heteroatoms e.g., 1, 2, 3, 4 or 5
  • a specified heteroatom type one or more of N, O and S
  • a monocyclic or polycyclic e.g., a bicyclic, tricyclic or more cyclic bridged ring, a fused ring or a spiro
  • heterocycloalkyl can be a 4-6-membered monocyclic heterocycloalkyl, a 7-10-membered spirocyclic heterocycloalkyl or a 7-10-membered bridged heterocycloalkyl.
  • heterocycloalkyl include, but are not limited to, morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, tetrahydropyranyl, oxetanyl, azetidinyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[3.3]heptyl, 2-oxabicyclo[2.2.2]octanyl or 8-azabicyclo[3.2.1]octanyl, e.g.
  • any appropriate ring atom in the heterocycloalkyl group may be substituted with oxo.
  • heterocycloalkenyl refers to a cyclic, unsaturated, monovalent hydrocarbon group with a specified number of ring atoms (e.g., 3-12, 4-6, 7-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified heteroatom type (one or more of N, O and S), which has one or more (e.g., 1, 2 or 3) carbon-carbon sp2 double bonds, is monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged rings, fused rings or spirocyclic systems), and is not aromatic.
  • ring atoms e.g., 3-12, 4-6, 7-10
  • heteroatoms e.g., 1, 2, 3, 4 or 5
  • a specified heteroatom type one or more of N, O and S
  • heterocycloalkenyl group is connected to the rest of the molecule through any suitable carbon atom or heteroatom.
  • heterocycloalkenyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridyl, such as In the present invention, any appropriate ring atom in the heterocycloalkenyl group may be substituted with oxo.
  • aryl refers to a cyclic, unsaturated, monovalent hydrocarbon group with a specified number of carbon atoms (e.g., C 6-10 ), which is monocyclic or polycyclic (e.g., 2 or 3). When it is polycyclic, the monocyclic rings share two atoms and a bond, and at least one ring is aromatic. The aryl group is connected to the rest of the molecule through an aromatic ring or a non-aromatic ring.
  • Aryl groups include, but are not limited to, phenyl, naphthyl or 1,2,3,4-tetrahydronaphthyl, for example
  • any suitable ring carbon atom on the non-aromatic ring may be substituted with oxygen.
  • heteroaryl refers to a cyclic, unsaturated, monovalent group with a specified number of ring atoms (e.g., 5-10 members, 5-6 members, 9-10 members), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified type of heteroatoms (one or more of N, O and S), which is monocyclic or polycyclic; when it is polycyclic, two atoms and one bond are shared between each two monocyclic rings, and at least one ring is aromatic.
  • ring atoms e.g., 5-10 members, 5-6 members, 9-10 members
  • heteroatoms e.g., 1, 2, 3, 4 or 5
  • a specified type of heteroatoms one or more of N, O and S
  • the heteroaryl group is connected to the rest of the molecule through any suitable carbon atom or heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl group is connected to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties. It can be a 5-6-membered monocyclic heteroaryl or a 9-10-membered polycyclic heteroaryl.
  • Heteroaryl includes, but is not limited to, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyrrolyl, quinolyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl, or 1,2,3,4-
  • halogen refers to fluorine, chlorine, bromine or iodine, especially to F or Cl.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive and progressive effect of the present invention is that the phosphoinositide 3-kinase allosteric inhibitor of the present invention can effectively allosterically target and inhibit PI3K ⁇ mutation, especially PI3K ⁇ H1047R mutation, has good selectivity, and is expected to treat and/or prevent related diseases or disorders.
  • the mixture was poured into ice water (150 mL), filtered, and the filter cake was washed with water, 0.5 mol/L sodium bicarbonate aqueous solution, and sodium thiosulfite aqueous solution, and dried.
  • the pure product 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester (19 g, yield 81%) was recrystallized from 2-propanol as a light yellow solid.
  • Step 1 4-bromo-3-methoxy-5-methylthiophene-2-carboxylic acid methyl ester
  • Step 1 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-ol and 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-ol
  • Step 2 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-one (Intermediate 3-1) and 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (Intermediate 3-2)
  • Triethylamine (2.44 g, 24 mmol, 2.0 eq) and 4-dimethylaminopyridine (0.03 g, 0.24 mmol, 0.02 eq) were added to a solution of 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one (3.0 g, 12 mmol, 1.0 eq) and benzoyl chloride (1.68 g, 12 mmol, 1.0 eq) in dichloromethane (50 mL) at 0°C, stirred at room temperature for 4 hours, water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column separation to give benzoic acid-4-bromo-5-methyl-2-propionylthiophen-3-yl ester (1.3 g, yield 91.5%) as a white solid.
  • Benzoic acid-4-bromo-5-methyl-2-propionylthiophen-3-yl ester 800 mg, 2.26 mmol, 1.0 eq
  • dimethyl sulfoxide 10 mL
  • 60% sodium hydrogen sulfide 210 mg, 6.80 mmol, 3.0 eq
  • the reaction was allowed to react for 1 hour, and 1 mol/L hydrochloric acid (30 mL) was added to quench the reaction.
  • Ethyl acetate (50 mL) was added, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was directly used in the next step reaction.
  • Step 7 Methyl 2- ⁇ [1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino ⁇ benzoate
  • reaction solution was diluted with water, extracted three times with ethyl acetate (30 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to give methyl 2- ⁇ [1-(2,6-dimethyl-7-oxygen-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino ⁇ benzoate (75 mg, yield 49%) as a white solid.
  • Step 8 2- ⁇ [1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino ⁇ benzoic acid
  • Step 1 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-3-hydroxy-2-methylpropan-1-one
  • Step 2 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-2-methylpropane-1,3-dione
  • Step 5 5-(2-Fluorophenyl)-3-(1-hydroxyethyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one
  • Step 6 3-(1-chloroethyl)-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one
  • Step 7 Methyl 2-( ⁇ 1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl ⁇ amino)benzoate
  • methyl 2-( ⁇ 1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl ⁇ amino)benzoate (115 mg, yield 65%) was prepared as a white solid.
  • Step 8 2-( ⁇ 1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl ⁇ amino)benzoic acid
  • 3-(1-methylpyrazol-4-yl)benzoic acid was prepared according to the method of patent WO2021066559, and 3-(1-methylpyrazol-4-yl)benzoic acid was subjected to chlorination reaction to obtain 3-(1-methylpyrazol-4-yl)benzoyl chloride (446 mg) as a white solid.
  • Step 1 4-bromo-3- ⁇ [(4-methoxyphenyl)methyl]oxy ⁇ -5-methylthiophene-2-carboxylic acid methyl ester
  • Step 3 4-Bromo-N-methoxy-3- ⁇ [(4-methoxyphenyl)methyl]oxy ⁇ -5,N-dimethylthiophene-2-carboxamide
  • Step 4 1-(4-bromo-3- ⁇ [(4-methoxyphenyl)methyl]oxy ⁇ -5-methylthien-2-yl)-3-(piperidin-1-yl)propane-1,3-dione
  • Acetylpiperidine (31.8 mg, 0.25 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), cooled to -78 °C, and 2.0 mol/L lithium bis(trimethylsilyl)amide (0.48 mL, 3.8 eq) was slowly added.
  • reaction solution was diluted with water (100 mL), extracted three times with dichloromethane (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to give 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione (330 mg, yield 77%).
  • Step 7 3-Acetyl-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one
  • Step 8 5-(Hexahydropyridin-1-yl)-3-(1-hydroxyethyl)-2-methyl-7H-thieno[3,2-b]pyran-7-one
  • Step 9 3-(1-chloroethyl)-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one
  • Step 10 Methyl 2-( ⁇ 1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl ⁇ amino)benzoate
  • Step 11 2-( ⁇ 1-[5-(Hexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl ⁇ amino)benzoic acid
  • Methyl 4-bromo-5-methyl-3- ⁇ [(methylamino)carbonyl]amino ⁇ thiophene-2-carboxylate (500 mg, 1.62 mmol, 1.0 eq) was dissolved in methanol (10 mL), sodium methoxide (262 mg, 4.86 mmol, 3.0 eq) was added at 0°C, stirred for 2 hours, concentrated, water (20 mL) and ethyl acetate (20 mL) were added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give 7-bromo-3,6-dimethyl-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2,4-dione (400 mg, yield 89%).
  • Step 4 7-Bromo-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one
  • Step 5 7-Acetyl-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one
  • Step 7 7-(1-chloroethyl)-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one
  • Step 8 Methyl 2-( ⁇ 1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl ⁇ amino)benzoate
  • Step 9 2-( ⁇ 1-[2-(Hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl ⁇ amino)benzoic acid
  • 5-fluoro-2,3-dihydro-1H-isoindole and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 5-fluoro-2- ( ⁇ 1-[2-(5-Fluoro-2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl ⁇ amino)benzoic acid (25 mg), white solid.
  • Steps 4, 5, 6, 7, and 8 were prepared by referring to Example 1 to obtain 2- ⁇ [1-(3,6-dimethyl-4-oxyylidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino ⁇ benzoic acid (4.6 mg) as a white solid.
  • 6-chloro-3-( ⁇ 1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl ⁇ amino)pyridine-2-carboxylic acid (3 mg) was prepared as a white solid according to the method of Example 30.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed in the present invention is a phosphoinositide 3-kinase allosteric inhibitor for treating a disease related to PI3K regulation. Specifically, provided is a compound as represented by formula I or a pharmaceutically acceptable salt thereof. The phosphoinositide 3-kinase allosteric inhibitor of the present invention can effectively conduct allosteric targeted inhibition on a PI3Kα mutation, in particular, a PI3KαH1047R mutation, has relatively good selectivity, and is expected to treat and/or prevent related diseases or disorders.

Description

用于治疗与PI3K调节相关疾病的磷酸肌醇3-激酶变构抑制剂Allosteric inhibitors of phosphoinositide 3-kinase for the treatment of diseases associated with PI3K regulation

本申请要求申请日为2023/8/24的中国专利申请2023110780761的优先权、申请日为2024/3/26的中国专利申请2024103545418的优先权和申请日为2024/5/23的中国专利申请2024106506504的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application No. 2023110780761 with a filing date of 2023/8/24, the priority of Chinese patent application No. 2024103545418 with a filing date of 2024/3/26, and the priority of Chinese patent application No. 2024106506504 with a filing date of 2024/5/23. This application cites the full text of the above Chinese patent application.

技术领域Technical Field

本发明涉及一种用于治疗与PI3K调节相关疾病的磷酸肌醇3-激酶变构抑制剂。The present invention relates to a phosphoinositide 3-kinase allosteric inhibitor for treating diseases associated with PI3K regulation.

背景技术Background Art

磷酸肌醇3-激酶(PI3K)是一种胞内磷脂酰肌醇激酶，其在细胞生长、增殖、分化和细胞内运输等关键细胞过程中起到调节作用。PI3K可以分为三类(I、II和III类)，其中研究最广泛的为I类PI3K，I类PI3K又可以根据信号通路和调节蛋白分为IA和IB两类。IA类PI3K(PI3Kα、PI3Kβ和PI3Kδ)位于受体酪氨酸激酶(RTK)的下游，是由催化亚基p110(分别是p110α、p110β和p110δ)和调节亚基p85(例如p85α、p85β、p55δ、p55α和p50α)组成的异源二聚体复合物；IB类PI3K(PI3Kγ)位于G蛋白偶联受体(GPCR)的下游，是由催化亚基p110γ和调节亚基p101或p84组成的异二聚体。I类PI3K被受体酪氨酸激酶或G蛋白偶联受体激活以生成PIP3，PIP3与下游效应物如Akt/PDKl、mTOR、Tec家族激酶和Rho家族GTP酶途径中的效应物结合。调节亚基含有允许锚定到细胞表面受体和其他调节蛋白的域；催化亚基(p110α、p110β、p110γ、p110δ)含有ATP结合域。催化亚基，尤其是其ATP结合位点，一直以来是PI3K小分子抑制剂研究的重点。Phosphoinositide 3-kinase (PI3K) is an intracellular phosphatidylinositol kinase that plays a regulatory role in key cellular processes such as cell growth, proliferation, differentiation, and intracellular trafficking. PI3K can be divided into three categories (I, II, and III), of which the most widely studied is class I PI3K, which can be divided into class IA and IB based on signaling pathways and regulatory proteins. Class IA PI3K (PI3Kα, PI3Kβ, and PI3Kδ) is located downstream of receptor tyrosine kinase (RTK) and is a heterodimeric complex composed of the catalytic subunit p110 (p110α, p110β, and p110δ, respectively) and the regulatory subunit p85 (e.g., p85α, p85β, p55δ, p55α, and p50α); class IB PI3K (PI3Kγ) is located downstream of G protein-coupled receptors (GPCRs) and is a heterodimer composed of the catalytic subunit p110γ and the regulatory subunit p101 or p84. Class I PI3Ks are activated by receptor tyrosine kinases or G protein-coupled receptors to generate PIP3, which binds to downstream effectors such as Akt/PDK1, mTOR, Tec family kinases, and effectors in the Rho family GTPase pathway. The regulatory subunits contain domains that allow anchoring to cell surface receptors and other regulatory proteins; the catalytic subunits (p110α, p110β, p110γ, p110δ) contain ATP-binding domains. The catalytic subunits, especially their ATP-binding sites, have long been the focus of research on small molecule inhibitors of PI3K.

PI3Kα和PI3Kβ在体内普遍表达，PI3Kγ和PI3Kδ主要存在于白细胞中。PI3Kα和PI3Kβ的失调与实体瘤疾病的发生、发展有关；而PI3Kγ和PI3Kδ的失调与炎性和免疫系统疾病有关，例如类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、肺部疾病如慢性阻塞性肺疾病(COPD)和哮喘、血液系统恶性肿瘤。PI3Kα and PI3Kβ are ubiquitously expressed in the body, while PI3Kγ and PI3Kδ are mainly present in leukocytes. The dysregulation of PI3Kα and PI3Kβ is associated with the occurrence and development of solid tumors, while the dysregulation of PI3Kγ and PI3Kδ is associated with inflammatory and immune system diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma, and hematological malignancies.

PI3Kα编码基因中的突变或引起PI3Kα上调的突变发生在许多人类癌症中，例如肺癌、胃癌、子宫内膜癌、卵巢癌、膀胱癌、乳腺癌、结肠癌、脑癌、前列腺癌和皮肤癌。PI3Kα编码基因中的突变是簇集在螺旋和激酶结构域的几个热点内的点突变，如E542K、E545K和H1047R。这些突变中的大部分已被证明是致癌功能获得型突变。因为PI3Kα的高突变率，该途径的靶向可提供有价值的治疗机会。Mutations in the PI3Kα encoding gene or mutations that cause PI3Kα upregulation occur in many human cancers, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Mutations in the PI3Kα encoding gene are point mutations clustered within several hotspots in the helical and kinase domains, such as E542K, E545K, and H1047R. Most of these mutations have been shown to be oncogenic gain-of-function mutations. Because of the high mutation rate of PI3Kα, targeting this pathway may provide valuable therapeutic opportunities.

由于PI3Kα在调节机体葡萄糖稳态中的核心作用，患者中的PI3Kα抑制经常导致高血糖症和/或高胰岛素血症。高水平的循环胰岛素可能对癌细胞具有促有丝分裂和/或抗凋亡作用，从而抵消PI3K抑制剂的抗增殖作用。在具有突变的PI3Kα的癌症的情况下，克服在全身性PI3Kα抑制后胰岛素和/或葡萄糖的代偿产生问题的一种方法是开发对突变型PI3Kα的选择性高于野生型PI3Kα的抑制剂，从而限制毒性并允许更高剂量和更完全地抑制药物靶标。Due to the central role of PI3Kα in regulating glucose homeostasis in the body, PI3Kα inhibition in patients often results in hyperglycemia and/or hyperinsulinemia. High levels of circulating insulin may have mitogenic and/or anti-apoptotic effects on cancer cells, thereby counteracting the anti-proliferative effects of PI3K inhibitors. In the case of cancers with mutant PI3Kα, one approach to overcome the problem of compensatory production of insulin and/or glucose following systemic PI3Kα inhibition is to develop inhibitors that are more selective for mutant PI3Kα than wild-type PI3Kα, thereby limiting toxicity and allowing higher doses and more complete inhibition of the drug target.

目前已经开发的多种PI3K抑制剂(例如Taselisib、Buparlisib等)，都是小分子化合物与ATP结合位点竞争性结合，以阻断PIP2的磷酸化、阻断PIP3的形成，这类抑制剂会抑制多种IA类PI3K亚 型，被称为“泛PI3K”抑制剂。泛PI3K抑制剂具有某些与靶点相关的毒性，包括腹泻、皮疹、疲劳和高血糖。PI3K抑制剂的毒性取决于其亚型选择性。PI3Kα的抑制与高血糖和皮疹有关，而PI3Kδ或PI3Kγ的抑制与腹泻、骨髓抑制和转氨酶有关(Hanker等人，Cancer Discovery(2019)PMID:30837161)。目前已开发的PI3Kα抑制剂(例如Alpelisib)，小分子化合物同样结合于PI3K的ATP结合位点，对PI3Kα野生型和突变型几乎等效，具有高血糖症等毒副作用。因此，仍需要继续开发小分子PI3Kα选择性抑制剂，放弃与PI3K的ATP结合位点结合，变构靶向抑制PI3Kα突变体(如PI3KαH1047R突变)，治疗相关疾病(例如癌症)，同时避免剂量限制性毒性。The various PI3K inhibitors that have been developed (such as Taselisib, Buparlisib, etc.) are all small molecule compounds that competitively bind to the ATP binding site to block the phosphorylation of PIP2 and the formation of PIP3. This type of inhibitor will inhibit a variety of IA PI3K subtypes. The type is called a "pan-PI3K" inhibitor. Pan-PI3K inhibitors have certain target-related toxicities, including diarrhea, rash, fatigue, and hyperglycemia. The toxicity of PI3K inhibitors depends on their subtype selectivity. Inhibition of PI3Kα is associated with hyperglycemia and rash, while inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, bone marrow suppression, and transaminases (Hanker et al., Cancer Discovery (2019) PMID: 30837161). Currently developed PI3Kα inhibitors (such as Alpelisib), small molecule compounds also bind to the ATP binding site of PI3K, are almost equivalent to wild-type and mutant PI3Kα, and have toxic side effects such as hyperglycemia. Therefore, there is still a need to continue to develop small molecule PI3Kα selective inhibitors that abandon binding to the ATP binding site of PI3K, allosterically target and inhibit PI3Kα mutants (such as PI3KαH1047R mutations), treat related diseases (such as cancer), and avoid dose-limiting toxicity.

发明内容Summary of the invention

本发明所要解决的技术问题是现有技术中PI3K抑制剂结构单一的缺陷，而提供了一种用于治疗和/或预防与PI3K调节相关的疾病或障碍的磷酸肌醇3-激酶变构抑制剂。本发明的磷酸肌醇3-激酶变构抑制剂可有效变构靶向抑制PI3Kα突变，特别是PI3KαH1047R突变，具有较好的选择性，有望治疗和/或预防相关疾病或障碍。The technical problem to be solved by the present invention is the defect of the single structure of PI3K inhibitors in the prior art, and a phosphoinositide 3-kinase allosteric inhibitor for treating and/or preventing diseases or disorders related to PI3K regulation is provided. The phosphoinositide 3-kinase allosteric inhibitor of the present invention can effectively allosterically target and inhibit PI3Kα mutations, especially PI3KαH1047R mutations, has good selectivity, and is expected to treat and/or prevent related diseases or disorders.

本发明是通过下述技术方案来解决上述技术问题。The present invention solves the above technical problems through the following technical solutions.

本发明提供了一种如式I所示的化合物或其药学上可接受的盐，
The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

其中：in:

R1为氢、羟基、-N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R1a取代；R 1 is hydrogen, hydroxyl, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 1a ;

每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6- 10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 2a ;

每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基； Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;

R7为氢、羟基、-N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、-C(O)N(R9)2、-C(O)R9、-C(O)OR9、-SO2R9、-SO2N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12- membered cycloalkenyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, C 6-10 aryl, and 5-10-membered heteroaryl are each independently optionally substituted with one or more R 4a ;

每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、-S(O)2R10、-S(O)2N(R11)2、-S(O)R10、-S(O)N(R11)2、-S(O)(NR11)OR11、-C(O)R10、-C(O)OR11、-C(O)N(R11)2、-C(O)N(R11)OR11、-OC(O)R10、-OC(O)N(R11)2、-N(R11)C(O)OR11、-N(R11)C(O)R10、-N(R11)C(O)N(R11)2、-N(R11)C(NR11)(R10)、-N(R11)C(NR11)N(R11)2、-N(R11)S(O)2N(R11)2、-N(R11)S(O)2R10、-P(O)(R10)2、-P(O)(R11)(OR11)、-B(OR11)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4-a取代；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(NR 11 )(R 10 ), -N(R 11 )C(NR 11 )N(R 11 ) 2 , -N(R 11 )S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 10 , -P(O)(R 10 ) 2 , -P(O)(R 11 )(OR 11 ), -B(OR 11 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C R 4- a; R 4- b; R 4 -c; R 4- d; R 4- d; R 4 - d; R 4-e; R 4 - f; R 4- g; R 4-h; R 4-i ...

每个R4-a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 4-a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R4B为氢、羟基、-N(R9)2、-C(O)N(R9)2、-C(O)R9、-C(O)OR9、-SO2R9、-SO2N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3- 12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4b取代； R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl , C 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、-S(O)2R10、-S(O)2N(R11)2、-S(O)R10、-S(O)N(R11)2、-S(O)(NR11)OR11、-C(O)R10、-C(O)OR11、-C(O)N(R11)2、-C(O)N(R11)OR11、-OC(O)R10、-OC(O)N(R11)2、-N(R11)C(O)OR11、-N(R11)C(O)R10、-N(R11)C(O)N(R11)2、-N(R11)C(NR11)(R10)、-N(R11)C(NR11)N(R11)2、-N(R11)S(O)2N(R11)2、-N(R11)S(O)2R10、-P(O)(R10)2、-P(O)(R11)(OR11)、-B(OR11)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4-b取代；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(NR 11 )(R 10 ), -N(R 11 )C(NR 11 )N(R 11 ) 2 , -N(R 11 )S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 10 , -P(O)(R 10 ) 2 , -P(O)(R 11 )(OR 11 ), -B(OR 11 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C R 4- b; R 4-b is substituted with one or more C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl and 5-10 membered heteroaryl;

每个R4-b独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 4-b is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R10独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地为任选被一个或多个R10a取代；each R 10 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a ;

每个R10a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 10a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R11独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地为任选被一个或多个R11a取代；Each R 11 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 11a ;

每个R11a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 11a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、-S(O)2R12、-S(O)2N(R13)2、-S(O)R12、-S(O)N(R13)2、-S(O)(NR13)OR13、-C(O)R12、-C(O)OR13、-C(O)N(R13)2、-C(O)N(R13)OR13、-OC(O)R12、-OC(O)N(R13)2、-N(R13)C(O)OR13、-N(R13)C(O)R12、-N(R13)C(O)N(R13)2、-N(R13)C(NR13)(R12)、-N(R13)C(NR13)N(R13)2、-N(R13)S(O)2N(R13)2、-N(R13)S(O)2R12、-P(O)(R12)2、-P(O)(R13)(OR13)、-B(OR13)2、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6烯基、被一个或多个R5-d取代的C2-6烯基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、C3-12环烷基、被一个或多个R5-f取代的C3-12环烷基、C3-12环烯基、被一个或多个R5-g取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)N(R 13 ) 2 , -N(R 13 )C(NR 13 )(R 12 ), -N(R 13 )C(NR 13 )N(R 13 ) 2 , -N(R 13 )S(O) 2 N(R 13 ) 2 , -N(R 13 )S(O) 2 R 12 , -P(O)(R 12 ) 2 , -P(O)(R 13 )(OR 13 ), -B(OR 13 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC substituted by one or more R 5-c , C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 5-d , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5 -e , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5-f , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5-g , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-c、R5-d、R5-e、R5-f、R5-g、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, —C(O)NH 2 , —O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or —OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2； Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;

每个R12独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R12a取代；each R 12 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a ;

每个R12a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 12a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R13独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R13a取代；Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a ;

每个R13a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 6a ;

每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每一“杂环烷基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heterocycloalkyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

每一“杂环烯基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heterocycloalkenyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

每一“杂芳基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heteroaryl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

且所述如式I所示的化合物不为以下化合物：
And the compound shown in formula I is not the following compound:

在某一方案中，如式I所示的化合物或其药学上可接受的盐里，某些基团具有如下定义，未提及 的基团的定义如本发明中任一方案所述(本段内容以下简称为“在某一方案中”)，In one embodiment, in the compound of formula I or a pharmaceutically acceptable salt thereof, certain groups have the following definitions, and no group is mentioned. The definition of the group is as described in any scheme of the present invention (hereinafter referred to as "in a certain scheme"),

R1为氢、羟基、-N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R1a取代；R 1 is hydrogen, hydroxyl, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 1a ;

每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6- 10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 2a ;

每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;

R7为氢、羟基、-N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、-C(O)N(R9)2、-C(O)R9、-C(O)OR9、-SO2R9、-SO2N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12- membered cycloalkenyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, C 6-10 aryl, and 5-10-membered heteroaryl are each independently optionally substituted with one or more R 4a ;

每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、-S(O)2R10、-S(O)2N(R11)2、-S(O)R10、-S(O)N(R11)2、-S(O)(NR11)OR11、-C(O)R10、-C(O)OR11、-C(O)N(R11)2、-C(O)N(R11)OR11、-OC(O)R10、 -OC(O)N(R11)2、-N(R11)C(O)OR11、-N(R11)C(O)R10、-N(R11)C(O)N(R11)2、-N(R11)C(NR11)(R10)、-N(R11)C(NR11)N(R11)2、-N(R11)S(O)2N(R11)2、-N(R11)S(O)2R10、-P(O)(R10)2、-P(O)(R11)(OR11)、-B(OR11)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4-a取代；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(NR 11 )(R 10 ), -N(R 11 )C(NR 11 )N(R 2 ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ R 4- a; R 4-a ; R 4- b; R 4- c; R 4- d; R 4-d; R 4-d; R 4-d; R 4 -d; R 4-d; R 4- d; R 4-d; R 4-d; R 4-d; R 4- d; R 4-d; R 4-d; R 4-d; R 4 - d; R 4- d; R 4- d; R 4-d; R 4-d; R 4- d; R 4-d; R 4 - d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d ; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4-d; R 4- d;

每个R4-a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 4-a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R4B为氢、羟基、-N(R9)2、-C(O)N(R9)2、-C(O)R9、-C(O)OR9、-SO2R9、-SO2N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3- 12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl , C 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、-S(O)2R10、-S(O)2N(R11)2、-S(O)R10、-S(O)N(R11)2、-S(O)(NR11)OR11、-C(O)R10、-C(O)OR11、-C(O)N(R11)2、-C(O)N(R11)OR11、-OC(O)R10、-OC(O)N(R11)2、-N(R11)C(O)OR11、-N(R11)C(O)R10、-N(R11)C(O)N(R11)2、-N(R11)C(NR11)(R10)、-N(R11)C(NR11)N(R11)2、-N(R11)S(O)2N(R11)2、-N(R11)S(O)2R10、-P(O)(R10)2、-P(O)(R11)(OR11)、-B(OR11)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4-b取代；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(NR 11 )(R 10 ), -N(R 11 )C(NR 11 )N(R 11 ) 2 , -N(R 11 )S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 10 , -P(O)(R 10 ) 2 , -P(O)(R 11 )(OR 11 ), -B(OR 11 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C R 4- b; R 4-b is substituted with one or more C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl and 5-10 membered heteroaryl;

每个R4-b独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 4-b is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R10独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地为任选被一个或多个R10a取代；each R 10 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a ;

每个R10a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 10a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R11独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地为任选被一个或多个R11a取代；Each R 11 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 11a ;

每个R11a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 11a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、-S(O)2R12、-S(O)2N(R13)2、-S(O)R12、-S(O)N(R13)2、-S(O)(NR13)OR13、-C(O)R12、-C(O)OR13、-C(O)N(R13)2、-C(O)N(R13)OR13、-OC(O)R12、-OC(O)N(R13)2、-N(R13)C(O)OR13、-N(R13)C(O)R12、-N(R13)C(O)N(R13)2、 -N(R13)C(NR13)(R12)、-N(R13)C(NR13)N(R13)2、-N(R13)S(O)2N(R13)2、-N(R13)S(O)2R12、-P(O)(R12)2、-P(O)(R13)(OR13)、-B(OR13)2、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6烯基、被一个或多个R5-d取代的C2-6烯基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、C3-12环烷基、被一个或多个R5-f取代的C3-12环烷基、C3-12环烯基、被一个或多个R5-g取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 , -N(R 13 )C(O)R 12 , -N(R 13 )C(O)N(R 13 ) 2 , -N(R 13 )C(NR 13 )(R 12 ), -N(R 13 )C(NR 13 )N(R 13 ) 2 , -N(R 13 )S(O) 2 N(R 13 ) 2 , -N(R 13 )S(O) 2 R 12 , -P(O)(R 12 ) 2 , -P(O)(R 13 )(OR 13 ), -B(OR 13 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC 1-6 alkyl, -SC 1-6 alkyl substituted by one or more R 5-c , C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 5-d , C substituted by one or more R 5-e , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e, C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5-f , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5-g , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-c、R5-d、R5-e、R5-f、R5-g、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5 -d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;

每个R12独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R12a取代；each R 12 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a ;

每个R12a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 12a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R13独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R13a取代；Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a ;

每个R13a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 6a ;

每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每一“杂环烷基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heterocycloalkyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

每一“杂环烯基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数 各自独立地为1个、2个、3个、4个或5个；In each "heterocycloalkenyl", the heteroatom species are independently selected from one, two or more of N, O and S. The number of heteroatoms is Each independently is 1, 2, 3, 4 or 5;

每一“杂芳基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heteroaryl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

且所述如式I所示的化合物不为以下化合物：
And the compound shown in formula I is not the following compound:

在某一方案中，R1为氢、羟基、-N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R1a取代；In a certain embodiment, R 1 is hydrogen, hydroxyl, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 1a ;

每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6- 10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 2a ;

每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;

R7为氢、羟基、-N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R8a取代； R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、-C(O)N(R9)2、-C(O)R9、-C(O)OR9、-SO2R9、-SO2N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12- membered cycloalkenyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, C 6-10 aryl, and 5-10-membered heteroaryl are each independently optionally substituted with one or more R 4a ;

每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、-S(O)2R10、-S(O)2N(R11)2、-S(O)R10、-S(O)N(R11)2、-S(O)(NR11)OR11、-C(O)R10、-C(O)OR11、-C(O)N(R11)2、-C(O)N(R11)OR11、-OC(O)R10、-OC(O)N(R11)2、-N(R11)C(O)OR11、-N(R11)C(O)R10、-N(R11)C(O)N(R11)2、-N(R11)C(NR11)(R10)、-N(R11)C(NR11)N(R11)2、-N(R11)S(O)2N(R11)2、-N(R11)S(O)2R10、-P(O)(R10)2、-P(O)(R11)(OR11)、-B(OR11)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4-a取代；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(NR 11 )(R 10 ), -N(R 11 )C(NR 11 )N(R 11 ) 2 , -N(R 11 )S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 10 , -P(O)(R 10 ) 2 , -P(O)(R 11 )(OR 11 ), -B(OR 11 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C R 4- a; R 4- b; R 4 -c; R 4- d; R 4- d; R 4 - d; R 4-e; R 4 - f; R 4- g; R 4-h; R 4-i ...

每个R4-a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 4-a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R4B为氢、羟基、-N(R9)2、-C(O)N(R9)2、-C(O)R9、-C(O)OR9、-SO2R9、-SO2N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3- 12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl , C 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、-S(O)2R10、-S(O)2N(R11)2、-S(O)R10、-S(O)N(R11)2、-S(O)(NR11)OR11、-C(O)R10、-C(O)OR11、-C(O)N(R11)2、-C(O)N(R11)OR11、-OC(O)R10、-OC(O)N(R11)2、-N(R11)C(O)OR11、-N(R11)C(O)R10、-N(R11)C(O)N(R11)2、-N(R11)C(NR11)(R10)、-N(R11)C(NR11)N(R11)2、-N(R11)S(O)2N(R11)2、-N(R11)S(O)2R10、-P(O)(R10)2、-P(O)(R11)(OR11)、-B(OR11)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4-b取代；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(NR 11 )(R 10 ), -N(R 11 )C(NR 11 )N(R 11 ) 2 , -N(R 11 )S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 10 , -P(O)(R 10 ) 2 , -P(O)(R 11 )(OR 11 ), -B(OR 11 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C R 4- b; R 4-b is substituted with one or more C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl and 5-10 membered heteroaryl;

每个R4-b独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 4-b is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R10独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地为任选被一个或多个R10a取代；each R 10 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a ;

每个R10a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 10a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R11独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷 基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地为任选被一个或多个R11a取代；Each R 11 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl R 11a, R 11a, R 11b , R 11c, R 11d ...

每个R11a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 11a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、-S(O)2R12、-S(O)2N(R13)2、-S(O)R12、-S(O)N(R13)2、-S(O)(NR13)OR13、-C(O)R12、-C(O)OR13、-C(O)N(R13)2、-C(O)N(R13)OR13、-OC(O)R12、-OC(O)N(R13)2、-N(R13)C(O)OR13、-N(R13)C(O)R12、-N(R13)C(O)N(R13)2、-N(R13)C(NR13)(R12)、-N(R13)C(NR13)N(R13)2、-N(R13)S(O)2N(R13)2、-N(R13)S(O)2R12、-P(O)(R12)2、-P(O)(R13)(OR13)、-B(OR13)2、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6烯基、被一个或多个R5-d取代的C2-6烯基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、C3-12环烷基、被一个或多个R5-f取代的C3-12环烷基、C3-12环烯基、被一个或多个R5-g取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)N(R 13 ) 2 , -N(R 13 )C(NR 13 )(R 12 ), -N(R 13 )C(NR 13 )N(R 13 ) 2 , -N(R 13 )S(O) 2 N(R 13 ) 2 , -N(R 13 )S(O) 2 R 12 , -P(O)(R 12 ) 2 , -P(O)(R 13 )(OR 13 ), -B(OR 13 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC substituted by one or more R 5-c , C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 5-d , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5 -e , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5-f , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5-g , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-c、R5-d、R5-e、R5-f、R5-g、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；each of R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R12独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R12a取代；each R 12 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a ;

每个R12a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 12a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R13独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R13a取代；Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a ;

每个R13a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 6a ;

每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每一“杂环烷基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heterocycloalkyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

每一“杂环烯基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heterocycloalkenyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5;

每一“杂芳基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个。In each "heteroaryl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

在某一方案中，R1为氢、羟基、-N(R9)2或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R1a取代；In one embodiment, R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ;

每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基或-S-C1-6烷基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ;

每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;

R7为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ;

每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;

R4B为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基； each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;

每个R11独立地为氢或C1-6烷基；Each R 11 is independently hydrogen or C 1-6 alkyl;

每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5- k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5 -c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 2-6 alkynyl substituted by one or more R 5-j 6-10 membered aryl, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R 5- k ;

每个R5-a、R5-b、R5-c、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, —C(O)NH 2 , —O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or —OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;

每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ;

每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R1为氢、羟基、-N(R9)2或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R1a取代；In one embodiment, R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ;

每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基或-S-C1-6烷基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ;

每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基； Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;

R7为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ;

每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;

R4B为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;

每个R11独立地为氢或C1-6烷基；Each R 11 is independently hydrogen or C 1-6 alkyl;

每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5- k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5 -c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 2-6 alkynyl substituted by one or more R 5-j 6-10 membered aryl, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R 5- k ;

每个R5-a、R5-b、R5-c、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;

每个R13独立地为氢或C1-6烷基； Each R 13 is independently hydrogen or C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ;

每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R1为氢、羟基、-N(R9)2或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R1a取代；In one embodiment, R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ;

每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基或-S-C1-6烷基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ;

每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S;

R7为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ;

每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;

R4B为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基； each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;

每个R11独立地为氢或C1-6烷基；Each R 11 is independently hydrogen or C 1-6 alkyl;

每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5-c , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or substituted by one or more R 5-k substituted 5-10 membered heteroaryl;

每个R5-a、R5-b、R5-c、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ;

每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R1为氢或C1-6烷基；In one embodiment, R 1 is hydrogen or C 1-6 alkyl;

R2和R3各自独立地为氢、卤素、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基；R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ;

R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R8a取代； R 8 is hydrogen, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4a取代；每个R4a独立地为氘、卤素、-NH2或羟基；R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl;

R4B为氢、C1-6烷基或-N(R9)2，其中所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen, C 1-6 alkyl or -N(R 9 ) 2 , wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、-NH2或羟基；Each R 4b is independently deuterium, halogen, cyano, -NH 2 or hydroxyl;

每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;

每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基。Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R1为氢或C1-6烷基；In one embodiment, R 1 is hydrogen or C 1-6 alkyl;

R2和R3各自独立地为氢、卤素、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基；R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ;

R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立 地任选被一个或多个R8a取代；R 8 is hydrogen, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein the C 1-6 alkyl and -OC 1-6 alkyl are each independently is optionally substituted with one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4a取代；每个R4a独立地为氘、卤素、-NH2或羟基；R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl;

R4B为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ;

每个R4b独立地为氘、卤素、-NH2或羟基；Each R 4b is independently deuterium, halogen, -NH 2 or hydroxy;

每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;

每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基。Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R1为氢或C1-6烷基；In one embodiment, R 1 is hydrogen or C 1-6 alkyl;

R2和R3各自独立地为氢、卤素、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基；R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl;

Cy1为 Cy 1 is

X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ;

R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

R8为氢、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R8a取代； R 8 is hydrogen, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl;

R4A为氢、氘、卤素、羟基、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4a取代；每个R4a独立地为氘、卤素、-NH2或羟基；R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl;

R4B为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ;

每个R4b独立地为氘、卤素、-NH2或羟基；Each R 4b is independently deuterium, halogen, -NH 2 or hydroxy;

每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each of R 5-a , R 5-b , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基。Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R1为氢或C1-6烷基；In one embodiment, R 1 is hydrogen or C 1-6 alkyl;

R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl;

Cy1为 Cy 1 is

X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ;

R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；每个R7a独立地为卤素；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen;

R8为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为氢、-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen, -NH 2 or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;

每个R4b为氘或氰基； each R 4b is deuterium or cyano;

每个R5分别独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、-NH2或羟基。Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy.

在某一方案中，R1为氢或C1-6烷基；In one embodiment, R 1 is hydrogen or C 1-6 alkyl;

R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl;

Cy1为 Cy 1 is

X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ;

R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；每个R7a独立地为卤素；R 7 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen;

R8为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为氢或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;

每个R4b为氘；each R 4b is deuterium;

每个R5分别独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基； Each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、-NH2或羟基。Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy.

在某一方案中，R1为氢或C1-6烷基；In one embodiment, R 1 is hydrogen or C 1-6 alkyl;

R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl;

Cy1为 Cy 1 is

X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ;

R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；每个R7a独立地为卤素；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen;

R8为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;

R4A和R4B分别独立地为氢或C1-6烷基；R 4A and R 4B are each independently hydrogen or C 1-6 alkyl;

每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基或-O-C1-6烷基； Each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢、氘、卤素、-NH2或羟基。Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为氢、-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen, -NH 2 or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;

每个R4b为氘或氰基；each R 4b is deuterium or cyano;

每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;

每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为氢或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;

每个R4b为氘；each R 4b is deuterium;

每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;

每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen;

R4A和R4B分别独立地为氢或C1-6烷基；R 4A and R 4B are each independently hydrogen or C 1-6 alkyl;

每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C6-10芳基、被一个或多 个R5-j取代的C6-10芳基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-j和R5-k各自独立地为C1-6烷基或-O-C1-6烷基；Each R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基； R8 is C1-6 alkyl;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘或氰基；R 4B is -NH 2 or C 1-6 alkyl; the C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium or cyano;

每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;

每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3中，一个为氢，另一个为C1-6烷基； Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基； R8 is C1-6 alkyl;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium;

每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;

每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基； R8 is C1-6 alkyl;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为C1-6烷基；R 4B is C 1-6 alkyl;

每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C6-10芳基或被一个或多 个R5-k取代的5-10元杂芳基；Each of R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl or substituted by one or more R 5-k substituted 5-10 membered heteroaryl;

每个R5-k独立地为C1-6烷基；Each R 5-k is independently C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基； R8 is C1-6 alkyl;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium;

每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为氰基、卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;

每个R5-k和R5-j各自独立地为C1-6烷基、氰基、氘代C1-6烷基、-O-C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；Each R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl, -OC 1-6 alkyl, or -OC 1-6 alkyl substituted with one or more R 5b' ;

每个R5b’独立地为-O-C1-6烷基；Each R 5b' is independently -OC 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3中，一个为氢，另一个为C1-6烷基； Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基； R8 is C1-6 alkyl;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium;

每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为氰基、卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;

每个R5-k和R5-j各自独立地为C1-6烷基、氰基、氘代C1-6烷基或-O-C1-6烷基；Each of R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl or -OC 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基； R8 is C1-6 alkyl;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium;

每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;

每个R5-k和R5-j各自独立地为C1-6烷基或-O-C1-6烷基； Each R 5-k and R 5-j is independently C 1-6 alkyl or -OC 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢；In one embodiment, R 1 is hydrogen;

R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl;

Cy1为 Cy 1 is

X为S，Y为CR8；X is S, Y is CR 8 ;

R8为C1-6烷基； R8 is C1-6 alkyl;

R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl;

R4B为C1-6烷基；R 4B is C 1-6 alkyl;

每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5e和R5f各自独立地为卤素、C1-6烷基、-O-C1-6烷基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-k独立地为C1-6烷基；Each R 5-k is independently C 1-6 alkyl;

Cy2为 Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R1为氢、羟基、-N(R9)2或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R1a取代；In one embodiment, R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ;

每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基或-S-C1-6烷基各自独立地任选被一个或多个R2a取代；In a certain embodiment, R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ;

每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R7为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷 基各自独立地任选被一个或多个R7a取代；In one embodiment, R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein the C 1-6 alkyl and -OC 1-6 alkyl The groups are each independently optionally substituted with one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1- 6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R8a取代；In a certain embodiment, R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R4a取代；In a certain embodiment, R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ;

每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；每个R11独立地为氢或C1-6烷基。Each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; each R 11 is independently hydrogen or C 1-6 alkyl.

在某一方案中，R4B为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4b取代；In a certain embodiment, R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl;

每个R11独立地为氢或C1-6烷基。Each R 11 is independently hydrogen or C 1-6 alkyl.

在某一方案中，每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、-S(O)2R12、-S(O)2N(R13)2、-S(O)R12、-S(O)N(R13)2、-S(O)(NR13)OR13、-C(O)R12、-C(O)OR13、-C(O)N(R13)2、-C(O)N(R13)OR13、-OC(O)R12、-OC(O)N(R13)2、-N(R13)C(O)OR13、-N(R13)C(O)R12、-N(R13)C(O)N(R13)2、-N(R13)C(NR13)(R12)、-N(R13)C(NR13)N(R13)2、-N(R13)S(O)2N(R13)2、-N(R13)S(O)2R12、-P(O)(R12)2、-P(O)(R13)(OR13)、-B(OR13)2、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6烯基、被一个或多个R5-d取代的C2-6烯基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、C3-12环烷基、被一个或多个R5-f取代的C3-12环烷基、C3-12环烯基、被一个或多个R5-g取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)N(R 13 ) 2 , -N(R 13 )C(NR 13 )(R 12 ), -N(R 13 )C(NR 13 )N(R 13 ) 2 , -N(R 13 )S(O) 2 N(R 13 ) 2 , -N(R 13 )S(O) 2 R 12 , -P(O)(R 12 ) 2 , -P(O)(R 13 )(OR 13 ), -B(OR 13 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC substituted by one or more R 5-c , C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 5-d , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5 -e , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5-f , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5-g , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-c、R5-d、R5-e、R5-f、R5-g、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5 -d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl;

每个R12独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R12a取代；each R 12 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a ;

每个R12a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 12a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R13独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷 基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R13a取代；Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl R 13a, R 13b, R 14c , R 15d, R 16d, R 17d, R 18d, R 19d, R 20d, R 21d, R 22d, R 23d, R 24d, R 25d, R 26d, R 27d, R 28d, R 29d, R 30d, R 31d, R 32d, R 33d, R 34d, R 35d, R 36d, R 37d, R 38d, R 39d, R 40d, R 41d, R 42d, R 43d, R 44d, R 45d, R 46d, R 47d, R 48d, R 49d, R 50d, R 51d, R 52d, R 53d, R 5

每个R13a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5- k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5 -c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 2-6 alkynyl substituted by one or more R 5-j 6-10 membered aryl, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R 5- k ;

每个R5-a、R5-b、R5-c、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, —C(O)NH 2 , —O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or —OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;

每个R13独立地为氢或C1-6烷基。Each R 13 is independently hydrogen or C 1-6 alkyl.

在某一方案中，每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ;

每个R13独立地为氢或C1-6烷基。Each R 13 is independently hydrogen or C 1-6 alkyl.

在某一方案中，R4B为氢、C1-6烷基或-N(R9)2，其中所述C1-6烷基独立地任选被一个或多个R4b取代；In one embodiment, R 4B is hydrogen, C 1-6 alkyl or -N(R 9 ) 2 , wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ;

每个R4b独立地为氘、卤素、氰基、-NH2或羟基；each R 4b is independently deuterium, halogen, cyano, -NH 2 or hydroxyl;

每个R9独立地为氢或C1-6烷基。Each R 9 is independently hydrogen or C 1-6 alkyl.

在某一方案中，每个R5分别独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12 元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In one embodiment, each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 5-membered heterocycloalkyl, 3-12-membered heterocycloalkyl substituted by one or more R 5c , 3-12-membered heterocycloalkenyl, 3-12-membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10-membered heteroaryl, or 5-10-membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2。Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 .

在某一方案中，R4B为氢、-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；In one embodiment, R 4B is hydrogen, -NH 2 or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;

每个R4b为氘或氰基。Each R 4b is deuterium or cyano.

在某一方案中，每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;

每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2。Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 .

在某一方案中，R4B为-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘或氰基。In a certain embodiment, R 4B is -NH 2 or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted with one or more R 4b ; each R 4b is deuterium or cyano.

在某一方案中，每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;

每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ;

每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2。Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 .

在某一方案中，每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、 被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In one embodiment, each R 5 is independently C 3-12 cycloalkyl , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为氰基、卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;

每个R5-k和R5-j各自独立地为C1-6烷基、氰基、氘代C1-6烷基、-O-C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；Each R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl, -OC 1-6 alkyl, or -OC 1-6 alkyl substituted with one or more R 5b' ;

每个R5b’独立地为-O-C1-6烷基。Each R 5b' is independently -OC 1-6 alkyl.

在某一方案中，每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5-c , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or substituted by one or more R 5-k substituted 5-10 membered heteroaryl;

每个R5-a、R5-b、R5-c、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl;

每个R13独立地为氢或C1-6烷基。Each R 13 is independently hydrogen or C 1-6 alkyl.

在某一方案中，Cy2为 In one embodiment, Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ;

每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R1为氢或C1-6烷基。In one embodiment, R 1 is hydrogen or C 1-6 alkyl.

在某一方案中，R2和R3各自独立地为氢、卤素、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基。In one embodiment, R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，X为NR7、N、O或S，Y为CR8。In one embodiment, X is NR 7 , N, O or S, and Y is CR 8 .

在某一方案中，R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代； In one embodiment, R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 7a ;

每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R8为氢、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R8a取代；In a certain embodiment, R 8 is hydrogen, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 8a ;

每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R4A为氢、氘、卤素、羟基、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1- 6烷基各自独立地任选被一个或多个R4a取代；每个R4a独立地为氘、卤素、-NH2或羟基。In a certain embodiment, R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl.

在某一方案中，R4B为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b独立地为氘、卤素、-NH2或羟基。In a certain embodiment, R 4B is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ; each R 4b is independently deuterium, halogen, -NH 2 or hydroxyl.

在某一方案中，每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each of R 5-a , R 5-b , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl;

每个R13独立地为氢或C1-6烷基。Each R 13 is independently hydrogen or C 1-6 alkyl.

在某一方案中，Cy2为 In one embodiment, Cy 2 is

每个R6独立地为氢、氘、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基。Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，R2和R3各自独立地为氢或C1-6烷基。In one embodiment, R2 and R3 are each independently hydrogen or C1-6 alkyl.

在某一方案中，R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；每个R7a独立地为卤素。In a certain embodiment, R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 7a ; each R 7a is independently halogen.

在某一方案中，R8为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素。In a certain embodiment, R 8 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 8a ; each R 8a is independently halogen.

在某一方案中，R4A为氢或C1-6烷基。In one embodiment, R 4A is hydrogen or C 1-6 alkyl.

在某一方案中，R4B为氢或C1-6烷基。In one embodiment, R 4B is hydrogen or C 1-6 alkyl.

在某一方案中，每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环 烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-i alkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基或-O-C1-6烷基。Each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，Cy2为 In one embodiment, Cy 2 is

每个R6独立地为氢、氘、卤素、-NH2或羟基。Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy.

在某一方案中，R1为氢。In one embodiment, R1 is hydrogen.

在某一方案中，X为S，Y为CR8。In one embodiment, X is S and Y is CR 8 .

在某一方案中，R8为C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素。In a certain embodiment, R 8 is C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 8a ; each R 8a is independently halogen.

在某一方案中，每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-j和R5-k各自独立地为C1-6烷基或-O-C1-6烷基。Each of R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，Cy2为 In one embodiment, Cy 2 is

每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen.

在某一方案中，R2和R3中，一个为H，另一个为C1-6烷基。In one embodiment, of R2 and R3 , one is H and the other is C1-6 alkyl.

在某一方案中，R8为C1-6烷基。In one embodiment, R 8 is C 1-6 alkyl.

在某一方案中，R4B为C1-6烷基。In one embodiment, R 4B is C 1-6 alkyl.

在某一方案中，每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C6-10芳基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-k独立地为C1-6烷基。Each R 5-k is independently a C 1-6 alkyl group.

在某一方案中，每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个 R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or substituted by one or more R 5f substituted 5-10 membered heteroaryl;

每个R5c、R5e和R5f各自独立地为卤素、C1-6烷基、-O-C1-6烷基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-k独立地为C1-6烷基。Each R 5-k is independently a C 1-6 alkyl group.

在某一方案中，每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、-S(O)2R12、-S(O)2N(R13)2、-S(O)R12、-S(O)N(R13)2、-S(O)(NR13)OR13、-C(O)R12、-C(O)OR13、-C(O)N(R13)2、-C(O)N(R13)OR13、-OC(O)R12、-OC(O)N(R13)2、-N(R13)C(O)OR13、-N(R13)C(O)R12、-N(R13)C(O)N(R13)2、-N(R13)C(NR13)(R12)、-N(R13)C(NR13)N(R13)2、-N(R13)S(O)2N(R13)2、-N(R13)S(O)2R12、-P(O)(R12)2、-P(O)(R13)(OR13)、-B(OR13)2、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6烯基、被一个或多个R5-d取代的C2-6烯基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、C3-12环烷基、被一个或多个R5-f取代的C3-12环烷基、C3-12环烯基、被一个或多个R5-g取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)N(R 13 ) 2 , -N(R 13 )C(NR 13 )(R 12 ), -N(R 13 )C(NR 13 )N(R 13 ) 2 , -N(R 13 )S(O) 2 N(R 13 ) 2 , -N(R 13 )S(O) 2 R 12 , -P(O)(R 12 ) 2 , -P(O)(R 13 )(OR 13 ), -B(OR 13 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC substituted by one or more R 5-c , C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 5-d , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5 -e , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5-f , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5-g , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-c、R5-d、R5-e、R5-f、R5-g、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基。Each of R5 -a , R5 -b , R5 -c , R5 -d , R5 -e , R5 -f , R5 -g , R5 -h , R5 -i , R5 -j and R5 -k is independently deuterium, halogen, cyano, -NH2 , hydroxyl, C1-6 alkyl or -OC1-6 alkyl.

在某一方案中，每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5- k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5 -c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 2-6 alkynyl substituted by one or more R 5-j 6-10 membered aryl, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R 5- k ;

每个R5-a、R5-b、R5-c、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基。Each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)—C 1-6 alkyl or deuterated C 1-6 alkyl.

在某一方案中，每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代 的5-10元杂芳基；In a certain embodiment, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or substituted by one or more R 5f A 5-10 membered heteroaryl group;

每个R5a、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-a、R5-b、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基。Each of R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently —NH 2 , hydroxy, C 1-6 alkyl, —OC 1-6 alkyl, cyano, —N(C 1-6 alkyl) 2 , —C(O)—C 1-6 alkyl or deuterated C 1-6 alkyl.

在某一方案中，每个R5分别独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ;

每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基。Each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, —OC 1-6 alkyl, cyano, —N(C 1-6 alkyl) 2 , —C(O)—C 1-6 alkyl or deuterated C 1-6 alkyl.

在某一方案中，R4B为氢或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；In one embodiment, R 4B is hydrogen or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ;

每个R4b为氘。Each R 4b is deuterium.

在某一方案中，每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ;

每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基。Each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, —OC 1-6 alkyl, cyano, —N(C 1-6 alkyl) 2 , —C(O)—C 1-6 alkyl or deuterated C 1-6 alkyl.

在某一方案中，R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘。In a certain embodiment, R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted with one or more R 4b ; each R 4b is deuterium.

在某一方案中，每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为氰基、卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;

每个R5-k和R5-j各自独立地为C1-6烷基、氰基、氘代C1-6烷基或-O-C1-6烷基。 Each of R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；In a certain embodiment, each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ;

每个R5a、R5c、R5e和R5f各自独立地为卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ;

每个R5-k和R5-j各自独立地为C1-6烷基或-O-C1-6烷基。Each of R 5-k and R 5-j is independently C 1-6 alkyl or -OC 1-6 alkyl.

在某一方案中，所述如式I所示的化合物为如下式(I-A)～(I-D)任一所示化合物：
In one embodiment, the compound as shown in formula I is a compound shown in any one of the following formulas (IA) to (ID):

在某一方案中，所述如式I所示的化合物为如下式(I-E)～(I-H)任一所示化合物：
In one embodiment, the compound shown in formula I is a compound shown in any one of the following formulas (IE) to (IH):

在某一方案中，各所述“C1-6烷基”分别独立地为C1-4烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基。In one embodiment, each of the "C 1-6 alkyl groups" is independently a C 1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

在某一方案中，各所述“C2-6炔基”分别独立地为C2-4炔基，例如乙炔基、丙炔基或炔丙基，优选为乙炔基。In a certain embodiment, each of the "C 2-6 alkynyl" is independently a C 2-4 alkynyl, such as ethynyl, propynyl or propargyl, preferably ethynyl.

在某一方案中，各所述“C2-6烯基”分别独立地为乙烯基、1-丙烯基、正烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基或戊-1,4-二烯基。In a certain embodiment, each of the "C 2-6 alkenyl groups" is independently vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl or pent-1,4-dienyl.

在某一方案中，各所述“C3-12环烷基”分别独立地为C3-6环烷基，例如环丙基、环丁基、环戊基或环己基。In a certain embodiment, each of the "C 3-12 cycloalkyl" is independently a C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

在某一方案中，各所述“C3-12环烷基”分别独立地为C3-6单环环烷基(例如环丙基、环丁基、环戊基或环己基)或C4-10桥环环烷基(例如)。In one embodiment, each of the "C 3-12 cycloalkyl" is independently a C 3-6 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or a C 4-10 bridged ring cycloalkyl (e.g., ).

在某一方案中，各所述“C3-12环烷基”分别独立地为C3-6单环环烷基(例如环丙基、环丁基、环 戊基或环己基)或C4-10桥环环烷基(例如又例如)。In one embodiment, each of the "C 3-12 cycloalkyl" is independently a C 3-6 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclo pentyl or cyclohexyl) or C 4-10 bridged ring cycloalkyl (e.g. Another example ).

在某一方案中，各所述“C3-12环烯基”分别独立地为C3-6环烯基，例如环丙烯基、环丁烯基、环戊烯基或环己烯基。In a certain embodiment, each of the "C 3-12 cycloalkenyl groups" is independently a C 3-6 cycloalkenyl group, such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.

在某一方案中，各所述“3-12元杂环烷基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数独立地为1个、2个或3个的3-12元杂环烷基，优选为4-6元单环杂环烷基(例如吗啉基、哌啶基、哌嗪基、四氢吡喃基、四氢吡咯基、氧杂环丁烷基或氮杂环丁烷基，又例如)或7-10元螺环杂环烷基(例如6-氮杂螺[2.5]辛烷基或2-氮杂螺[3.3]庚烷基，又例如还例如)。In a certain embodiment, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, and for example ) or 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example For example ).

在某一方案中，各所述“3-12元杂环烷基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数独立地为1个、2个或3个的3-12元杂环烷基，优选为4-6元单环杂环烷基(例如吗啉基、哌啶基、哌嗪基、四氢吡喃基、四氢吡咯基、氧杂环丁烷基或氮杂环丁烷基，又例如)或7-10元螺环杂环烷基(例如6-氮杂螺[2.5]辛烷基或2-氮杂螺[3.3]庚烷基，又例如还例如 )。In a certain embodiment, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, and for example ) or 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example For example ).

在某一方案中，各所述“3-12元杂环烷基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数独立地为1个、2个或3个的3-12元杂环烷基，优选为4-6元单环杂环烷基(例如吗啉基、哌啶基、哌嗪基、四氢吡喃基、四氢吡咯基、氧杂环丁烷基或氮杂环丁烷基，又例如)、7-10元螺环杂环烷基(例如6-氮杂螺[2.5]辛烷基或2-氮杂螺[3.3]庚烷基，又例如)或7-10 元桥环杂环烷基(例如8-氮杂双环[3.2.1]辛烷基或2-氧杂双环[2.2.2]辛烷基，又例如 )。In a certain embodiment, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, and for example ), 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example ) or 7-10 2-oxabicyclo[2.2.2]octyl, 8-azabicyclo[3.2.1]octyl, 2-oxabicyclo[2.2.2]octyl, 2-oxa ... ).

在某一方案中，各所述“3-12元杂环烷基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数独立地为1个、2个或3个的3-12元杂环烷基，优选为4-6元单环杂环烷基(例如吗啉基、哌啶基、哌嗪基、四氢吡喃基、四氢吡咯基、氧杂环丁烷基或氮杂环丁烷基，又例如)、7-10元螺环杂环烷基(例如6-氮杂螺[2.5]辛烷基或2-氮杂螺[3.3]庚烷基，又例如)或7-10元桥环杂环烷基(例如8-氮杂双环[3.2.1]辛烷基，又例如)。In a certain embodiment, each of the "3-12 membered heterocycloalkyl" is independently a 3-12 membered heterocycloalkyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl group (for example, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, and for example ), 7-10 membered spirocyclic heterocycloalkyl (e.g. 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example ) or 7-10 membered bridged heterocycloalkyl (e.g. 8-azabicyclo[3.2.1]octanyl, for example ).

在某一方案中，各所述“3-12元杂环烯基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个或3个的3-12元杂环烯基，优选为5-6元单环杂环烯基，例如(1,2,3,6-四氢吡啶基)，又例如 In a certain embodiment, each of the "3-12 membered heterocycloalkenyl" is independently a 3-12 membered heterocycloalkenyl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heterocycloalkenyl group, for example (1,2,3,6-tetrahydropyridinyl), for example

在某一方案中，各所述“C6-10芳基”分别独立地为苯基或萘基，优选苯基。In a certain embodiment, each of the "C 6-10 aryl groups" is independently phenyl or naphthyl, preferably phenyl.

在某一方案中，各所述“5-10元杂芳基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个或3个的5-10元杂芳基，优选为5-6元单环杂芳基(例如吡啶基、嘧啶基、吡唑基、噻吩基或吡咯基，又例如)或9-10元并环杂芳基(例如喹啉基、喹唑啉基、吲哚基、1H-吡咯并[2,3-b]吡啶基、吲唑基、1H-吡唑并[4,3-b]吡啶基、异吲哚啉基或1,2,3,4-四氢异喹啉基，又例如 还例如 )。In a certain embodiment, each of the "5-10 membered heteroaryl" is independently a 5-10 membered heteroaryl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl or pyrrolyl, for example ) or a 9-10 membered heteroaryl ring (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl or 1,2,3,4-tetrahydroisoquinolinyl, for example For example ).

在某一方案中，各所述“5-10元杂芳基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个或3个的5-10元杂芳基，优选为5-6元单环杂芳基(例如吡啶基、嘧啶基、吡唑基、噻吩基、1,2,4-恶二唑基、吡嗪基、哒嗪基或吡咯基，又例如)或9-10元并环杂芳基(例如喹啉基、喹唑啉基、吲哚基、1H-吡咯并[2,3-b]吡啶基、苯并[d][1,3]二氧杂环戊烯基、咪唑并[1,2-b]哒嗪基、吲唑基、1H-吡唑并[4,3-b]吡啶基、异吲哚啉基或1,2,3,4-四氢异喹啉基，又例如 还例如 )。In a certain embodiment, each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl or pyrrolyl, for example ) or a 9-10 membered heteroaryl ring (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl or 1,2,3,4-tetrahydroisoquinolinyl, for example For example ).

在某一方案中，各所述“5-10元杂芳基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个或4个的5-10元杂芳基，优选为5-6元单环杂芳基(例如1H-四唑基、2H-四唑基、吡啶基、嘧啶基、吡唑基、噻吩基、1,2,4-恶二唑基、 吡嗪基、哒嗪基、1,2,3-三唑基、1,3,4-噻二唑基、1,3,4-恶二唑基或吡咯基，又例如 )或9-10元并环杂芳基(例如喹啉基、喹唑啉基、吲哚基、1H-吡咯并[2,3-b]吡啶基、苯并[d][1,3]二氧杂环戊烯基、咪唑并[1,2-b]哒嗪基、吲唑基、1H-吡唑并[4,3-b]吡啶基、异吲哚啉基、[1,2,4]三唑并[4,3-b]哒嗪基或1,2,3,4-四氢异喹啉基，又例如 )。In a certain embodiment, each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group whose heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group (e.g., 1H-tetrazolyl, 2H-tetrazolyl, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or pyrrolyl, for example ) or a 9-10 membered heteroaryl ring (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl or 1,2,3,4-tetrahydroisoquinolinyl, for example ).

在某一方案中，各所述“5-10元杂芳基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个或4个的5-10元杂芳基，优选为5-6元单环杂芳基(例如吡啶基、嘧啶基、吡唑基、噻吩基、1,2,4-恶二唑基、吡嗪基、哒嗪基、1,2,3-三唑基、1,3,4-噻二唑基、1,3,4-恶二唑基或吡咯基，又例如 )或9-10元并环杂芳基(例如喹啉基、喹唑啉基、吲哚基、1H-吡咯并[2,3-b]吡啶基、 苯并[d][1,3]二氧杂环戊烯基、咪唑并[1,2-b]哒嗪基、吲唑基、1H-吡唑并[4,3-b]吡啶基、异吲哚啉基、[1,2,4]三唑并[4,3-b]哒嗪基或1,2,3,4-四氢异喹啉基，又例如 )。In a certain embodiment, each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group whose heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group (for example, pyridyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or pyrrolyl, for example ) or 9-10 membered heteroaryl (e.g., quinolinyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl or 1,2,3,4-tetrahydroisoquinolyl, for example ).

在某一方案中，各所述“卤素”分别独立地为氟、氯、溴或碘，优选氟或氯。In one embodiment, each of the "halogen" is independently fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

在某一方案中，各所述“氘代C1-6烷基”分别独立地为氘代甲烷或氘代乙烷，例如-CD3。In one embodiment, each of the "deuterated C 1-6 alkyl" is independently deuterated methane or deuterated ethane, for example -CD 3 .

在某一方案中，各所述“-O-C1-6烷基”分别独立地为-O-C1-4烷基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基或乙氧基，更优选甲氧基。In one embodiment, each of the "-OC 1-6 alkyl" is independently -OC 1-4 alkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy, more preferably methoxy.

在某一方案中，所述如式I所示的化合物还不为以下化合物：
In a certain embodiment, the compound as shown in Formula I is not the following compound:

在某一方案中，R2和R3中，一个为H，另一个为甲基。In one embodiment, R2 and R3 , one is H and the other is methyl.

在某一方案中，X为S，Y为CCH3或CCF3。In one embodiment, X is S, and Y is CCH 3 or CCF 3 .

在某一方案中，R4A为氢或甲基。In one embodiment, R 4A is hydrogen or methyl.

在某一方案中，R4B为甲基、氨基、-CH2CN或-CD3。In one embodiment, R 4B is methyl, amino, -CH 2 CN or -CD 3 .

在某一方案中，R4B为甲基或-CD3。In one embodiment, R 4B is methyl or -CD 3 .

在某一方案中，R4B为甲基。In one embodiment, R 4B is methyl.

在某一方案中，每个R5独立地为苯基、

In one embodiment, each R 5 is independently phenyl,

在某一方案中，每个R5独立地为苯基、
In one embodiment, each R 5 is independently phenyl,

在某一方案中，每个R5独立地为苯基、 In one embodiment, each R 5 is independently phenyl,

在某一方案中，每个R5独立地为苯基、 In one embodiment, each R 5 is independently phenyl,

在某一方案中，Cy1为



In one embodiment, Cy 1 is



在某一方案中，Cy1为


In one embodiment, Cy 1 is


在某一方案中，Cy1为

In one embodiment, Cy 1 is

在某一方案中，Cy1为
In one embodiment, Cy 1 is

在某一方案中，Cy2为 In one embodiment, Cy 2 is

在某一方案中，所述如式I所示的化合物为如下任一化合物：





In one embodiment, the compound as shown in formula I is any of the following compounds:





在一些实施方式中，所述如式I所示的化合物含有或不含有手性中心，当含有手性中心时，所述如式I所示的化合物为各立体异构体或其混合物，例如，当含有1个手性中心时，所述如式I所示的化合物为R构型、S构型或R、S构型外消旋体。In some embodiments, the compound as shown in Formula I contains or does not contain a chiral center. When it contains a chiral center, the compound as shown in Formula I is a stereoisomer or a mixture thereof. For example, when it contains 1 chiral center, the compound as shown in Formula I is an R configuration, an S configuration, or an R, S configuration racemate.

在一些实施方式中，所述如式I所示的化合物为如下任一化合物：


In some embodiments, the compound as shown in Formula I is any of the following compounds:


在一些实施方式中，所述如式I所示的化合物为如下任一化合物：In some embodiments, the compound as shown in Formula I is any of the following compounds:

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝40/60；流速:100mL/min；检测波长:214nm； The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /methanol=40/60; Flow rate: 100 mL/min; Detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝40/60；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /methanol=40/60; Flow rate: 100 mL/min; Detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[甲醇:乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO 2 /[methanol:acetonitrile=1:1]=50/50; flow rate: 100 mL/min; detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝50/50；流速:100mL/min；检测波长:214nm； The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /methanol=50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /methanol=50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm;

在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝50/50；流速:100mL/min；检测波长:214nm。The compound that eluted later under the following conditions was The following table describes the method for detecting one stereoisomer in the chromatogram: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35° C.; mobile phase: CO 2 /methanol=50/50; flow rate: 100 mL/min; detection wavelength: 214 nm.

本发明还提供了一种上述如式I所示的化合物的制备方法，其为如下任一路线：The present invention also provides a method for preparing the compound as shown in Formula I, which is any of the following routes:

路线一：
Route 1:

步骤1：在碱性或中性条件下，在缩合试剂存在下进行缩合反应，所述缩合反应的操作条件可为本领域该类反应的常规操作和条件，所述缩合试剂可为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)或1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)；Step 1: Under alkaline or neutral conditions, a condensation reaction is carried out in the presence of a condensation reagent. The operating conditions of the condensation reaction may be conventional operations and conditions for such reactions in the art. The condensation reagent may be 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI);

步骤2：在碱存在下进行转位反应，所述转位反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为钠氢或双三甲基硅基胺基锂(LiHMDS)；Step 2: performing a transposition reaction in the presence of a base, wherein the operating conditions of the transposition reaction may be conventional operations and conditions of such reactions in the art, and the base may be sodium hydrogen or lithium bis(trimethylsilyl)amide (LiHMDS);

步骤3：在酸存在下进行关环反应，所述关环反应的操作条件可为本领域该类反应的常规操作和条件，所述酸可为硫酸或氢溴酸；Step 3: performing a ring-closing reaction in the presence of an acid, wherein the operating conditions of the ring-closing reaction may be conventional operations and conditions of such reactions in the art, and the acid may be sulfuric acid or hydrobromic acid;

步骤4：在钯催化剂存在下的偶联反应，所述偶联反应的操作条件可为本领域该类反应的常规操作和条件，所述钯催化剂可为四三苯基膦钯或二三苯基膦氯化钯；Step 4: a coupling reaction in the presence of a palladium catalyst, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium catalyst may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;

步骤5：在还原剂存在下进行羰基还原反应，所述还原反应的操作条件可为本领域该类反应的常 规操作和条件，所述还原剂可为硼氢化钠或氰基硼氢化钠；Step 5: Carry out carbonyl reduction reaction in the presence of a reducing agent. The operating conditions of the reduction reaction may be conventional conditions for such reactions in the art. The reducing agent may be sodium borohydride or sodium cyanoborohydride;

步骤6：在氯代试剂存在下进行氯代反应，所述氯代反应的操作条件可为本领域该类反应的常规操作和条件，所述氯代试剂可为三氯氧磷或二氯亚砜；Step 6: performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;

步骤7：在碱存在下进行亲核取代，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为二异丙基乙胺(DIPEA)或碳酸钠；Step 7: performing nucleophilic substitution in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions for such reactions in the art, and the base may be diisopropylethylamine (DIPEA) or sodium carbonate;

步骤8：在碱存在下进行酯水解反应，所述酯水解反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为氢氧化钠或氢氧化锂；Step 8: performing an ester hydrolysis reaction in the presence of a base. The operating conditions of the ester hydrolysis reaction may be conventional operations and conditions of this type of reaction in the art. The base may be sodium hydroxide or lithium hydroxide.

路线二：
Route 2:

步骤1：在碱存在下进行羟醛反应，所述羟醛反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为氢氧化钾或二异丙基氨基锂(LDA)；Step 1: performing an aldol reaction in the presence of a base, wherein the operating conditions of the aldol reaction may be conventional operations and conditions of such reactions in the art, and the base may be potassium hydroxide or lithium diisopropylamide (LDA);

步骤2：在氧化剂存在下进行羟基氧化反应，所述氧化反应的操作条件可为本领域该类反应的常规操作和条件，所述氧化剂可为Dess-Martin氧化剂或二氧化锰；Step 2: performing a hydroxyl oxidation reaction in the presence of an oxidant, wherein the operating conditions of the oxidation reaction may be conventional operations and conditions of such reactions in the art, and the oxidant may be a Dess-Martin oxidant or manganese dioxide;

步骤3：在酸存在下进行脱甲基及关环反应，所述反应的操作条件可为本领域该类反应的常规操作和条件，所述酸可为氢溴酸醋酸溶液或氢溴酸水溶液；Step 3: performing demethylation and ring-closing reactions in the presence of an acid, wherein the operating conditions of the reaction may be conventional operations and conditions of such reactions in the art, and the acid may be a hydrobromic acid acetic acid solution or a hydrobromic acid aqueous solution;

步骤4：在钯试剂存在下进行偶联反应，所述偶联反应的操作条件可为本领域该类反应的常规操作和条件，所述钯试剂可为四三苯基膦钯或二三苯基膦氯化钯；Step 4: performing a coupling reaction in the presence of a palladium reagent, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;

步骤5：在还原剂存在下进行羰基还原反应，所述还原反应的操作条件可为本领域该类反应的常规操作和条件，所述还原剂可为硼氢化钠或氰基硼氢化钠；Step 5: performing a carbonyl reduction reaction in the presence of a reducing agent, wherein the operating conditions of the reduction reaction may be conventional operations and conditions of such reactions in the art, and the reducing agent may be sodium borohydride or sodium cyanoborohydride;

步骤6：在氯代试剂存在下进行氯代反应，所述氯代反应的操作条件可为本领域该类反应的常规操作和条件，所述氯代试剂可为三氯氧磷或二氯亚砜；Step 6: performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;

步骤7：在碱存在下进行亲核取代，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为DIPEA或碳酸钠；Step 7: performing nucleophilic substitution in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or sodium carbonate;

步骤8：在碱存在下进行酯水解反应，所述水解反应的操作条件可为本领域该类反应的常规操作和条件，所述碱为氢氧化钠或氢氧化锂； Step 8: performing an ester hydrolysis reaction in the presence of a base, wherein the operating conditions of the hydrolysis reaction may be conventional operations and conditions of such reactions in the art, and the base may be sodium hydroxide or lithium hydroxide;

路线三：
Route 3:

其中P1为羟基保护基，例如Boc、PMB、Bn或Cbz；Wherein P 1 is a hydroxyl protecting group, such as Boc, PMB, Bn or Cbz;

步骤1：在碱存在下进行亲核取代反应，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为碳酸钾或碳酸钠；Step 1: performing a nucleophilic substitution reaction in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be potassium carbonate or sodium carbonate;

步骤2：在碱存在下进行酯水解反应，所述水解反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为氢氧化钠或氢氧化锂；Step 2: performing an ester hydrolysis reaction in the presence of a base, wherein the operating conditions of the hydrolysis reaction may be conventional operations and conditions of such reactions in the art, and the base may be sodium hydroxide or lithium hydroxide;

步骤3：在缩合剂存在下进行酸胺缩合反应，所述缩合反应的操作条件可为本领域该类反应的常规操作和条件，所述缩合剂可为HATU或EDCI；Step 3: carrying out an acid-amine condensation reaction in the presence of a condensing agent, wherein the operating conditions of the condensation reaction may be conventional operations and conditions of such reactions in the art, and the condensing agent may be HATU or EDCI;

步骤4：在碱存在下进行亲核取代反应，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为LDA或LiHMDS；Step 4: performing a nucleophilic substitution reaction in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be LDA or LiHMDS;

步骤5：在脱保护试剂存在下进行脱保护反应，所述脱保护反应的操作条件可为本领域该类反应的常规操作和条件，所述脱保护试剂可为三氟醋酸或氯化氢；Step 5: performing a deprotection reaction in the presence of a deprotection reagent, wherein the operating conditions of the deprotection reaction may be conventional operations and conditions of such reactions in the art, and the deprotection reagent may be trifluoroacetic acid or hydrogen chloride;

步骤6：在环化试剂存在下进行环化反应，所述环化反应的操作条件可为本领域该类反应的常规操作和条件，所述环化试剂可为三氟甲磺酸酐或甲磺酸酐；Step 6: performing a cyclization reaction in the presence of a cyclization reagent, wherein the operating conditions of the cyclization reaction may be conventional operations and conditions of such reactions in the art, and the cyclization reagent may be trifluoromethanesulfonic anhydride or methanesulfonic anhydride;

步骤7：在钯试剂存在下进行偶联反应，所述偶联反应的操作条件可为本领域该类反应的常规操作和条件，所述钯试剂可为四三苯基膦钯或二三苯基膦氯化钯；Step 7: performing a coupling reaction in the presence of a palladium reagent, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;

步骤8：在还原剂存在下进行羰基还原反应，所述还原反应的操作条件可为本领域该类反应的常规操作和条件，所述还原剂可为硼氢化钠或氰基硼氢化钠；Step 8: performing a carbonyl reduction reaction in the presence of a reducing agent, wherein the operating conditions of the reduction reaction may be conventional operations and conditions of such reactions in the art, and the reducing agent may be sodium borohydride or sodium cyanoborohydride;

步骤9：在氯代试剂存在下进行氯代反应，所述氯代反应的操作条件可为本领域该类反应的常规操作和条件，所述氯代试剂可为三氯氧磷或二氯亚砜；Step 9: performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;

步骤10：在碱存在下进行亲核取代反应，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为DIPEA或碳酸钠；Step 10: performing a nucleophilic substitution reaction in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or sodium carbonate;

步骤11：在碱存在下进行酯水解反应，所述水解反应的操作条件可为本领域该类反应的常规操作 和条件，所述碱可为氢氧化钠或氢氧化锂；Step 11: Carry out ester hydrolysis reaction in the presence of a base. The operating conditions of the hydrolysis reaction can be conventional operations of this type of reaction in the art. and conditions, the base can be sodium hydroxide or lithium hydroxide;

路线四：
Route 4:

步骤1：在卤代试剂存在下进行卤代反应，所述卤代反应的操作条件可为本领域该类反应的常规操作和条件，所述卤代试剂可为液溴或N-溴代丁二酰亚胺(NBS)；Step 1: performing a halogenation reaction in the presence of a halogenation reagent, wherein the operating conditions of the halogenation reaction may be conventional operations and conditions of such reactions in the art, and the halogenation reagent may be liquid bromine or N-bromosuccinimide (NBS);

步骤2：在碱存在下进行脲合成反应，所述脲合成反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为DIPEA或碳酸钾；Step 2: performing a urea synthesis reaction in the presence of a base, wherein the operating conditions of the urea synthesis reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or potassium carbonate;

步骤3：在碱存在下进行关环反应，所述关环反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为甲醇钠或叔丁醇钾；Step 3: performing a ring-closing reaction in the presence of a base, wherein the operating conditions of the ring-closing reaction may be conventional operations and conditions of such reactions in the art, and the base may be sodium methoxide or potassium tert-butoxide;

步骤4：在缩合剂存在下进行亲核取代反应，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述缩合剂可为三吡咯烷基溴化鏻六氟磷酸盐(Pybrop)或1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(Pybop)；Step 4: carrying out a nucleophilic substitution reaction in the presence of a condensing agent, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the condensing agent may be tripyrrolidinophosphonium bromide hexafluorophosphate (Pybrop) or 1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (Pybop);

步骤5：在钯试剂存在下进行偶联反应，所述偶联反应的操作条件可为本领域该类反应的常规操作和条件，所述钯试剂可为四三苯基膦钯或二三苯基膦氯化钯；Step 5: performing a coupling reaction in the presence of a palladium reagent, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;

步骤6：在还原剂存在下进行羰基还原反应，所述还原反应的操作条件可为本领域该类反应的常规操作和条件，所述还原剂可为硼氢化钠或氰基硼氢化钠；Step 6: performing a carbonyl reduction reaction in the presence of a reducing agent, wherein the operating conditions of the reduction reaction may be conventional operations and conditions of such reactions in the art, and the reducing agent may be sodium borohydride or sodium cyanoborohydride;

步骤7：在氯代试剂存在下进行氯代反应，所述氯代反应的操作条件可为本领域该类反应的常规操作和条件，所述氯代试剂可为三氯氧磷或二氯亚砜；Step 7: performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;

步骤8：在碱存在下进行亲核取代反应，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为DIPEA或碳酸钾；Step 8: performing a nucleophilic substitution reaction in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or potassium carbonate;

步骤9：在碱存在下进行酯水解反应，所述水解反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为氢氧化钠或氢氧化锂；Step 9: performing an ester hydrolysis reaction in the presence of a base. The operating conditions of the hydrolysis reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium hydroxide or lithium hydroxide.

路线五：
Route 5:

步骤1：在水解试剂存在下进行酯水解反应，所述酯水解反应的操作条件可为本领域该类反应的常规操作和条件，所述水解试剂可为氢氧化钠或氢氧化锂；Step 1: performing an ester hydrolysis reaction in the presence of a hydrolysis agent, wherein the operating conditions of the ester hydrolysis reaction may be conventional operations and conditions of such reactions in the art, and the hydrolysis agent may be sodium hydroxide or lithium hydroxide;

步骤2：在缩合剂存在下进行酸胺缩合反应,所述酸胺缩合反应的操作条件可为本领域该类反应的常规操作和条件，所述缩合剂可为HATU或EDCI；Step 2: carrying out an acid-amine condensation reaction in the presence of a condensing agent, wherein the operating conditions of the acid-amine condensation reaction may be conventional operations and conditions of such reactions in the art, and the condensing agent may be HATU or EDCI;

步骤3：在氧化剂存在下进行环化反应，所述环化反应的操作条件可为本领域该类反应的常规操作和条件，所述氧化剂为碘或2,3-二氯-5,6-二氰基苯醌(DDQ)；Step 3: performing a cyclization reaction in the presence of an oxidant, wherein the operating conditions of the cyclization reaction may be conventional operations and conditions for such reactions in the art, and the oxidant may be iodine or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ);

步骤4：在钯试剂存在下进行偶联反应，所述偶联反应的操作条件可为本领域该类反应的常规操作和条件，所述钯试剂可为四三苯基膦钯或二三苯基膦氯化钯；Step 4: performing a coupling reaction in the presence of a palladium reagent, wherein the operating conditions of the coupling reaction may be conventional operations and conditions of such reactions in the art, and the palladium reagent may be tetrakistriphenylphosphine palladium or ditriphenylphosphine palladium chloride;

步骤5：在还原剂存在下进行羰基还原反应，所述还原反应的操作条件可为本领域该类反应的常规操作和条件，所述还原剂可为硼氢化钠或氰基硼氢化钠；Step 5: performing a carbonyl reduction reaction in the presence of a reducing agent, wherein the operating conditions of the reduction reaction may be conventional operations and conditions of such reactions in the art, and the reducing agent may be sodium borohydride or sodium cyanoborohydride;

步骤6：在氯代试剂存在下进行氯代反应，所述氯代反应的操作条件可为本领域该类反应的常规操作和条件，所述氯代试剂可为三氯氧磷或二氯亚砜；Step 6: performing a chlorination reaction in the presence of a chlorination agent, wherein the operating conditions of the chlorination reaction may be conventional operations and conditions of such reactions in the art, and the chlorination agent may be phosphorus oxychloride or thionyl chloride;

步骤7：在碱存在下进行亲核取代，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为DIPEA或碳酸钾；Step 7: performing nucleophilic substitution in the presence of a base, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the base may be DIPEA or potassium carbonate;

步骤8：在碱存在下进行酯水解反应，所述水解反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为氢氧化钠或氢氧化锂。Step 8: Carry out ester hydrolysis reaction in the presence of a base. The operating conditions of the hydrolysis reaction may be conventional operations and conditions for such reactions in the art. The base may be sodium hydroxide or lithium hydroxide.

本发明还提供了如下式(I-1)～(I-4)任一项所示的化合物：
The present invention also provides a compound represented by any one of the following formulas (I-1) to (I-4):

其中，R4A、R4B、X、Y如上所定义；wherein R 4A , R 4B , X, and Y are as defined above;

优选地，各R4A可独立地为H或甲基；R4B可为甲基；X可为S；Y可为CR8(例如CCH3)； Preferably, each R 4A may be independently H or methyl; R 4B may be methyl; X may be S; Y may be CR 8 (eg, CCH 3 );

进一步优选地，所述如式I-1所示的化合物为所述如式I-2所示的化合物为所述如式I-3所示的化合物为所述如式I-4所示的化合物为 More preferably, the compound as shown in formula I-1 is The compound shown in formula I-2 is The compound shown in formula I-3 is The compound shown in formula I-4 is

本发明还提供了一种如式I-2所示的化合物的制备方法，The present invention also provides a method for preparing the compound shown in formula I-2.

其中X为S，Y为CR8； Wherein X is S, Y is CR 8 ;

具体地，包括如下步骤：
Specifically, the steps include:

其中，X为卤素原子(例如Cl、Br或I)，Wherein, X is a halogen atom (such as Cl, Br or I),

步骤1：在加成试剂存在下进行加成反应，所述加成反应的操作条件可为本领域该类反应的常规操作和条件，所述加成试剂可为液溴或氯气；Step 1: performing an addition reaction in the presence of an addition reagent, wherein the operating conditions of the addition reaction may be conventional operations and conditions of such reactions in the art, and the addition reagent may be liquid bromine or chlorine gas;

步骤2：在碱存在下进行环化反应，所述环化反应的操作条件可为本领域该类反应的常规操作和条件，所述碱可为甲醇钠或乙醇钠；Step 2: performing a cyclization reaction in the presence of a base. The operating conditions of the cyclization reaction may be conventional operations and conditions of such reactions in the art. The base may be sodium methoxide or sodium ethoxide;

步骤3：在卤代试剂存在下进行亲电卤代反应，所述亲电卤代反应的操作条件可为本领域该类反应的常规操作和条件，所述卤代试剂可为液溴或NBS；Step 3: performing an electrophilic halogenation reaction in the presence of a halogenating agent, wherein the operating conditions of the electrophilic halogenation reaction may be conventional operations and conditions of such reactions in the art, and the halogenating agent may be liquid bromine or NBS;

步骤4：在甲基化试剂存在下进行甲基化反应，所述甲基化反应的操作条件可为本领域该类反应的常规操作和条件，所述甲基化试剂可为碘甲烷或硫酸二甲酯；Step 4: performing a methylation reaction in the presence of a methylating agent, wherein the operating conditions of the methylation reaction may be conventional operations and conditions of such reactions in the art, and the methylating agent may be methyl iodide or dimethyl sulfate;

步骤5：在还原剂存在下进行酯还原反应，所述酯还原反应的操作条件可为本领域该类反应的常 规操作和条件，所述还原剂可为四氢铝锂或硼烷；Step 5: Carry out ester reduction reaction in the presence of a reducing agent. The operating conditions of the ester reduction reaction can be the conventional conditions for such reactions in the art. Standard operation and conditions, the reducing agent can be lithium aluminum tetrahydride or borane;

步骤6：在氧化剂存在下进行羟基氧化反应，所述氧化反应的操作条件可为本领域该类反应的常规操作和条件，所述氧化剂可为Dess-Martin氧化剂或二氧化锰；Step 6: performing a hydroxyl oxidation reaction in the presence of an oxidant, wherein the operating conditions of the oxidation reaction may be conventional operations and conditions of such reactions in the art, and the oxidant may be a Dess-Martin oxidant or manganese dioxide;

步骤7：在亲核试剂存在下进行亲核取代反应，所述亲核取代反应的操作条件可为本领域该类反应的常规操作和条件，所述亲核试剂可为格式试剂、锂试剂或锌试剂；Step 7: performing a nucleophilic substitution reaction in the presence of a nucleophilic reagent, wherein the operating conditions of the nucleophilic substitution reaction may be conventional operations and conditions of such reactions in the art, and the nucleophilic reagent may be a Grignard reagent, a lithium reagent or a zinc reagent;

步骤8：在氧化剂存在下进行羟基氧化反应，所述氧化反应的操作条件可为本领域该类反应的常规操作和条件，所述氧化剂可为Dess-Martin氧化剂或二氧化锰；Step 8: performing a hydroxyl group oxidation reaction in the presence of an oxidant, wherein the operating conditions of the oxidation reaction may be conventional operations and conditions of such reactions in the art, and the oxidant may be a Dess-Martin oxidant or manganese dioxide;

步骤9：在脱甲基试剂存在下进行脱甲基反应，所述脱甲基反应的操作条件可为本领域该类反应的常规操作和条件，所述脱甲基试剂可为氢溴酸水溶液、氢溴酸醋酸溶液或三溴化硼。Step 9: carrying out a demethylation reaction in the presence of a demethylation agent. The operating conditions of the demethylation reaction may be conventional operations and conditions for such reactions in the art. The demethylation agent may be an aqueous solution of hydrobromic acid, a hydrobromic acid-acetic acid solution or boron tribromide.

本发明还提供了一种药物组合物，其包含物质A和药用辅料(或药学上可接受的载体)；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐。所述的物质A可为治疗有效量的。The present invention also provides a pharmaceutical composition, which comprises a substance A and a pharmaceutical excipient (or a pharmaceutically acceptable carrier); the substance A is the compound shown in the above formula I or a pharmaceutically acceptable salt thereof. The substance A can be in a therapeutically effective amount.

本发明还提供了一种物质A或上述的药物组合物在制备PI3Kα抑制剂中的应用，所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐。在所述的应用中，所述的PI3Kα抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为抑制PI3Kα的效果提供快速检测。The present invention also provides an application of a substance A or the above-mentioned pharmaceutical composition in the preparation of a PI3Kα inhibitor, wherein the substance A is the above-mentioned compound as shown in Formula I or a pharmaceutically acceptable salt thereof. In the application, the PI3Kα inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or a control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting PI3Kα.

本发明还提供了一种物质A或上述的药物组合物在制备药物中的应用，所述的药物用于治疗和/或预防与PI3Kα调节相关的疾病或障碍；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐；所述的物质A为治疗有效量的；所述与PI3Kα调节相关的疾病或障碍优选为癌症，例如子宫内膜癌、胃癌、白血病、淋巴瘤、肉瘤、结肠直肠癌、肺癌、卵巢癌、皮肤癌、头颈癌、乳腺癌、脑癌或前列腺癌。The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent diseases or disorders related to PI3Kα regulation; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount; the disease or disorder related to PI3Kα regulation is preferably cancer, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

本发明还提供了一种物质A或上述的药物组合物在制备药物中的应用，所述的药物用于治疗和/或预防与PI3Kα调节相关的疾病或障碍；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐；所述的物质A为治疗有效量的；所述与PI3Kα调节相关的疾病或障碍优选为CLOVES综合征(例如表现为先天性脂肪瘤过度生长、血管畸形、表皮痣、脊柱侧凸、骨骼或脊柱综合征)或PI3Kα有关的过度生长综合征(PROS)。The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent diseases or disorders related to PI3Kα regulation; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount; the disease or disorder related to PI3Kα regulation is preferably CLOVES syndrome (for example, manifested as congenital lipoma overgrowth, vascular malformation, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3Kα-related overgrowth syndrome (PROS).

本发明还提供了一种物质A或上述的药物组合物在制备药物中的应用，所述的药物用于治疗和/或预防癌症；所述癌症优选为子宫内膜癌、胃癌、白血病、淋巴瘤、肉瘤、结肠直肠癌、肺癌、卵巢癌、皮肤癌、头颈癌、乳腺癌、脑癌或前列腺癌；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐；所述的物质A为治疗有效量的。The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent cancer; the cancer is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount.

本发明还提供了一种物质A或上述的药物组合物在制备药物中的应用，所述的药物用于治疗和/或预防CLOVES综合征(例如表现为先天性脂肪瘤过度生长、血管畸形、表皮痣、脊柱侧凸、骨骼或脊柱综合征)或PI3Kα有关的过度生长综合征(PROS)；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐；所述的物质A为治疗有效量的。The present invention also provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the drug is used to treat and/or prevent CLOVES syndrome (for example, manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3Kα-related overgrowth syndrome (PROS); the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount.

本发明还提供了一种抑制PI3Kα的方法，其包括向患者施用治疗有效量的物质A或上述的药物组合物；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐。The present invention also provides a method for inhibiting PI3Kα, which comprises administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof.

本发明还提供了一种治疗和/或预防与PI3Kα调节相关的疾病或障碍的方法，其包括向患者施用 治疗有效量的物质A或上述的药物组合物；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐；所述与PI3Kα调节相关的疾病或障碍优选为癌症，例如子宫内膜癌、胃癌、白血病、淋巴瘤、肉瘤、结肠直肠癌、肺癌、卵巢癌、皮肤癌、头颈癌、乳腺癌、脑癌或前列腺癌。The present invention also provides a method for treating and/or preventing a disease or disorder associated with PI3Kα regulation, comprising administering to a patient A therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the disease or disorder related to PI3Kα regulation is preferably cancer, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

本发明还提供了一种治疗和/或预防与PI3Kα调节相关的疾病或障碍的方法，其包括向患者施用治疗有效量的物质A或上述的药物组合物；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐；所述与PI3Kα调节相关的疾病或障碍优选为CLOVES综合征(例如表现为先天性脂肪瘤过度生长、血管畸形、表皮痣、脊柱侧凸、骨骼或脊柱综合征)或PI3Kα有关的过度生长综合征(PROS)。The present invention also provides a method for treating and/or preventing a disease or disorder associated with PI3Kα regulation, comprising administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the disease or disorder associated with PI3Kα regulation is preferably CLOVES syndrome (e.g., manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3Kα-related overgrowth syndrome (PROS).

本发明还提供了一种治疗和/或预防癌症的方法，其包括向患者施用治疗有效量的物质A或上述的药物组合物；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐；所述癌症优选为子宫内膜癌、胃癌、白血病、淋巴瘤、肉瘤、结肠直肠癌、肺癌、卵巢癌、皮肤癌、头颈癌、乳腺癌、脑癌或前列腺癌。The present invention also provides a method for treating and/or preventing cancer, comprising administering a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition to a patient; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof; the cancer is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.

本发明还提供了一种治疗和/或预防CLOVES综合征(例如表现为先天性脂肪瘤过度生长、血管畸形、表皮痣、脊柱侧凸、骨骼或脊柱综合征)或PI3Kα有关的过度生长综合征(PROS)的方法，其包括向患者施用治疗有效量的物质A或上述的药物组合物；所述的物质A为上述的如式I所示的化合物或其药学上可接受的盐。The present invention also provides a method for treating and/or preventing CLOVES syndrome (e.g., manifested as congenital lipoma overgrowth, vascular malformations, epidermal nevus, scoliosis, bone or spinal syndrome) or PI3Kα-related overgrowth syndrome (PROS), which comprises administering to the patient a therapeutically effective amount of substance A or the above-mentioned pharmaceutical composition; the substance A is the above-mentioned compound as shown in formula I or a pharmaceutically acceptable salt thereof.

如上所述的PI3Kα为PI3Kα突变，优选为PI3KαH1047R突变或PI3KαE545K突变，更优选为PI3KαH1047R突变。The PI3Kα as described above is a PI3Kα mutation, preferably a PI3Kα H1047R mutation or a PI3Kα E545K mutation, and more preferably a PI3Kα H1047R mutation.

除前述以外，当用于本申请时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in this application, the following terms have the meanings indicated below unless specifically stated otherwise.

术语“多个”是指2个、3个、4个或5个。The term "plurality" refers to 2, 3, 4 or 5.

本领域技术人员可以理解，根据本领域中使用的惯例，本发明描述基团的结构式中所使用的是指，相应的基团R通过该位点与化合物中的其它片段、基团进行连接。当基团R未指明其连接位点时，所述基团R可通过其任意可允许的连接位点与化合物中的其他部分相连；例如6-氮杂螺[2.5]辛烷基表示可以通过其任一环上的任一可允许的环原子与化合物中的其他部分相连，例如连接位点可以在含杂原子的环上(例如)，也可以在不含杂原子的环上(例如)。It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group R is connected to other fragments and groups in the compound through this site. When the group R does not specify its connection site, the group R can be connected to other parts in the compound through any permissible connection site; for example, 6-azaspiro[2.5]octanol It means that it can be connected to other parts in the compound through any permissible ring atom on any ring, for example, the connection point can be on a ring containing a heteroatom (e.g. ), or on a ring containing no heteroatoms (e.g. ).

术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化 合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸、有机酸。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts ... When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes an inorganic acid and an organic acid. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

本发明中，“药物组合物”是指包含本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In the present invention, "pharmaceutical composition" refers to a preparation comprising a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (e.g., humans). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

本发明中，“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如药用辅料)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。In the present invention, "pharmaceutically acceptable" refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention and are relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.

术语“药用辅料”或“药学上可接受的载体”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009Sixth Edition)。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。The term "pharmaceutical excipients" or "pharmaceutically acceptable carriers" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. They are all substances contained in pharmaceutical preparations except the active ingredients. Please refer to Part IV of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredients at the desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredients after the subject receives the composition. The pharmaceutical excipients may be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

术语“立体异构体”是指顺反异构体或旋光异构体，顺反异构体是因双键或成环碳原子的单键不能自由旋转而引起的异构体，旋光异构体是因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体。它们可以根据对于氨基酸的绝对立体化学定义为(R)-/(S)-或者(D)-/(L)-或者(R,R)-/(R,S)-/(S,S)-。旋光(+)和(-)，(R)-和(S)-以及(R,R)-/(R,S)-/(S,S)-或(D)-和(L)-异构体可以使用手性原料合成、手性拆分制备，或者可以使用常规技术例如但不限于使用手性柱的高效液相(HPLC)拆分。化学结构中，键并未指定构型，即如果化学结构中存在构型异构，键可以为或者同时包含两种构型。The term "stereoisomer" refers to cis-trans isomers or optical isomers. Cis-trans isomers are isomers caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely, and optical isomers are stereoisomers with different optical properties caused by the lack of anti-axis symmetry in the molecule. They can be defined as (R)-/(S)- or (D)-/(L)- or (R,R)-/(R,S)-/(S,S)- according to the absolute stereochemistry of amino acids. Optically active (+) and (-), (R)- and (S)- and (R,R)-/(R,S)-/(S,S)- or (D)- and (L)- isomers can be synthesized using chiral raw materials, prepared by chiral resolution, or can be resolved using conventional techniques such as, but not limited to, high performance liquid chromatography (HPLC) using a chiral column. In the chemical structure, the bonds The configuration is not specified, that is, if there are configurational isomers in the chemical structure, the bond Can be or both Two configurations.

术语“治疗”指治疗性疗法或缓解性措施。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。“治疗”也可以指与不接受治疗的期望存活相比延长生存期。The term "treat" refers to therapeutic treatment or palliative measures. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

术语“预防”是指获得或发生疾病或障碍的风险降低。The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。 The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。The term "patient" refers to any animal that is about to or has been administered the compound or composition according to embodiments of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

在本发明中，术语“取代”或“取代基”是基团中的氢原子被指定的基团所代替。当没有指明取代位置时，取代可以在任何位置，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。举例说明如下：结构表示环A上的氢原子被p个R4所取代。当未指明连接位点时，所述取代基可通过任意可允许的连接位点与分子其他部分相连；例如6-氮杂螺[2.5]辛烷基表示可以通过任一环上的任一可允许的环原子与分子其他部分相连，例如连接位点可以在含杂原子的环上(例如)，也可以在不含杂原子的环上(例如)。In the present invention, the term "substituted" or "substituent" means that the hydrogen atom in a group is replaced by a specified group. When the substitution position is not specified, the substitution can be in any position, but only a stable or chemically feasible chemical is formed. Examples are as follows: The structure indicates that the hydrogen atoms on ring A are replaced by p R 4. When the attachment site is not specified, the substituent can be attached to the rest of the molecule through any permissible attachment site; for example, 6-azaspiro[2.5]octanyl means that it can be attached to the rest of the molecule through any permissible ring atom on any ring, for example, the attachment site can be on a ring containing a heteroatom (e.g. ), or on a ring containing no heteroatoms (e.g. ).

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被一个或多个R所取代，则所述基团可以任选地至少被一个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in a compound composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with one or more R, the group may be optionally substituted with at least one R, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

在本发明中，术语“烷基”是指饱和的直链或支链的一价烃基。C1-6烷基是指具有1-6个碳原子的烷基，优选为具有1-4个碳原子的C1-4烷基，其具体为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。In the present invention, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. C1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, preferably a C1-4 alkyl group having 1 to 4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

在本发明中，术语“-O-C1-6烷基”是指烷氧基，其中“C1-6烷基”如上所定义。优选为具有1-4个碳原子的烷氧基，例如甲氧基或乙氧基。In the present invention, the term "-OC 1-6 alkyl" refers to an alkoxy group, wherein "C 1-6 alkyl" is as defined above. Preferably, it is an alkoxy group having 1 to 4 carbon atoms, such as methoxy or ethoxy.

在本发明中，术语“氘代C1-6烷基”是指在C1-6烷基上，一个或多个氢原子被氘原子取代，例如-CD3。In the present invention, the term "deuterated C 1-6 alkyl" refers to a C 1-6 alkyl group in which one or more hydrogen atoms are replaced by a deuterium atom, such as -CD 3 .

在本发明中，术语“-C(O)-C1-6烷基”中“C1-6烷基”如上所定义，例如-C(O)-CH3、-C(O)-CH2CH3。In the present invention, the "C 1-6 alkyl" in the term "-C(O)-C 1-6 alkyl" is as defined above, for example, -C(O)-CH 3 , -C(O)-CH 2 CH 3 .

在本发明中，术语“C2-6炔基”是指碳原子数为C2～C6的、直链或支链的、不饱和的一价烃基，其具有一个或多个(例如，1个、2个或3个)碳-碳sp3三键，优选C2-4炔基。炔基包括但不限于：乙炔基、等。In the present invention, the term "C 2-6 alkynyl" refers to a C 2 to C 6 , linear or branched, unsaturated, monovalent hydrocarbon group having one or more (e.g., 1, 2 or 3) carbon-carbon sp 3 triple bonds, preferably a C 2-4 alkynyl group. Alkyl groups include, but are not limited to, ethynyl, wait.

在本发明中，术语“C2-6烯基”是指碳原子数为C2～C6的、直链或支链的、不饱和的一价烃基，其具有一个或多个(例如，1个、2个或3个)碳-碳sp2双键，优选C2-4烯基。烯基包括但不限于：乙烯基、等。In the present invention, the term "C 2-6 alkenyl" refers to a linear or branched, unsaturated, monovalent hydrocarbon group with a carbon number of C 2 to C 6 , which has one or more (e.g., 1, 2 or 3) carbon-carbon sp 2 double bonds, preferably a C 2-4 alkenyl group. Alkenyl groups include, but are not limited to, vinyl, wait.

在本发明中，术语“环烷基”是指饱和的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接。如具有3 至12个碳原子的3-12元环烷基，更优选具有3至7个碳原子的3-7元单环环烷基(最优选具有3至6个碳原子的3-6元单环环烷基)或4至10个碳原子的4-10元桥环环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基、等，例如本发明中，所述环烷基中，任一环碳原子可被氧代。In the present invention, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) carbocyclic substituent, and it can be connected to the rest of the molecule through a single bond via any suitable carbon atom. The cycloalkyl group is preferably a 3-12-membered cycloalkyl group having 3 to 12 carbon atoms, more preferably a 3-7-membered monocyclic cycloalkyl group having 3 to 7 carbon atoms (most preferably a 3-6-membered monocyclic cycloalkyl group having 3 to 6 carbon atoms) or a 4-10-membered bridged ring cycloalkyl group having 4 to 10 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc., for example In the present invention, any ring carbon atom in the cycloalkyl group may be substituted with oxygen.

在本发明中，术语“环烯基”意指具有至少一个双键(如碳碳双键)的部分不饱和的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的非芳香性碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；如具有3至12个碳原子的3-12元环烯基，更优选具有3至7个碳原子的3-7元环烯基，最优选具有3至6个碳原子的3-6元环烯基。环烯基的实例包括但不限于环丙烯基、环丁烯基、环戊烯基(例如)、环戊二烯基(例如)、环己烯基(例如)、环庚烯基、环己二烯基等。本发明中，所述环烯基中，任何适宜的环碳原子可被氧代。In the present invention, the term "cycloalkenyl" means a partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged ring, fused ring or spirocyclic system) non-aromatic carbocyclic substituent having at least one double bond (e.g., carbon-carbon double bond), and which can be connected to the rest of the molecule by a single bond via any suitable carbon atom; such as a 3-12-membered cycloalkenyl having 3 to 12 carbon atoms, more preferably a 3-7-membered cycloalkenyl having 3 to 7 carbon atoms, and most preferably a 3-6-membered cycloalkenyl having 3 to 6 carbon atoms. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl (e.g., ), cyclopentadienyl (e.g. ), cyclohexenyl (e.g. ), cycloheptenyl, cyclohexadienyl, etc. In the present invention, any suitable ring carbon atom in the cycloalkenyl group may be substituted with oxygen.

在本发明中，术语“杂环烷基”是指具有指定环原子数(例如，3-12元、4-6元、7-10元)的、指定杂原子数(例如，1个、2个、3个、4个或5个)的、指定杂原子种类(N、O和S中的一种或多种)的、单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的、饱和的一价基团，其通过任何适宜的碳原子或杂原子与分子其余部分相连。其可为4-6元单环杂环烷基、7-10元螺环杂环烷基或或7-10元桥环杂环烷基。杂环烷基的实例包括但不限于吗啉基、哌啶基、哌嗪基、四氢吡咯基、四氢吡喃基、氧杂环丁烷基、氮杂环丁烷基、6-氮杂螺[2.5]辛烷基、2-氮杂螺[3.3]庚烷基、2-氧杂双环[2.2.2]辛烷基或8-氮杂双环[3.2.1]辛烷基，例如 本发明中，所述杂环烷基中，任何适宜的环原子可被氧代。In the present invention, the term "heterocycloalkyl" refers to a saturated monovalent group having a specified number of ring atoms (e.g., 3-12, 4-6, 7-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified heteroatom type (one or more of N, O and S), a monocyclic or polycyclic (e.g., a bicyclic, tricyclic or more cyclic bridged ring, a fused ring or a spirocyclic system), which is connected to the rest of the molecule through any suitable carbon atom or heteroatom. It can be a 4-6-membered monocyclic heterocycloalkyl, a 7-10-membered spirocyclic heterocycloalkyl or a 7-10-membered bridged heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, morpholinyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, tetrahydropyranyl, oxetanyl, azetidinyl, 6-azaspiro[2.5]octanyl, 2-azaspiro[3.3]heptyl, 2-oxabicyclo[2.2.2]octanyl or 8-azabicyclo[3.2.1]octanyl, e.g. In the present invention, any appropriate ring atom in the heterocycloalkyl group may be substituted with oxo.

在本发明中，术语“杂环烯基”是指具有指定环原子数(例如，3-12元、4-6元、7-10元)的、指定杂原子数(例如，1个、2个、3个、4个或5个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、不饱和的一价烃基，其具有一个或多个(例如，1个、2个或3个)碳-碳sp2双键，其为单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的，不具有芳香性。杂环烯基通过任何适宜的碳原子或杂原子与分子其余部分相连。杂环烯基的实例包括但不限于1,2,3,6-四氢吡啶基，例如本发明中，所述杂环烯基中，任何适宜的环原子可被氧代。 In the present invention, the term "heterocycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon group with a specified number of ring atoms (e.g., 3-12, 4-6, 7-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified heteroatom type (one or more of N, O and S), which has one or more (e.g., 1, 2 or 3) carbon-carbon sp2 double bonds, is monocyclic or polycyclic (e.g., bicyclic, tricyclic or more cyclic bridged rings, fused rings or spirocyclic systems), and is not aromatic. The heterocycloalkenyl group is connected to the rest of the molecule through any suitable carbon atom or heteroatom. Examples of heterocycloalkenyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridyl, such as In the present invention, any appropriate ring atom in the heterocycloalkenyl group may be substituted with oxo.

本发明中，术语“芳基”是指具有指定碳原子数(例如，C6-10)的、环状的、不饱和的一价烃基，其为单环或多环(例如，2个或3个)，为多环时，单环之间共用两个原子和一根键，且至少一个环具有芳香性。芳基通过具有芳香性的环或不具有芳香性的环与分子其余部分相连。芳基包括但不限于：苯基、萘基或1,2,3,4-四氢萘基，例如等。本发明中，当所述芳基中存在不具有芳香性的环时，所述不具有芳香性的环上，任何适宜的环碳原子可被氧代。In the present invention, the term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon group with a specified number of carbon atoms (e.g., C 6-10 ), which is monocyclic or polycyclic (e.g., 2 or 3). When it is polycyclic, the monocyclic rings share two atoms and a bond, and at least one ring is aromatic. The aryl group is connected to the rest of the molecule through an aromatic ring or a non-aromatic ring. Aryl groups include, but are not limited to, phenyl, naphthyl or 1,2,3,4-tetrahydronaphthyl, for example In the present invention, when there is a non-aromatic ring in the aryl group, any suitable ring carbon atom on the non-aromatic ring may be substituted with oxygen.

本发明中，术语“杂芳基”是指具有指定环原子数(例如，5-10元、5-6元、9-10元)的、指定杂原子数(例如，1个、2个、3个、4个或5个)的、指定杂原子种类(N、O和S中的一种或多种)的、环状的、不饱和的一价基团，其为单环或多环；为多环时，每两个单环之间共用两个原子和一根键，且至少一个环具有芳香性。杂芳基通过任何适宜的碳原子或杂原子与分子其余部分相连；杂芳基通过具有杂原子的环或不具有杂原子的环与分子其余部分相连；杂芳基通过具有芳香性的环或不具有芳香性的环与分子其余部分相连。其可为5-6元单环杂芳基或9-10元并环杂芳基。杂芳基包括但不限于1H-四唑基、2H-四唑基、吡啶基、嘧啶基、吡唑基、噻吩基、1,2,4-恶二唑基、吡嗪基、哒嗪基、1,2,3-三唑基、1,3,4-噻二唑基、1,3,4-恶二唑基、吡咯基、喹啉基、喹唑啉基、吲哚基、1H-吡咯并[2,3-b]吡啶基、苯并[d][1,3]二氧杂环戊烯基、咪唑并[1,2-b]哒嗪基、吲唑基、1H-吡唑并[4,3-b]吡啶基、异吲哚啉基、[1,2,4]三唑并[4,3-b]哒嗪基或1,2,3,4-四氢异喹啉基，例如 等。本发明中，当所述杂芳基中存在不具有芳香性的环时，所述不具有芳香性的环上，任何适宜的环原子可被氧代。In the present invention, the term "heteroaryl" refers to a cyclic, unsaturated, monovalent group with a specified number of ring atoms (e.g., 5-10 members, 5-6 members, 9-10 members), a specified number of heteroatoms (e.g., 1, 2, 3, 4 or 5), a specified type of heteroatoms (one or more of N, O and S), which is monocyclic or polycyclic; when it is polycyclic, two atoms and one bond are shared between each two monocyclic rings, and at least one ring is aromatic. The heteroaryl group is connected to the rest of the molecule through any suitable carbon atom or heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl group is connected to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties. It can be a 5-6-membered monocyclic heteroaryl or a 9-10-membered polycyclic heteroaryl. Heteroaryl includes, but is not limited to, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyrimidinyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyrrolyl, quinolyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl, or 1,2,3,4-tetrahydroisoquinolyl, for example In the present invention, when a non-aromatic ring exists in the heteroaryl group, any suitable ring atom on the non-aromatic ring may be substituted with oxygen.

本发明中，术语“卤素”是指氟、氯、溴或碘，尤其指F或Cl。In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine, especially to F or Cl.

在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。 On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are commercially available.

本发明的积极进步效果在于：本发明的磷酸肌醇3-激酶变构抑制剂可有效变构靶向抑制PI3Kα突变，特别是PI3KαH1047R突变，具有较好的选择性，有望治疗和/或预防相关疾病或障碍。The positive and progressive effect of the present invention is that the phosphoinositide 3-kinase allosteric inhibitor of the present invention can effectively allosterically target and inhibit PI3Kα mutation, especially PI3KαH1047R mutation, has good selectivity, and is expected to treat and/or prevent related diseases or disorders.

具体实施方式DETAILED DESCRIPTION

下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

中间体1:4-溴-3-羟基-5-甲基噻吩-2-甲酸甲酯
Intermediate 1: 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester

步骤：4-溴-3-羟基-5-甲基噻吩-2-甲酸甲酯Step: 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester

参考专利JP05078348A合成得到3-羟基-5-甲基噻吩-2-甲酸甲酯(53g),室温下，3-羟基-5-甲基噻吩-2-甲酸甲酯(16g,93mmol,1.0eq)溶于乙酸(20mL)中，惰性保护，搅拌，加入液溴(44.6g,278.8mmol,3.0eq)反应3小时，混合物倒入冰水(150mL)中，过滤，水、0.5mol/L碳酸氢钠水溶液、硫代亚硫酸钠水溶液洗涤滤饼，干燥。2-丙醇重结晶得到纯产物4-溴-3-羟基-5-甲基噻吩-2-甲酸甲酯(19g,收率81％)，淡黄色固体。3-Hydroxy-5-methylthiophene-2-carboxylic acid methyl ester (53 g) was synthesized by referring to patent JP05078348A. At room temperature, 3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester (16 g, 93 mmol, 1.0 eq) was dissolved in acetic acid (20 mL), inert protection, stirred, and liquid bromine (44.6 g, 278.8 mmol, 3.0 eq) was added to react for 3 hours. The mixture was poured into ice water (150 mL), filtered, and the filter cake was washed with water, 0.5 mol/L sodium bicarbonate aqueous solution, and sodium thiosulfite aqueous solution, and dried. The pure product 4-bromo-3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester (19 g, yield 81%) was recrystallized from 2-propanol as a light yellow solid.

MS m/z:251.2/253.2[M+H]+ MS m/z:251.2/253.2[M+H] +

1H NMR(400MHz,氘代氯仿)δ3.86(s,3H),2.45(s,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 3.86 (s, 3H), 2.45 (s, 3H).

中间体2：4-溴-3-甲氧基噻吩-2-甲醛
Intermediate 2: 4-bromo-3-methoxythiophene-2-carbaldehyde

步骤1：4-溴-3-甲氧基-5-甲基噻吩-2-甲酸甲酯Step 1: 4-bromo-3-methoxy-5-methylthiophene-2-carboxylic acid methyl ester

4-溴-3-羟基-5-甲基噻吩-2-甲酸甲酯(2g,8.0mmol,1.0eq)溶于N,N-二甲基甲酰胺(DMF)(200mL)中，加入硫酸二甲酯(1.51g,12.1mmol,1.5eq)和碳酸钾(2.2g,16mmol,2.0eq)，室温反应1小时，加水,乙酸乙酯萃取3次，有机相无水硫酸钠干燥浓缩，粗品柱层析分离得到4-溴-3-甲氧基-5-甲基噻吩-2-甲酸甲酯(1.7g,收率80.5％)。4-Bromo-3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester (2g, 8.0mmol, 1.0eq) was dissolved in N,N-dimethylformamide (DMF) (200mL), and dimethyl sulfate (1.51g, 12.1mmol, 1.5eq) and potassium carbonate (2.2g, 16mmol, 2.0eq) were added. The mixture was reacted at room temperature for 1 hour, and water was added. The mixture was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography to obtain 4-bromo-3-methoxy-5-methylthiophene-2-carboxylic acid methyl ester (1.7g, yield 80.5%).

MS m/z:265.1/267.1[M+H]+ MS m/z:265.1/267.1[M+H] +

1H NMR(400MHz,氘代氯仿)δ4.03(s,3H),3.88(s,3H),2.43(s,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 4.03 (s, 3H), 3.88 (s, 3H), 2.43 (s, 3H).

步骤2：(4-溴-3-甲氧基-5-甲基噻吩-2-基)甲醇Step 2: (4-bromo-3-methoxy-5-methylthiophen-2-yl)methanol

0℃下，向4-溴-3-甲氧基-5-甲基噻吩-2-甲酸甲酯(3g,11.3mmol,1.0eq)的无水四氢呋喃(15mL) 溶液中，缓慢加入氢化锂铝(0.43g,11.3mmol,1.0eq)，0℃下反应1小时，缓慢加入水(3mL)，15％氢氧化钠(3mL)，水(9mL)，过滤除去固体，浓缩，粗品柱层析分离得到产物4-溴-3-甲氧基-5-甲基噻吩-2-甲醇(2.4g,收率89.5％)。At 0°C, add 4-bromo-3-methoxy-5-methylthiophene-2-carboxylic acid methyl ester (3 g, 11.3 mmol, 1.0 eq) in anhydrous tetrahydrofuran (15 mL) Slowly add lithium aluminum hydride (0.43 g, 11.3 mmol, 1.0 eq) to the solution, react at 0°C for 1 hour, slowly add water (3 mL), 15% sodium hydroxide (3 mL), and water (9 mL), filter out the solid, concentrate, and separate the crude product by column chromatography to obtain the product 4-bromo-3-methoxy-5-methylthiophene-2-methanol (2.4 g, yield 89.5%).

MS m/z:237/239[M+H]+ MS m/z:237/239[M+H] +

1H NMR(400MHz,DMSO-d6)δ5.43(t,J＝5.6Hz,1H),4.54(d,J＝5.7Hz,2H),3.77(s,3H),2.31(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ5.43 (t, J = 5.6 Hz, 1H), 4.54 (d, J = 5.7 Hz, 2H), 3.77 (s, 3H), 2.31 (s, 3H).

步骤3：4-溴-3-甲氧基-5-甲基噻吩-2-甲醛Step 3: 4-Bromo-3-methoxy-5-methylthiophene-2-carbaldehyde

4-溴-3-甲氧基-5-甲基噻吩-2-甲醇(18g,75.9mmol,1.0eq)溶于二氯甲烷(65mL)，分3批加入Dess-Martin氧化剂(35.4g,83.5mol,1.1eq)，搅拌2小时，过滤，滤液用饱和碳酸氢钠水溶液(200mL)洗涤，二氯甲烷萃取3次，无水硫酸钠干燥，浓缩，粗品柱层析分离得到4-溴-3-甲氧基-5-甲基噻吩-2-甲醛(15.1g,收率84.5％)。4-Bromo-3-methoxy-5-methylthiophene-2-methanol (18 g, 75.9 mmol, 1.0 eq) was dissolved in dichloromethane (65 mL), and Dess-Martin oxidant (35.4 g, 83.5 mol, 1.1 eq) was added in 3 batches. The mixture was stirred for 2 hours and filtered. The filtrate was washed with saturated aqueous sodium bicarbonate solution (200 mL), extracted with dichloromethane 3 times, dried over anhydrous sodium sulfate, concentrated, and the crude product was separated by column chromatography to obtain 4-bromo-3-methoxy-5-methylthiophene-2-carbaldehyde (15.1 g, yield 84.5%).

MS m/z:235/237[M+H]+ MS m/z:235/237[M+H] +

1H NMR(400MHz,氘代氯仿)δ10.05(s,1H),4.18(s,3H),2.47(s,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 10.05 (s, 1H), 4.18 (s, 3H), 2.47 (s, 3H).

中间体3-1和3-2：1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)乙-1-酮和1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)丙-1-酮
Intermediates 3-1 and 3-2: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-one and 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one

步骤1：1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)乙-1-醇和1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)丙-1-醇Step 1: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-ol and 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-ol

100mL三口烧瓶中加入4-溴-3-甲氧基-5-甲基噻吩-2-甲醛(1.0g,4.25mmol,1.0eq)和THF(10mL)，氩气保护，-78℃滴加甲基溴化镁(4.25mL,4.3mmol,1.0eq)，-78℃反应0.5h。加入水(50mL)稀释，乙酸乙酯(50mL)萃取三次，合并有机相，饱和食盐水(50mL)洗涤，有机相无水硫酸钠干燥，过滤，减压浓缩得到1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)乙-1-醇(0.95g,收率89％)，黄色油状物。4-Bromo-3-methoxy-5-methylthiophene-2-carboxaldehyde (1.0 g, 4.25 mmol, 1.0 eq) and THF (10 mL) were added to a 100 mL three-necked flask, argon was protected, methylmagnesium bromide (4.25 mL, 4.3 mmol, 1.0 eq) was added dropwise at -78 °C, and the mixture was reacted for 0.5 h at -78 °C. Water (50 mL) was added for dilution, and ethyl acetate (50 mL) was used for extraction three times. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1-(4-bromo-3-methoxy-5-methylthiophene-2-yl)ethan-1-ol (0.95 g, yield 89%), a yellow oil.

MS m/z:251/253[M+H]+ MS m/z:251/253[M+H] +

使用上述方法制备得到1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)丙-1-醇(0.66g,收率78％)，白色固体。The above method was used to prepare 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-ol (0.66 g, yield 78%) as a white solid.

MS m/z:265/267[M+H]+ MS m/z:265/267[M+H] +

步骤2：1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)乙-1-酮(中间体3-1)和1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)丙-1-酮(中间体3-2) Step 2: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-one (Intermediate 3-1) and 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (Intermediate 3-2)

1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)丙-1醇(19.5g，74mmol,1.0eq)溶于二氯甲烷(200mL)中，分3批加入Dess-Martin氧化剂(34.4g，81mmol,1.0eq)，搅拌2小时，过滤，滤液饱和碳酸氢钠水溶液(200mL)洗涤，二氯甲烷(300mL)萃取3次，有机相无水硫酸钠干燥，浓缩，粗品柱层析分离得到产物1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)丙-1-酮(16.3g，收率83％)。1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-ol (19.5 g, 74 mmol, 1.0 eq) was dissolved in dichloromethane (200 mL), and Dess-Martin oxidant (34.4 g, 81 mmol, 1.0 eq) was added in 3 batches. The mixture was stirred for 2 hours, filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate solution (200 mL), extracted with dichloromethane (300 mL) 3 times, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated by column chromatography to obtain the product 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (16.3 g, yield 83%).

MS m/z:263/265[M+H]+ MS m/z:263/265[M+H] +

1H NMR(400MHz,氘代氯仿)δ4.02(s,3H),2.96(q,J＝7.3Hz,2H),2.43(s,3H),1.21(t,J＝7.3Hz,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 4.02 (s, 3H), 2.96 (q, J = 7.3 Hz, 2H), 2.43 (s, 3H), 1.21 (t, J = 7.3 Hz, 3H).

使用上述方法制备得到1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)乙-1-酮(3.6g,收率76％)，黄色固体。The above method was used to prepare 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)ethan-1-one (3.6 g, yield 76%) as a yellow solid.

MS m/z:249/251[M+H]+ MS m/z:249/251[M+H] +

中间体4-1和4-2：1-(4-溴-3-羟基-5-甲基噻吩-2-基)乙-1-酮和1-(4-溴-3-羟基-5-甲基噻吩-2-基)丙-1-酮
Intermediates 4-1 and 4-2: 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one and 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one

步骤:step:

室温下，1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)丙-1-酮(13g，49.5mmol,1.0eq)加入到HBr醋酸溶液(15mL)中，120℃加热1小时，减压浓缩至干，柱层析分离得到1-(4-溴-3-羟基-5-甲基噻吩-2-基)丙-1-酮(中间体4-2)(11g,收率89.4％)，白色固体。At room temperature, 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (13 g, 49.5 mmol, 1.0 eq) was added to HBr acetic acid solution (15 mL), heated at 120 ° C for 1 hour, concentrated to dryness under reduced pressure, and separated by column chromatography to obtain 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one (intermediate 4-2) (11 g, yield 89.4%) as a white solid.

MS:m/z:249/251[M+H]+ MS:m/z:249/251[M+H] +

使用上述方法制备得到1-(4-溴-3-羟基-5-甲基噻吩-2-基)乙-1-酮(中间体4-1)(6.3g,收率85％)，白色固体。The above method was used to prepare 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one (Intermediate 4-1) (6.3 g, yield 85%) as a white solid.

MS m/z:235/237[M+H]+ MS m/z:235/237[M+H] +

实施例1：2-{[1-(2,6-二甲基-7-氧亚基-5-苯基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}苯甲酸
Example 1: 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoic acid

步骤1：苯甲酸-4-溴-5-甲基-2-丙酰基噻吩-3-基酯
Step 1: 4-Bromo-5-methyl-2-propionylthiophen-3-yl benzoate

0℃下，三乙胺(2.44g,24mmol,2.0eq)和4-二甲氨基吡啶(0.03g,0.24mmol,0.02eq)加入到1-(4-溴-3-羟基-5-甲基噻吩-2-基)丙-1-酮(3.0g,12mmol,1.0eq)和苯甲酰氯(1.68g,12mmol,1.0eq)的二氯甲烷(50mL)溶液中，室温搅拌4小时，加入水，分离有机相，无水硫酸钠干燥，浓缩，柱分离纯化得到苯甲酸-4-溴-5-甲基-2-丙酰基噻吩-3-基酯(1.3g,收率91.5％)，白色固体。Triethylamine (2.44 g, 24 mmol, 2.0 eq) and 4-dimethylaminopyridine (0.03 g, 0.24 mmol, 0.02 eq) were added to a solution of 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one (3.0 g, 12 mmol, 1.0 eq) and benzoyl chloride (1.68 g, 12 mmol, 1.0 eq) in dichloromethane (50 mL) at 0°C, stirred at room temperature for 4 hours, water was added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column separation to give benzoic acid-4-bromo-5-methyl-2-propionylthiophen-3-yl ester (1.3 g, yield 91.5%) as a white solid.

MS m/z:353/355[M+H]+ MS m/z:353/355[M+H] +

步骤2：1-(4-溴-3-羟基-5-甲基噻吩-2-基)-2-甲基-3-苯基丙烷-1,3-二酮
Step 2: 1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)-2-methyl-3-phenylpropane-1,3-dione

苯甲酸-4-溴-5-甲基-2-丙酰基噻吩-3-基酯(800mg,2.26mmol,1.0eq)溶于二甲亚砜(10mL)，冷却至0℃，加入60％钠氢(210mg,6.80mmol,3.0eq)，反应1小时，加入1mol/L盐酸(30mL)淬灭反应，加入乙酸乙酯(50mL)，有机相无水硫酸钠干燥，浓缩，残渣直接用于下一步反应。Benzoic acid-4-bromo-5-methyl-2-propionylthiophen-3-yl ester (800 mg, 2.26 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (10 mL), cooled to 0 ° C, and 60% sodium hydrogen sulfide (210 mg, 6.80 mmol, 3.0 eq) was added. The reaction was allowed to react for 1 hour, and 1 mol/L hydrochloric acid (30 mL) was added to quench the reaction. Ethyl acetate (50 mL) was added, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was directly used in the next step reaction.

MS m/z:353/355[M+H]+ MS m/z:353/355[M+H] +

步骤3：3-溴-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 3: 3-Bromo-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one

1-(4-溴-3-羟基-5-甲基噻吩-2-基)-2-甲基-3-苯基丙烷-1,3-二酮(1.18g，3.4mmol,1.0eq)溶于无水乙酸(20mL)中，加入一滴浓硫酸，120℃下反应2小时，反应液倒入水(50mL)中，乙酸乙酯(30mL)萃取三次，合并有机层，盐水洗涤，无水硫酸钠干燥，浓缩，粗产物柱层析纯化得到3-溴-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮(884mg，收率79％)，白色固体。1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)-2-methyl-3-phenylpropane-1,3-dione (1.18 g, 3.4 mmol, 1.0 eq) was dissolved in anhydrous acetic acid (20 mL), and a drop of concentrated sulfuric acid was added. The mixture was reacted at 120°C for 2 hours. The reaction solution was poured into water (50 mL), extracted three times with ethyl acetate (30 mL), and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give 3-bromo-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (884 mg, yield 79%) as a white solid.

MS m/z:335/336[M+H]+ MS m/z:335/336[M+H] +

步骤4：3-乙酰基-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 4: 3-Acetyl-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one

3-溴-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮(880mg，2.6mmol，1.0eq)溶于二氧六环(20mL)中，加入三丁基(1-乙氧基乙烯)锡(1144mg，3.2mmol，1.2eq)、双三苯基磷二氯化钯(185mg,0.26mmol,0.1eq)和四(三苯基膦)钯(300mg,0.26mmol,0.1eq)，100℃氩气体系中反应16小时，反应液中加入6mol/L盐酸溶液(5mL)，继续搅拌30分钟，反应液倒入水(50mL)中，乙酸乙酯(30mL)萃取两次，合并有机层，盐水洗涤，无水硫酸钠干燥，浓缩，粗产物柱层析纯化得到3-乙酰基-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮(597mg，收率76％)，白色固体。3-Bromo-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (880 mg, 2.6 mmol, 1.0 eq) was dissolved in dioxane (20 mL), and tributyl(1-ethoxyethylene)tin (1144 mg, 3.2 mmol, 1.2 eq), bistriphenylphosphine palladium dichloride (185 mg, 0.26 mmol, 0.1 eq) and tetrakis(triphenylphosphine)palladium (300 mg, 0.26 mmol, 0.1 eq), reacted in an argon system at 100°C for 16 hours, 6 mol/L hydrochloric acid solution (5 mL) was added to the reaction solution, and stirring was continued for 30 minutes. The reaction solution was poured into water (50 mL), extracted twice with ethyl acetate (30 mL), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to obtain 3-acetyl-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (597 mg, yield 76%) as a white solid.

MS m/z:299.1[M+H]+ MS m/z:299.1[M+H] +

1H NMR(400MHz,氘代氯仿)δ7.67–7.61(m,2H),7.59–7.52(m,3H),2.86(s,3H),2.66(s,3H),2.21(s,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 7.67–7.61 (m, 2H), 7.59–7.52 (m, 3H), 2.86 (s, 3H), 2.66 (s, 3H), 2.21 (s, 3H).

步骤5：3-(1-羟基乙基)-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 5: 3-(1-Hydroxyethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one

0℃下，向3-乙酰基-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮(300mg，1.0mmol，1.0eq)无水甲醇(20mL)溶液中加入硼氢化钠(50mg，1.3mol，1.3eq)，升至室温，反应1小时，缓慢加入2.0mol/L盐酸水溶液(2mL)淬灭，倒入水中(50mL)中，乙酸乙酯(30mL)萃取，合并有机层，盐水洗涤，无水硫酸钠干燥，浓缩，粗产物柱层析纯化得到3-(1-羟基乙基)-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮(279mg，收率93％)，白色固体。To a solution of 3-acetyl-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (300 mg, 1.0 mmol, 1.0 eq) in anhydrous methanol (20 mL) was added sodium borohydride (50 mg, 1.3 mol, 1.3 eq) at 0°C, the temperature was raised to room temperature, the reaction was carried out for 1 hour, 2.0 mol/L aqueous hydrochloric acid solution (2 mL) was slowly added to quench, the mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to give 3-(1-hydroxyethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (279 mg, yield 93%) as a white solid.

MS m/z:301.1[M+H]+ MS m/z:301.1[M+H] +

1H NMR(400MHz,氘代氯仿)δ7.65–7.59(m,2H),7.54(dt,J＝4.6,2.9Hz,3H),5.16(q,J＝6.6Hz,1H),2.60(s,3H),2.32(d,J＝13.9Hz,1H),2.18(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ7.65–7.59 (m, 2H), 7.54 (dt, J=4.6, 2.9 Hz, 3H), 5.16 (q, J=6.6 Hz, 1H), 2.60 (s, 3H), 2.32 (d, J=13.9 Hz, 1H), 2.18 (s, 3H), 1.63 (d, J=6.7 Hz, 3H).

步骤6：3-(1-氯乙基)-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 6: 3-(1-chloroethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one

在0℃下，向3-(1-羟基乙基)-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮(200mg，0.66mmol，1.0eq)的二氯甲烷(20mL)溶液中加入二氯亚砜(0.5mL)，加完升至室温，反应5小时，减压浓缩，粗产物柱层析纯化得到3-(1-氯乙基)-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮(159mg，收率75％)，白色固体。To a solution of 3-(1-hydroxyethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (200 mg, 0.66 mmol, 1.0 eq) in dichloromethane (20 mL) was added thionyl chloride (0.5 mL) at 0°C. The mixture was warmed to room temperature and reacted for 5 hours. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give 3-(1-chloroethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (159 mg, yield 75%) as a white solid.

MS m/z:319/321[M+H]+ MS m/z:319/321[M+H] +

步骤7：2-{[1-(2,6-二甲基-7-氧亚基-5-苯基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}苯甲酸甲酯
Step 7: Methyl 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoate

3-(1-氯乙基)-2,6-二甲基-5-苯基-7H-噻吩并[3,2-b]吡喃-7-酮(120mg，0.51mmol，1.0eq)，碘化钾(78.5mg，0.50mmol，1.0eq)，18-冠-6(124.6mg，0.50mmol，1.0eq)，2-氨基苯甲酸甲酯(211mg，1.41mmol，3.0eq)溶解在无水N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(195mg，1.41mmol，3.0eq)，80℃下反应16小时，用水稀释反应液，乙酸乙酯(30mL)萃取三次，合并有机层，无水硫酸钠干燥，过滤并浓缩，柱层析纯化得到2-{[1-(2,6-二甲基-7-氧亚基-5-苯基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}苯甲酸甲酯(75mg，产率49％)，白色固体。3-(1-Chloroethyl)-2,6-dimethyl-5-phenyl-7H-thieno[3,2-b]pyran-7-one (120 mg, 0.51 mmol, 1.0 eq), potassium iodide (78.5 mg, 0.50 mmol, 1.0 eq), 18-crown-6 (124.6 mg, 0.50 mmol, 1.0 eq), methyl 2-aminobenzoate (211 mg, 1.41 mmol, 3.0 eq) were dissolved in anhydrous N,N-dimethylformamide To the amine (10 mL), potassium carbonate (195 mg, 1.41 mmol, 3.0 eq) was added, and the reaction was carried out at 80 ° C for 16 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate (30 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to give methyl 2-{[1-(2,6-dimethyl-7-oxygen-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoate (75 mg, yield 49%) as a white solid.

MS m/z:434[M+H]+ MS m/z:434[M+H] +

步骤8：2-{[1-(2,6-二甲基-7-氧亚基-5-苯基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}苯甲酸
Step 8: 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoic acid

2-{[1-(2,6-二甲基-7-氧亚基-5-苯基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}苯甲酸甲酯(82.1mg，0.2mmol，1.0eq)，一水合氢氧化锂(47mg,1.1mmol，5.9eq)，水(0.5mL)溶于甲醇和四氢呋喃的混合溶液(4mL,V/V＝1:1)中，50℃下搅拌12小时，冷却至室温，减压浓缩，残留物制备液相分离得到2-{[1-(2,6-二甲基-7-氧亚基-5-苯基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}苯甲酸(36mg，收率46％)，白色固体。Methyl 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoate (82.1 mg, 0.2 mmol, 1.0 eq), lithium hydroxide monohydrate (47 mg, 1.1 mmol, 5.9 eq), and water (0.5 mL) were dissolved in a mixed solution of methanol and tetrahydrofuran (4 mL, V/V=1:1), stirred at 50°C for 12 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was separated by preparative liquid phase to give 2-{[1-(2,6-dimethyl-7-oxyylidene-5-phenylthieno[3,2-b]pyran-3-yl)ethyl]amino}benzoic acid (36 mg, yield 46%) as a white solid.

MS m/z:420[M+H]+ MS m/z:420[M+H] +

实施例2：2-({1-[2,6-二甲基-5-(2-甲基苯基)-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 2: 2-({1-[2,6-dimethyl-5-(2-methylphenyl)-7-oxythieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以邻甲基苯甲酰氯为原料，按照实施例1方法制备2-({1-[2,6-二甲基-5-(2-甲基苯基)-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(1.8mg)，白色固体。 Using o-methylbenzoyl chloride as starting material, 2-({1-[2,6-dimethyl-5-(2-methylphenyl)-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (1.8 mg) was prepared as a white solid according to the method of Example 1.

MS m/z:434[M+H]+ MS m/z:434[M+H] +

实施例3：2-({1-[5-(2-氟苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 3: 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxydethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

步骤1：1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)-3-(2-氟苯基)-3-羟基-2-甲基丙-1-酮
Step 1: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-3-hydroxy-2-methylpropan-1-one

1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)丙-1-酮(150mg,0.5mmol,1.0eq)溶于四氢呋喃/水＝3:2混合溶剂(5mL)中，加入2-氟苯甲醛(212mg,1.7mmol,3.0eq),氢氧化钾(192mg,3.4mmol,6.0eq)，30℃下加热6小时，冷却至室温，加入二氯甲烷(5mL)，过滤，浓缩，残渣柱层析分离得到1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)-3-(2-氟苯基)-3-羟基-2-甲基丙-1-酮(110mg,收率52％)，灰白色固体。1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)propan-1-one (150 mg, 0.5 mmol, 1.0 eq) was dissolved in a tetrahydrofuran/water = 3:2 mixed solvent (5 mL), 2-fluorobenzaldehyde (212 mg, 1.7 mmol, 3.0 eq) and potassium hydroxide (192 mg, 3.4 mmol, 6.0 eq) were added, and the mixture was heated at 30 ° C for 6 hours, cooled to room temperature, and dichloromethane (5 mL) was added. The mixture was filtered and concentrated, and the residue was separated by column chromatography to give 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-3-hydroxy-2-methylpropan-1-one (110 mg, yield 52%) as an off-white solid.

MS m/z:387/389[M+H]+ MS m/z:387/389[M+H] +

步骤2：1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)-3-(2-氟苯基)-2-甲基丙烷-1,3-二酮
Step 2: 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-2-methylpropane-1,3-dione

1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)-3-(2-氟苯基)-3-羟基-2-甲基丙-1-酮(1.0g,2.6mmol,1.0eq)溶于乙酸乙酯中，分批加入Dess-Martin氧化剂(3.29g,7.7mmol,3.0eq)，搅拌2小时，反应液过滤，滤液用饱和碳酸氢钠溶液(200mL)洗涤，有机相无水硫酸钠干燥浓缩，残渣柱层析分离得到1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)-3-(2-氟苯基)-2-甲基丙烷-1,3-二酮(710mg，收率71.5％)。1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-3-hydroxy-2-methylpropan-1-one (1.0 g, 2.6 mmol, 1.0 eq) was dissolved in ethyl acetate, and Dess-Martin oxidant (3.29 g, 7.7 mmol, 3.0 eq) was added in batches. The mixture was stirred for 2 hours, and the reaction solution was filtered. The filtrate was washed with saturated sodium bicarbonate solution (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was separated by column chromatography to obtain 1-(4-bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-2-methylpropane-1,3-dione (710 mg, yield 71.5%).

MS m/z:385/387[M+H]+ MS m/z:385/387[M+H] +

步骤3：3-溴-5-(2-氟苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 3: 3-Bromo-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

1-(4-溴-3-甲氧基-5-甲基噻吩-2-基)-3-(2-氟苯基)-2-甲基丙烷-1,3-二酮(500mg，1.3mmol,1.0eq)溶于40％氢溴酸乙酸溶液(10mL)，在120℃下反应2小时，反应液倒入水(50mL)中，乙酸乙酯(30mL)萃取三次，合并的有机相盐水洗涤，硫酸钠干燥，浓缩，残渣柱层析纯化得到3-溴-5-(2-氟苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(260mg，收率57％)，白色固体。1-(4-Bromo-3-methoxy-5-methylthiophen-2-yl)-3-(2-fluorophenyl)-2-methylpropane-1,3-dione (500 mg, 1.3 mmol, 1.0 eq) was dissolved in 40% hydrobromic acid acetic acid solution (10 mL) and reacted at 120°C for 2 hours. The reaction solution was poured into water (50 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to give 3-bromo-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (260 mg, yield 57%) as a white solid.

MS m/z:353/355[M+H]+ MS m/z:353/355[M+H] +

步骤4：3-乙酰基-5-(2-氟苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 4: 3-Acetyl-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

按照实施例1步骤4方法制备得到3-乙酰基-5-(2-氟苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(162mg,收率79％)。According to the method of step 4 of Example 1, 3-acetyl-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (162 mg, yield 79%) was prepared.

MS m/z:317[M+H]+ MS m/z:317[M+H] +

步骤5：5-(2-氟苯基)-3-(1-羟基乙基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 5: 5-(2-Fluorophenyl)-3-(1-hydroxyethyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

按照实施例1步骤5方法制备得到5-(2-氟苯基)-3-(1-羟基乙基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(153mg,收率95％)，白色固体。According to the method of step 5 of example 1, 5-(2-fluorophenyl)-3-(1-hydroxyethyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (153 mg, yield 95%) was prepared as a white solid.

MS m/z:319[M+H]+ MS m/z:319[M+H] +

步骤6：3-(1-氯乙基)-5-(2-氟苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 6: 3-(1-chloroethyl)-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

按照实施例1步骤6方法制备得到3-(1-氯乙基)-5-(2-氟苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(134mg,收率78％)，白色固体。According to the method of step 6 of Example 1, 3-(1-chloroethyl)-5-(2-fluorophenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (134 mg, yield 78%) was prepared as a white solid.

MS m/z:337/339[M+H]+ MS m/z:337/339[M+H] +

步骤7：2-({1-[5-(2-氟苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸甲酯
Step 7: Methyl 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate

按照实施例1步骤7方法制备得到2-({1-[5-(2-氟苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸甲酯(115mg,收率65％)，白色固体。According to the method of step 7 of Example 1, methyl 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate (115 mg, yield 65%) was prepared as a white solid.

MS m/z:451[M+H]+ MS m/z:451[M+H] +

步骤8：2-({1-[5-(2-氟苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸Step 8: 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

按照实施例1步骤8方法制备得到2-({1-[5-(2-氟苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(38mg,收率34％)，白色固体。According to the method of step 8 of Example 1, 2-({1-[5-(2-fluorophenyl)-2,6-dimethyl-7-oxydithieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (38 mg, yield 34%) was prepared as a white solid.

MS m/z:438[M+H]+ MS m/z:438[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),8.31(d,J＝7.2Hz,1H),7.78(dd,J＝7.9,1.7Hz,1H),7.72-7.59(m,2H),7.50－7.37(m,2H),7.28(ddd,J＝8.7,7.1,1.7Hz,1H),6.61-6.45(m,2H),4.92(q,J＝6.9Hz,1H),2.64(s,3H),1.84(d,J＝1.6Hz,3H),1.57(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.57(s,1H),8.31(d,J＝7.2Hz,1H),7.78(dd,J＝7.9,1.7Hz,1H),7.72-7.59(m,2H),7.50-7.37(m,2H),7.2 8(ddd,J＝8.7,7.1,1.7Hz,1H),6.61-6.45(m,2H),4.92(q,J＝6.9Hz,1H),2.64(s,3H),1.84(d,J＝1.6Hz,3H),1.57(d,J＝6.8Hz,3H).

实施例4：2-({1-[5-(2,3-二氟苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 4: 2-({1-[5-(2,3-difluorophenyl)-2,6-dimethyl-7-oxydethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以2,3-二氟苯甲醛为原料，按照实施例3的方法制备2-({1-[5-(2,3-二氟苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(70mg)，白色固体。Using 2,3-difluorobenzaldehyde as raw material, 2-({1-[5-(2,3-difluorophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (70 mg) was prepared according to the method of Example 3 as a white solid.

MS m/z:456[M+H]+ MS m/z:456[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.31(d,J＝7.3Hz,1H),7.83–7.63(m,2H),7.44(dt,J＝8.0,4.8Hz,2H),7.27(ddd,J＝8.6,7.2,1.7Hz,1H),6.53(ddd,J＝10.3,7.9,2.0Hz,2H),4.94(t,J＝7.0Hz,1H),3.35(s,1H),2.65(s,3H),1.85(d,J＝1.6Hz,3H),1.57(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.31(d,J＝7.3Hz,1H),7.83–7.63(m,2H),7.44(dt,J＝8.0,4.8Hz,2H),7.27(ddd,J＝8.6,7.2,1.7H z,1H),6.53(ddd,J＝10.3,7.9,2.0Hz,2H),4.94(t,J＝7.0Hz,1H),3.35(s,1H),2.65(s,3H),1.85(d,J＝1.6Hz,3H),1.57(d,J＝6.8Hz,3H).

实施例5：2-({1-[5-(2-甲氧基苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 5: 2-({1-[5-(2-methoxyphenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以邻甲氧基苯甲酰氯为原料，按照实施例1方法制备2-({1-[5-(2-甲氧基苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(44.8mg)，白色固体。Using o-methoxybenzoyl chloride as starting material, 2-({1-[5-(2-methoxyphenyl)-2,6-dimethyl-7-oxyidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (44.8 mg) was prepared according to the method of Example 1 as a white solid.

MS m/z:450[M+H]+ MS m/z:450[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),8.30(d,J＝7.0Hz,1H),7.78(dd,J＝7.9,1.7Hz,1H),7.57(ddd,J＝8.8,7.4,1.8Hz,1H),7.43(dd,J＝7.5,1.8Hz,1H),7.29(ddd,J＝8.7,7.0,1.7Hz,1H),7.22(d,J＝8.4Hz,1H),7.12(td,J＝7.5,1.0Hz,1H),6.59-6.48(m,2H),4.90(p,J＝6.9Hz,1H),3.81(s,3H),2.60(s,3H),1.76(s,3H),1.56(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.30(d,J＝7.0Hz,1H),7.78(dd,J＝7.9,1.7Hz, 1H),7.57(ddd,J＝8.8,7.4,1.8Hz,1H),7.43(dd,J＝7.5,1.8Hz,1H),7.29(ddd,J＝8.7, 7.0,1.7Hz,1H),7.22(d,J＝8.4Hz,1H),7.12(td,J＝7.5,1.0Hz,1H),6.59-6.48(m,2H) ,4.90(p,J＝6.9Hz,1H),3.81(s,3H),2.60(s,3H),1.76(s,3H),1.56(d,J＝6.8Hz,3H).

实施例6：2-[(1-{2,6-二甲基-5-[3-(1-甲基吡唑-4-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]苯甲酸
Example 6: 2-[(1-{2,6-dimethyl-5-[3-(1-methylpyrazol-4-yl)phenyl]-7-oxydithieno[3,2-b]pyran-3-yl}ethyl)amino]benzoic acid

以3-(1-甲基吡唑-4-基)苯甲酰氯为原料，按照实施例1的方法制备2-[(1-{2,6-二甲基-5-[3-(1-甲基吡唑-4-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]苯甲酸(3.04mg)，白色固体。2-[(1-{2,6-dimethyl-5-[3-(1-methylpyrazol-4-yl)phenyl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]benzoic acid (3.04 mg) was prepared as a white solid using 3-(1-methylpyrazol-4-yl)benzoyl chloride as the starting material according to the method of Example 1.

MS m/z:500[M+H]+ MS m/z:500[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),8.46(s,1H),8.24(s,1H),8.03-7.89(m,2H),7.85-7.72(m,2H),7.60-7.46(m,2H),7.37-7.27(m,1H),6.66-6.46(m,2H),4.98(t,J＝6.8Hz,1H),3.88(s,3H),2.63(s,3H),2.06(s,3H),1.60(d,J＝6.8Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ12.69(s,1H),8.46(s,1H),8.24(s,1H),8.03-7.89(m,2H),7.85-7.72(m,2H),7.60-7.46(m,2H), 7.37-7.27(m,1H),6.66-6.46(m,2H),4.98(t,J＝6.8Hz,1H),3.88(s,3H),2.63(s,3H),2.06(s,3H),1.60(d,J＝6.8Hz,3H).

3-(1-甲基吡唑-4-基)苯甲酰氯的制备
Preparation of 3-(1-methylpyrazol-4-yl)benzoyl chloride

按照专利WO2021066559方法制备得到3-(1-甲基吡唑-4-基)苯甲酸，3-(1-甲基吡唑-4-基)苯甲酸经氯化反应得到3-(1-甲基吡唑-4-基)苯甲酰氯(446mg)，白色固体。3-(1-methylpyrazol-4-yl)benzoic acid was prepared according to the method of patent WO2021066559, and 3-(1-methylpyrazol-4-yl)benzoic acid was subjected to chlorination reaction to obtain 3-(1-methylpyrazol-4-yl)benzoyl chloride (446 mg) as a white solid.

实施例7：2-({1-[5-(6-甲氧基吡啶-3-基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 7: 2-({1-[5-(6-methoxypyridin-3-yl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以6-甲氧基吡啶-3-甲酰氯为原料，按照实施例1的方法制备2-({1-[5-(6-甲氧基吡啶-3-基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸，白色固体。2-({1-[5-(6-methoxypyridin-3-yl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid was prepared using 6-methoxypyridine-3-carbonyl chloride as a raw material according to the method of Example 1 as a white solid.

MS m/z:451.1[M+H]+ MS m/z:451.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.57(d,J＝2.5Hz,1H),8.41(s,1H),8.02(dd,J＝8.7,2.5Hz,1H),7.78(dd,J＝8.0,1.7Hz,1H),7.32-7.24(m,1H),7.03(d,J＝8.6Hz,1H),6.63-6.48(m,2H),4.98(t,J＝6.8Hz,1H),3.96(s,3H),2.64(s,3H),2.02(s,3H),1.60(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.57(d,J＝2.5Hz,1H),8.41(s,1H),8.02(dd,J＝8.7,2.5Hz,1H),7.78(dd,J＝8.0,1.7Hz,1H),7.32-7.24(m, 1H),7.03(d,J＝8.6Hz,1H),6.63-6.48(m,2H),4.98(t,J＝6.8Hz,1H),3.96(s,3H),2.64(s,3H),2.02(s,3H),1.60(d,J＝6.8Hz,3H).

实施例8：2-({1-[5-(2,3-二氟苯基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 8: 2-({1-[5-(2,3-difluorophenyl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以2,3-二氟苯甲醛和1-(4-溴-3-羟基-5-甲基噻吩-2-基)乙-1-酮为原料，按照实施例3的方法制备2-({1-[5-(2,3-二氟苯基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(0.64mg)，白色固体。Using 2,3-difluorobenzaldehyde and 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one as raw materials, 2-({1-[5-(2,3-difluorophenyl)-2-methyl-7-oxydithieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (0.64 mg) was prepared as a white solid according to the method of Example 3.

MS m/z:442[M+H]+ MS m/z:442[M+H] +

实施例9：2-[(1-{2-甲基-5-[3-(1-甲基吡唑-4-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]苯甲酸
Example 9: 2-[(1-{2-methyl-5-[3-(1-methylpyrazol-4-yl)phenyl]-7-oxydithieno[3,2-b]pyran-3-yl}ethyl)amino]benzoic acid

以3-(1-甲基吡唑-4-基)苯甲酰氯和1-(4-溴-3-羟基-5-甲基噻吩-2-基)乙-1-酮为原料，按照实施例1的方法制备2-[(1-{2-甲基-5-[3-(1-甲基吡唑-4-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]苯甲酸(12mg)，白色固体。Using 3-(1-methylpyrazol-4-yl)benzoyl chloride and 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one as raw materials, 2-[(1-{2-methyl-5-[3-(1-methylpyrazol-4-yl)phenyl]-7-oxydithieno[3,2-b]pyran-3-yl}ethyl)amino]benzoic acid (12 mg) was prepared as a white solid according to the method of Example 1.

MS m/z:486[M+H]+ MS m/z:486[M+H] +

1HNMR(400MHz,DMSO-d6)δ12.72(s,1H),8.59(d,J＝6.9Hz,1H),8.30(s,1H),8.25(d,J＝2.0Hz,1H),8.04(s,1H),7.92-7.85(m,1H),7.79(dd,J＝7.9,1.7Hz,2H),7.57(t,J＝7.8Hz,1H),7.33(ddd,J＝8.7,7.1,1.7Hz, 1H),7.21(s,1H),6.66(d,J＝8.5Hz,1H),6.56(t,J＝7.5Hz,1H),5.10(p,J＝6.7Hz,1H),3.88(s,3H),2.68(s,3H),1.71(d,J＝6.8Hz,3H)。 1 HNMR (400MHz, DMSO-d6) δ12.72(s,1H),8.59(d,J＝6.9Hz,1H),8.30(s,1H),8.25(d,J＝2.0Hz,1H),8.04(s ,1H),7.92-7.85(m,1H),7.79(dd,J＝7.9,1.7Hz,2H),7.57(t,J＝7.8Hz,1H),7.33(ddd,J＝8.7,7.1,1.7Hz, 1H), 7.21 (s, 1H), 6.66 (d, J = 8.5Hz, 1H), 6.56 (t, J = 7.5Hz, 1H), 5.10 (p, J = 6.7Hz, 1H), 3.88 (s, 3H), 2.68 (s, 3H), 1.71 (d, J = 6.8Hz, 3H).

实施例10：2-({1-[2-甲基-5-(2-甲基苯基)-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 10: 2-({1-[2-methyl-5-(2-methylphenyl)-7-oxythieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以2-甲基苯甲酰氯和1-(4-溴-3-羟基-5-甲基噻吩-2-基)乙-1-酮为原料，按照实施例1的方法制备2-({1-[2-甲基-5-(2-甲基苯基)-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(9.1mg)，白色固体。Using 2-methylbenzoyl chloride and 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)ethan-1-one as raw materials, 2-({1-[2-methyl-5-(2-methylphenyl)-7-oxythieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (9.1 mg) was prepared as a white solid according to the method of Example 1.

MS m/z:420[M+H]+ MS m/z:420[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),8.36(d,J＝6.5Hz,1H),7.79(dd,J＝7.9,1.7Hz,1H),7.57(dd,J＝7.6,1.5Hz,1H),7.48(td,J＝7.5,1.5Hz,1H),7.41-7.35(m,2H),7.28(ddd,J＝8.7,7.1,1.7Hz,1H),6.58-6.49(m,2H),6.49(s,1H),4.96(t,J＝6.7Hz,1H),2.62(s,3H),2.44(s,3H),1.61(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),8.36(d,J＝6.5Hz,1H),7.79(dd,J＝7.9,1.7Hz,1H),7.57(dd,J＝7.6,1.5Hz,1H),7.48(td,J＝7.5,1.5Hz,1H),7.41 -7.35(m,2H),7.28(ddd,J＝8.7,7.1,1.7Hz,1H),6.58-6.49(m,2H),6.49(s, 1H), 4.96 (t, J = 6.7Hz, 1H), 2.62 (s, 3H), 2.44 (s, 3H), 1.61 (d, J = 6.8Hz, 3H).

实施例11：2-({1-[5-(六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 11: 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

步骤1：4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-甲酸甲酯
Step 1: 4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylic acid methyl ester

将4-溴-3-羟基-5-甲基噻吩-2-羧酸甲酯(5g,20mmol,1.0eq)溶于N,N-二甲基甲酰胺(200mL)中，依次加入4-甲氧基氯苄(PMBCl)(4g,24mmol,1.2eq)和碳酸钾(3.59g,26mmol,1.3eq)，80℃下反应1小时，加水,乙酸乙酯萃取3次。有机相硫酸钠干燥，浓缩得到粗品，柱层析纯化得到4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-甲酸甲酯(4.9g,产率66％)。4-Bromo-3-hydroxy-5-methylthiophene-2-carboxylic acid methyl ester (5g, 20mmol, 1.0eq) was dissolved in N,N-dimethylformamide (200mL), and 4-methoxybenzyl chloride (PMBCl) (4g, 24mmol, 1.2eq) and potassium carbonate (3.59g, 26mmol, 1.3eq) were added in sequence, reacted at 80°C for 1 hour, and water was added, and extracted with ethyl acetate three times. The organic phase was dried over sodium sulfate and concentrated to obtain a crude product, which was purified by column chromatography to obtain 4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylic acid methyl ester (4.9g, yield 66%).

MS m/z:371/373[M+H]+ MS m/z:371/373[M+H] +

步骤2：4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-甲酸
Step 2: 4-Bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylic acid

将4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-甲酸甲酯(4.6g,12.39mmol,1.0eq)，氢氧化钠(0.5g,12.39mmol,1.0eq)加入到四氢呋喃(9mL)，甲醇(9mL)和水(9mL)的混合液中，室温下搅拌5h，1.0mol/L HCl溶液调节至PH＝5，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，有机相用无水硫酸纳干燥，减压浓缩，残渣柱层析纯化得到4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-甲酸(4.1g，产率92％)。Methyl 4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylate (4.6 g, 12.39 mmol, 1.0 eq) and sodium hydroxide (0.5 g, 12.39 mmol, 1.0 eq) were added to a mixture of tetrahydrofuran (9 mL), methanol (9 mL) and water (9 mL), and stirred at room temperature for 5 h. The pH was adjusted to 5 with 1.0 mol/L HCl solution, and the mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylic acid (4.1 g, yield 92%).

MS m/z:357/359[M+H]+ MS m/z:357/359[M+H] +

步骤3：4-溴-N-甲氧基-3-{[(4-甲氧基苯基)甲基]氧基}-5,N-二甲基噻吩-2-甲酰胺
Step 3: 4-Bromo-N-methoxy-3-{[(4-methoxyphenyl)methyl]oxy}-5,N-dimethylthiophene-2-carboxamide

将4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-甲酸(6.4g,17.9mmol,1.0eq)溶于N,N-二甲基甲酰胺(DMF)(50mL)中，加入N,O-二甲基羟胺(1.1g,17.92mmol,1.0eq)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(10.2g,26.9mmol,1.5eq)，二异丙基乙胺(DIPEA)(5.4g,53.8mmol,3.0eq)，30℃搅拌2h，反应液浓缩柱层析纯化得到4-溴-N-甲氧基-3-{[(4-甲氧基苯基)甲基]氧基}-5,N-二甲基噻吩-2-甲酰胺(4.7g,收率65.5％)，白色固体。4-Bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-carboxylic acid (6.4 g, 17.9 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (DMF) (50 mL), and N,O-dimethylhydroxylamine (1.1 g, 17.92 mmol, 1.0 eq) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate were added. (HATU) (10.2 g, 26.9 mmol, 1.5 eq), diisopropylethylamine (DIPEA) (5.4 g, 53.8 mmol, 3.0 eq), stirred at 30 ° C for 2 h, the reaction solution was concentrated and purified by column chromatography to give 4-bromo-N-methoxy-3-{[(4-methoxyphenyl)methyl]oxy}-5,N-dimethylthiophene-2-carboxamide (4.7 g, yield 65.5%) as a white solid.

MS m/z:400/402[M+H]+ MS m/z:400/402[M+H] +

步骤4：1-(4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-基)-3-(六氢吡啶-1-基)丙烷-1,3-二酮
Step 4: 1-(4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthien-2-yl)-3-(piperidin-1-yl)propane-1,3-dione

乙酰基哌啶(31.8mg,0.25mmol,1.0eq)溶于四氢呋喃(20mL)中，降温至-78℃，缓慢加入2.0mol/L双三甲基硅基胺基锂(0.48mL,3.8eq)，-78℃下反应30分钟，加入4-溴-N-甲氧基-3-{[(4-甲氧基苯基)甲基]氧基}-5,N-二甲基噻吩-2-甲酰胺(100mg，0.25mmol,1.0eq)，-78℃下反应1h，柠檬酸水溶液(100mL)稀释反应液，用乙酸乙酯萃取3次，有机相无水硫酸钠干燥，浓缩，粗品柱层析纯化得到1-(4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-基)-3-(六氢吡啶-1-基)丙烷-1,3-二酮(78mg,产率65％)。Acetylpiperidine (31.8 mg, 0.25 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), cooled to -78 °C, and 2.0 mol/L lithium bis(trimethylsilyl)amide (0.48 mL, 3.8 eq) was slowly added. The mixture was reacted at -78 °C for 30 minutes, and 4-bromo-N-methoxy-3-{[(4-methoxyphenyl)methyl]oxy}-5,N-dimethylthiophene-2-carboxamide (100 mg , 0.25mmol, 1.0eq), reacted at -78°C for 1h, diluted the reaction solution with citric acid aqueous solution (100mL), extracted with ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain 1-(4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophene-2-yl)-3-(hexahydropyridine-1-yl)propane-1,3-dione (78mg, yield 65%).

MS m/z:466/468[M+H]+ MS m/z:466/468[M+H] +

步骤5：1-(4-溴-3-羟基-5-甲基噻吩-2-基)-3-(六氢吡啶-1-基)丙烷-1,3-二酮
Step 5: 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)-3-(piperidin-1-yl)propane-1,3-dione

0℃下，将1-(4-溴-3-{[(4-甲氧基苯基)甲基]氧基}-5-甲基噻吩-2-基)-3-(六氢吡啶-1-基)丙烷-1,3-二酮(580mg,1.24mmol,1.0eq)加入到三氟醋酸/二氯甲烷(10mL/10mL)中，30℃下搅拌1h。加水(100mL)稀释反应液，二氯甲烷(50mL)萃取三次，有机相无水硫酸钠干燥，过滤并浓缩，粗品柱层析纯化得到1-(4-溴-3-羟基-5-甲基噻吩-2-基)-3-(六氢吡啶-1-基)丙烷-1,3-二酮(330mg,产率77％)。1-(4-bromo-3-{[(4-methoxyphenyl)methyl]oxy}-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione (580 mg, 1.24 mmol, 1.0 eq) was added to trifluoroacetic acid/dichloromethane (10 mL/10 mL) at 0°C and stirred at 30°C for 1 h. The reaction solution was diluted with water (100 mL), extracted three times with dichloromethane (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to give 1-(4-bromo-3-hydroxy-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione (330 mg, yield 77%).

MS m/z:346/348[M+H]+ MS m/z:346/348[M+H] +

步骤6：3-溴-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 6: 3-Bromo-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one

1-(4-溴-3-羟基-5-甲基噻吩-2-基)-3-(六氢吡啶-1-基)丙烷-1,3-二酮(130mg,0.37mmol,1.0eq)溶于二氯甲烷(5mL)中，加入三氟甲磺酸酐(472mg,1.68mmol,4.5eq)，室温下搅拌2小时，加入甲醇(5mL)搅拌1小时，加水稀释，乙酸乙酯萃取，无水硫酸钠干燥，浓缩，残渣柱层析纯化得到3-溴-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮(110mg,产率90％)。1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)-3-(hexahydropyridin-1-yl)propane-1,3-dione (130 mg, 0.37 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), trifluoromethanesulfonic anhydride (472 mg, 1.68 mmol, 4.5 eq) was added, and the mixture was stirred at room temperature for 2 hours. Methanol (5 mL) was added and stirred for 1 hour, and the mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give 3-bromo-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (110 mg, yield 90%).

MS m/z:328/330[M+H]+ MS m/z:328/330[M+H] +

步骤7：3-乙酰基-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 7: 3-Acetyl-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one

以3-溴-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮(110mg)为原料，按照实施例1步骤4方法制备3-乙酰基-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮(95mg，产率96％)。Using 3-bromo-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (110 mg) as raw material, 3-acetyl-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (95 mg, yield 96%) was prepared according to the method of step 4 of Example 1.

MS m/z:292[M+H]+ MS m/z:292[M+H] +

步骤8：5-(六氢吡啶-1-基)-3-(1-羟基乙基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 8: 5-(Hexahydropyridin-1-yl)-3-(1-hydroxyethyl)-2-methyl-7H-thieno[3,2-b]pyran-7-one

以3-乙酰基-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮(95mg)为原料，按照实施例1步骤5方法制备5-(六氢吡啶-1-基)-3-(1-羟基乙基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮(89mg，产率94％)。Using 3-acetyl-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (95 mg) as raw material, 5-(hexahydropyridin-1-yl)-3-(1-hydroxyethyl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (89 mg, yield 94%) was prepared according to the method of step 5 of Example 1.

MS m/z:276[M-H2O+H]+ MS m/z:276[MH 2 O+H] +

步骤9：3-(1-氯乙基)-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 9: 3-(1-chloroethyl)-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one

以5-(六氢吡啶-1-基)-3-(1-羟基乙基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮(89mg)为原料，按照实施例1步骤6方法制备3-(1-氯乙基)-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮(68mg，产率72％)，白色固体。Using 5-(hexahydropyridin-1-yl)-3-(1-hydroxyethyl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (89 mg) as raw material, 3-(1-chloroethyl)-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (68 mg, yield 72%) was prepared according to the method of Step 6 of Example 1 as a white solid.

MS m/z:312/314[M+H]+ MS m/z:312/314[M+H] +

步骤10：2-({1-[5-(六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸甲酯
Step 10: Methyl 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate

以3-(1-氯乙基)-5-(六氢吡啶-1-基)-2-甲基-7H-噻吩并[3,2-b]吡喃-7-酮(68mg)为原料，按照实施例1步骤7方法制备2-({1-[5-(六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸甲酯(51mg，产率55％)，白色固体。Using 3-(1-chloroethyl)-5-(hexahydropyridin-1-yl)-2-methyl-7H-thieno[3,2-b]pyran-7-one (68 mg) as raw material, 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid methyl ester (51 mg, yield 55%) was prepared according to the method of Step 7 of Example 1 as a white solid.

MS m/z:427[M+H]MS m/z:427[M+H]

步骤11：2-({1-[5-(六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Step 11: 2-({1-[5-(Hexahydropyridin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以2-({1-[5-(六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸甲酯(51mg)为原料，按照实施例1步骤8方法制备2-({1-[5-(六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(6.1mg，产率12％)，白色固体。Using methyl 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxythieno[3,2-b]pyran-3-yl]ethyl}amino)benzoate (51 mg) as raw material, 2-({1-[5-(hexahydropyridin-1-yl)-2-methyl-7-oxythieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (6.1 mg, yield 12%) was prepared as a white solid according to the method of Step 8 of Example 1.

MS m/z:413[M+H]+ MS m/z:413[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),8.40(d,J＝6.3Hz,1H),7.79(dd,J＝7.9,1.7Hz,1H),7.36-7.22(m,1H),6.68-6.38(m,2H),5.36(s,1H),4.89(t,J＝6.7Hz,1H),3.52-3.40(m,4H),2.60(s,3H),1.61-1.55(m,6H),1.21(d,J＝26.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.40(d,J＝6.3Hz,1H),7.79(dd,J＝7.9,1.7Hz,1H),7.36-7.22(m,1H),6.68-6.38 (m,2H),5.36(s,1H),4.89(t,J＝6.7Hz,1H),3.52-3.40(m,4H),2.60(s,3H),1.61-1.55(m,6H),1.21(d,J＝26.6Hz,3H).

实施例12：2-({1-[2-甲基-7-氧亚基-5-(1,2,3,4-四氢异喹啉-2-基)噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 12: 2-({1-[2-methyl-7-oxyylidene-5-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以1,2,3,4-四氢异喹啉为原料，按照实施例12的方法制备2-({1-[2-甲基-7-氧亚基-5-(1,2,3,4-四氢异喹啉-2-基)噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(5mg)，白色固体。Using 1,2,3,4-tetrahydroisoquinoline as the starting material, 2-({1-[2-methyl-7-oxylidene-5-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (5 mg) was prepared as a white solid according to the method of Example 12.

MS m/z:461[M+H]+ MS m/z:461[M+H] +

实施例13：2-({1-[5-(4,4-二氟六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)-5-氟苯甲酸
Example 13: 2-({1-[5-(4,4-difluorohexahydropyridin-1-yl)-2-methyl-7-oxydethieno[3,2-b]pyran-3-yl]ethyl}amino)-5-fluorobenzoic acid

以4,4-二氟六氢吡啶和2-氨基-5-氟苯甲酸甲酯为原料，按照实施例12的方法制备2-({1-[5-(4,4-二氟六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)-5-氟苯甲酸(3mg)，白色固体。Using 4,4-difluoropiperidine and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[5-(4,4-difluoropiperidin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)-5-fluorobenzoic acid (3 mg) was prepared according to the method of Example 12 as a white solid.

MS m/z:467[M+H]+ MS m/z:467[M+H] +

1H NMR(400MHz,DMSO-d6)δ13.05(s,1H),8.25(s,1H),7.51(dd,J＝9.8,3.2Hz,1H),7.24(t,J＝8.5Hz,1H),6.53(dd,J＝9.3,4.5Hz,1H),5.53(s,1H),4.94-4.83(m,1H),3.61(t,J＝5.9Hz,4H),2.61(s,3H),2.14-1.98(m,4H),1.61(dd,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ13.05(s,1H),8.25(s,1H),7.51(dd,J＝9.8,3.2Hz,1H),7.24(t,J＝8.5Hz,1H),6.53(dd,J＝9.3,4 .5Hz,1H),5.53(s,1H),4.94-4.83(m,1H),3.61(t,J＝5.9Hz,4H),2.61(s,3H),2.14-1.98(m,4H),1.61(dd,J＝6.8Hz,3H).

实施例14：2-({1-[5-(4,4-二氟六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 14: 2-({1-[5-(4,4-difluorohexahydropyridin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以4,4-二氟六氢吡啶为原料，按照实施例12的方法制备2-({1-[5-(4,4-二氟六氢吡啶-1-基)-2-甲基 -7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(4.5mg)，白色固体。Using 4,4-difluorohexahydropyridine as a raw material, 2-({1-[5-(4,4-difluorohexahydropyridine-1-yl)-2-methyl -7-Oxylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (4.5 mg), white solid.

MS m/z:449[M+H]+ MS m/z:449[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.84-7.74(m,1H),7.43-7.24(m,1H),6.61-6.45(m,2H),5.53(s,1H),4.90(t,J＝6.8Hz,1H),3.62(t,J＝5.9Hz,4H),2.62(s,3H),2.13-2.01(m,4H),1.60(d,J＝6.1Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.84-7.74(m,1H),7.43-7.24(m,1H),6.61-6.45(m,2H),5.53(s,1 H), 4.90 (t, J = 6.8Hz, 1H), 3.62 (t, J = 5.9Hz, 4H), 2.62 (s, 3H), 2.13-2.01 (m, 4H), 1.60 (d, J = 6.1Hz, 3H).

实施例15：2-({1-[2-甲基-5-(1,4-氧杂氮杂环己-4-基)-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 15: 2-({1-[2-methyl-5-(1,4-oxazepine-4-yl)-7-oxythieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以吗啉为原料，按照实施例12的方法制备2-({1-[2-甲基-5-(1,4-氧杂氮杂环己-4-基)-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(6.1mg)，白色固体。Using morpholine as starting material, 2-({1-[2-methyl-5-(1,4-oxazepan-4-yl)-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (6.1 mg) was prepared according to the method of Example 12 as a white solid.

MS m/z:415[M+H]+ MS m/z:415[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),8.40(d,J＝6.5Hz,1H),7.80(dd,J＝8.0,1.7Hz,1H),7.30(t,J＝7.5Hz,1H),6.63–6.48(m,2H),5.38(s,1H),4.91(t,J＝6.8Hz,1H),3.70(q,J＝8.6,6.9Hz,4H),3.44(dq,J＝10.7,5.2,4.6Hz,4H),2.61(s,3H),1.64(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),8.40(d,J＝6.5Hz,1H),7.80(dd,J＝8.0,1.7Hz,1H),7.30(t,J＝7.5Hz,1H),6.63–6.48(m,2H),5 .38(s,1H),4.91(t,J＝6.8Hz,1H),3.70(q,J＝8.6,6.9Hz,4H),3.44(dq,J＝10.7,5.2,4.6Hz,4H),2.61(s,3H),1.64(d,J＝6.8Hz,3H).

实施例16：2-({1-[2-(六氢吡啶-1-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 16: 2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

步骤1：3-氨基-4-溴-5-甲基噻吩-2-甲酸甲酯
Step 1: 3-Amino-4-bromo-5-methylthiophene-2-carboxylic acid methyl ester

3-氨基-5-甲基噻吩-2-甲酸甲酯(5.0g,29.2mmol,1.0eq)溶于醋酸(50mL)中，反应液20℃搅拌，分四批加入N-溴代丁二酰亚胺(NBS)(5.98g,33.6mmol,1.1eq)，20℃继续反应1小时，反应液加入 饱和碳酸氢钠水溶液(100mL)稀释，乙酸乙酯(80mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到3-氨基-4-溴-5-甲基噻吩-2-甲酸甲酯(5.94g,收率81.32％)，白色固体。3-Amino-5-methylthiophene-2-carboxylic acid methyl ester (5.0 g, 29.2 mmol, 1.0 eq) was dissolved in acetic acid (50 mL). The reaction solution was stirred at 20°C. N-bromosuccinimide (NBS) (5.98 g, 33.6 mmol, 1.1 eq) was added in four batches. The reaction was continued at 20°C for 1 hour. The mixture was diluted with saturated aqueous sodium bicarbonate solution (100 mL), extracted three times with ethyl acetate (80 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give methyl 3-amino-4-bromo-5-methylthiophene-2-carboxylate (5.94 g, yield 81.32%) as a white solid.

MS m/z:250.1/252.1[M+H]+ MS m/z:250.1/252.1[M+H] +

1H NMR(400MHz,氘代氯仿)δ5.44(s,2H),3.84(s,3H),2.40(s,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 5.44 (s, 2H), 3.84 (s, 3H), 2.40 (s, 3H).

步骤2：4-溴-5-甲基-3-{[(甲基氨基)羰基]氨基}噻吩-2-甲酸甲酯
Step 2: Methyl 4-bromo-5-methyl-3-{[(methylamino)carbonyl]amino}thiophene-2-carboxylate

3-氨基-4-溴-5-甲基噻吩-2-甲酸甲酯(150mg,0.61mmol,1.0eq)，二异丙基乙胺(387.6mg,3.0mmol,5.0eq)，4-二甲氨基吡啶(DMAP)(14.65mg,0.12mmol,0.2eq)和二氯甲烷(DCM)(5mL),氩气保护下，0℃搅拌，加入三光气(88.98mg,0.30mmol,0.5eq)，室温搅拌0.5小时，加入甲胺盐酸盐(81.0mg,1.20mmol,2.0eq)，室温搅拌1小时，加入水(50mL)，过滤，滤饼用乙腈(10mL)打浆，过滤，干燥，得到4-溴-5-甲基-3-{[(甲基氨基)羰基]氨基}噻吩-2-甲酸甲酯(167.64mg，收率91％)，白色固体。3-Amino-4-bromo-5-methylthiophene-2-carboxylic acid methyl ester (150 mg, 0.61 mmol, 1.0 eq), diisopropylethylamine (387.6 mg, 3.0 mmol, 5.0 eq), 4-dimethylaminopyridine (DMAP) (14.65 mg, 0.12 mmol, 0.2 eq) and dichloromethane (DCM) (5 mL) were stirred at 0 ° C under argon protection, and triphosgene (88.98 mg, 0 .30mmol, 0.5eq), stirred at room temperature for 0.5 hour, added methylamine hydrochloride (81.0mg, 1.20mmol, 2.0eq), stirred at room temperature for 1 hour, added water (50mL), filtered, the filter cake was slurried with acetonitrile (10mL), filtered, and dried to obtain 4-bromo-5-methyl-3-{[(methylamino)carbonyl]amino}thiophene-2-carboxylic acid methyl ester (167.64mg, yield 91%) as a white solid.

MS m/z:307/309[M+H]+ MS m/z:307/309[M+H] +

步骤3:7-溴-3,6-二甲基-1,2,3,4-四氢噻吩并[3,2-d]嘧啶-2,4-二酮
Step 3: 7-Bromo-3,6-dimethyl-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2,4-dione

4-溴-5-甲基-3-{[(甲基氨基)羰基]氨基}噻吩-2-甲酸甲酯(500mg,1.62mmol,1.0eq)溶于甲醇中(10mL)，0℃加入甲醇钠(262mg,4.86mmol,3.0eq)，搅拌2小时，浓缩，加入水(20mL)，乙酸乙酯(20mL)，分离有机相，无水硫酸钠干燥，浓缩，残渣柱层析纯化得到7-溴-3,6-二甲基-1,2,3,4-四氢噻吩并[3,2-d]嘧啶-2,4-二酮(400mg,产率89％)。Methyl 4-bromo-5-methyl-3-{[(methylamino)carbonyl]amino}thiophene-2-carboxylate (500 mg, 1.62 mmol, 1.0 eq) was dissolved in methanol (10 mL), sodium methoxide (262 mg, 4.86 mmol, 3.0 eq) was added at 0°C, stirred for 2 hours, concentrated, water (20 mL) and ethyl acetate (20 mL) were added, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to give 7-bromo-3,6-dimethyl-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2,4-dione (400 mg, yield 89%).

MS m/z:275/277[M+H]+ MS m/z:275/277[M+H] +

步骤4:7-溴-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 4: 7-Bromo-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

室温下，7-溴-3,6-二甲基-1,2,3,4-四氢噻吩并[3,2-d]嘧啶-2,4-二酮(400mg,1.46mmol,1.0eq)溶于N`N-二甲基甲酰胺(10mL)中，加入三吡咯烷基溴化鏻六氟磷酸盐(Pybrop)(748mg,1.60mmol,1.1eq)，二异丙基乙胺(DIPEA)(570mg,4.38mmol,3.0eq)，80℃下搅拌0.5小时，加入哌啶(248mg,2.92mmol,2.0eq)，80℃搅拌1.0小时。反应液冷却至室温，加入乙酸乙酯稀释，加入水，分离有机相，水相乙酸乙酯萃取一次，合并有机相，依次用水、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物柱层析纯化得到7-溴-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(387mg，收率77％)，白色固体。At room temperature, 7-bromo-3,6-dimethyl-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-2,4-dione (400 mg, 1.46 mmol, 1.0 eq) was dissolved in N`N-dimethylformamide (10 mL), and tripyrrolidinylphosphonium bromide hexafluorophosphate (Pybrop) (748 mg, 1.60 mmol, 1.1 eq) and diisopropylethylamine (DIPEA) (570 mg, 4.38 mmol, 3.0 eq) were added. The mixture was stirred at 80°C for 0.5 hour, and piperidine (248 mg, 2.92 mmol, 2.0 eq) was added. The mixture was stirred at 80°C for 1.0 hour. The reaction solution was cooled to room temperature, diluted with ethyl acetate, added with water, the organic phase was separated, the aqueous phase was extracted once with ethyl acetate, the organic phases were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 7-bromo-2-(hexahydropyridine-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (387 mg, yield 77%) as a white solid.

MS m/z：342.1[M+H]+ MS m/z：342.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ3.46(s,3H),3.17(t,J＝5.2Hz,4H),2.53(s,3H),1.70-1.58(m,6H)。 1 H NMR (400MHz, DMSO-d6) δ3.46 (s, 3H), 3.17 (t, J = 5.2Hz, 4H), 2.53 (s, 3H), 1.70-1.58 (m, 6H).

步骤5:7-乙酰基-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 5: 7-Acetyl-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

7-溴-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(387mg,1.13mmol，1.0eq)，四三苯基膦钯(130mg,0.113mmol,0.1eq)，双三苯基膦二氯化钯(79mg,0.113mmol,0.1eq)和三丁基(1-乙氧基乙烯)锡(611mg,1.69mmol,1.5eq)溶于二氧六环(10mL)中，氩气保护，100℃下搅拌16小时，冷却至室温，加入2mol/L盐酸(1.0mL)，搅拌0.5小时，加入饱和氟化钾溶液(1.0mL)，搅拌0.5小时，反应物硅藻土过滤，滤饼用二氯甲烷：甲醇(10：1)洗三次，有机相无水硫酸钠干燥，减压浓缩，残留物柱层析纯化得到产物7-乙酰基-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(270mg，收率78％)，白色固体。7-Bromo-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (387 mg, 1.13 mmol, 1.0 eq), tetrakistriphenylphosphine palladium (130 mg, 0.113 mmol, 0.1 eq), bistriphenylphosphine palladium dichloride (79 mg, 0.113 mmol, 0.1 eq) and tributyl(1-ethoxyethylene)tin (611 mg, 1.69 mmol, 1.5 eq) were dissolved in dioxane (10 mL) under argon protection at 100 °C. The mixture was stirred for 16 hours at room temperature, cooled to room temperature, 2 mol/L hydrochloric acid (1.0 mL) was added, stirred for 0.5 hours, saturated potassium fluoride solution (1.0 mL) was added, stirred for 0.5 hours, the reactant was filtered through diatomaceous earth, the filter cake was washed three times with dichloromethane: methanol (10: 1), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give the product 7-acetyl-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (270 mg, yield 78%) as a white solid.

MS m/z：306.1[M+H]+ MS m/z：306.1[M+H] +

步骤6：2-(六氢吡啶-1-基)-7-(1-羟基乙基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 6: 2-(Hexahydropyridin-1-yl)-7-(1-hydroxyethyl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

以7-乙酰基-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，按照实施例1步骤5的方法制备2-(六氢吡啶-1-基)-7-(1-羟基乙基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(240mg,产率86％)，白色固体。 Using 7-acetyl-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as raw material, 2-(hexahydropyridin-1-yl)-7-(1-hydroxyethyl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (240 mg, yield 86%) was prepared according to the method of step 5 of Example 1 as a white solid.

MS m/z：308.1[M+H]+ MS m/z：308.1[M+H] +

1H NMR(400MHz,氘代氯仿)δ5.02(q,J＝6.6Hz,1H),3.59(s,3H),3.17(t,J＝5.3Hz,4H),2.48(s,3H),1.80–1.66(m,6H),1.57(d,J＝6.6Hz,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 5.02 (q, J = 6.6 Hz, 1H), 3.59 (s, 3H), 3.17 (t, J = 5.3 Hz, 4H), 2.48 (s, 3H), 1.80–1.66 (m, 6H), 1.57 (d, J = 6.6 Hz, 3H).

步骤7:7-(1-氯乙基)-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 7: 7-(1-chloroethyl)-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

以2-(六氢吡啶-1-基)-7-(1-羟基乙基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，按照实施例1步骤6的方法制备7-(1-氯乙基)-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(286mg，收率100％)，黄色固体。Using 2-(hexahydropyridin-1-yl)-7-(1-hydroxyethyl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as raw material, 7-(1-chloroethyl)-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (286 mg, yield 100%) was prepared according to the method of Step 6 of Example 1 as a yellow solid.

MS m/z：326.1/328.1[M+H]+ MS m/z：326.1/328.1[M+H] +

步骤8:2-({1-[2-(六氢吡啶-1-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸甲酯
Step 8: Methyl 2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoate

以7-(1-氯乙基)-2-(六氢吡啶-1-基)-3,6-二甲基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，按照实施例1步骤7的方法制备2-({1-[2-(六氢吡啶-1-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸甲酯(51mg，收率32％)，白色固体。Using 7-(1-chloroethyl)-2-(hexahydropyridin-1-yl)-3,6-dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as raw material, 2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid methyl ester (51 mg, yield 32%) was prepared as a white solid according to the method of step 7 of Example 1.

MS m/z：441.1[M+H]+ MS m/z：441.1[M+H] +

步骤9:2-({1-[2-(六氢吡啶-1-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Step 9: 2-({1-[2-(Hexahydropyridin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以2-({1-[2-(六氢吡啶-1-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸甲酯为原料，按照实施例1步骤8的方法制备2-({1-[2-(六氢吡啶-1-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d] 嘧啶-7-基]乙基}氨基)苯甲酸(5mg，收率10％)，白色固体。2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid methyl ester was used as a raw material to prepare 2-({1-[2-(hexahydropyridin-1-yl)-3,6-dimethyl-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid methyl ester according to the method of step 8 of Example 1 [0137]pyrimidin-7-yl]ethyl}amino)benzoic acid (5 mg, yield 10%), white solid.

MS m/z：427.1[M+H]+ MS m/z：427.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.49(s,1H),7.75(dd,J＝7.9,1.7Hz,1H),7.26(ddd,J＝8.7,7.0,1.7Hz,1H),6.65(d,J＝8.5Hz,1H),6.53–6.45(m,1H),5.02(d,J＝6.8Hz,1H),3.44(s,3H),3.17(t,J＝5.2Hz,4H),2.58(s,3H),1.76–1.58(m,9H)。 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.49(s,1H),7.75(dd,J＝7.9,1.7Hz,1H),7.26(ddd,J＝8.7,7.0,1.7Hz,1H),6.65(d, J＝8.5Hz,1H),6.53–6.45(m,1H),5.02(d,J＝6.8Hz,1H),3.44(s,3H),3.17(t,J＝5.2Hz,4H),2.58(s,3H),1.76–1.58(m,9H).

实施例17：2-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,4-四氢异喹啉-2-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 17: 2-({1-[3,6-dimethyl-4-oxylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以1,2,3,4-四氢异喹啉为原料，按照实施例16的方法制备2-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,4-四氢异喹啉-2-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(6mg)，白色固体。2-({1-[3,6-dimethyl-4-oxylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (6 mg) was prepared from 1,2,3,4-tetrahydroisoquinoline as a white solid according to the method of Example 16.

MS m/z：475.1[M+H]+ MS m/z：475.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.69-8.54(m,1H),7.75(dd,J＝8.0,1.7Hz,1H),7.24(dt,J＝26.4,4.3Hz,5H),6.66(d,J＝8.5Hz,1H),6.49(t,J＝7.5Hz,1H),5.09-4.97(m,1H),4.61-4.44(m,2H),3.50(s,3H),3.01(dt,J＝6.7,3.5Hz,2H),2.61(s,3H),1.77-1.70(m,2H),1.61(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.69-8.54(m,1H),7.75(dd,J＝8.0,1.7Hz,1H),7.24(dt,J＝26.4,4.3Hz,5H),6.66(d,J＝8.5Hz,1H),6.49(t,J ＝7.5Hz,1H),5.09-4.97(m,1H),4.61-4.44(m,2H),3.50(s,3H),3.01(dt, J＝6.7,3.5Hz,2H),2.61(s,3H),1.77-1.70(m,2H),1.61(d,J＝6.7Hz,3H).

实施例18：2-({1-[3,6-二甲基-4-氧亚基-2-(四氢-1H-吡咯-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 18: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(tetrahydro-1H-pyrrol-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以吡咯和2-氨基-5-氟苯甲酸甲酯为原料，按照实施例16的方法制备2-({1-[3,6-二甲基-4-氧亚基-2-(四氢-1H-吡咯-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(7mg)，白色固体。Using pyrrole and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[3,6-dimethyl-4-oxyylidene-2-(tetrahydro-1H-pyrrol-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (7 mg) was prepared as a white solid according to the method of Example 16.

MS m/z：431.2[M+H]+ MS m/z：431.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ7.42(dd,J＝9.7,3.3Hz,1H),7.16(td,J＝8.6,3.4Hz,1H),6.64(dd,J＝9.4,4.5Hz,1H),4.91(q,J＝6.8Hz,1H),3.47(d,J＝8.2Hz,4H),3.89(s,3H),3.37(s,3H),1.85(q,J＝5.6Hz,4H),1.57(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ7.42(dd,J＝9.7,3.3Hz,1H),7.16(td,J＝8.6,3.4Hz,1H),6.64(dd,J＝9.4,4.5Hz,1H),4.9 1(q,J＝6.8Hz,1H),3.47(d,J＝8.2Hz,4H),3.89(s,3H),3.37(s,3H),1.85(q,J＝5.6Hz,4H),1.57(d,J＝6.7Hz,3H).

实施例19：2-({1-[5-(4,4-二甲基六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 19: 2-({1-[5-(4,4-dimethylpiperidin-1-yl)-2-methyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以4,4-二甲基六氢吡啶为原料，按照实施例11的方法制备2-({1-[5-(4,4-二甲基六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(12mg)，白色固体。Using 4,4-dimethylpiperidine as the starting material, 2-({1-[5-(4,4-dimethylpiperidin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (12 mg) was prepared as a white solid according to the method of Example 11.

MS m/z：441.1[M+H]+ MS m/z：441.1[M+H] +

实施例20：2-({1-[2-甲基-7-氧亚基-5-(6-氮杂螺[2.5]辛-6-基)噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸
Example 20: 2-({1-[2-methyl-7-oxylidene-5-(6-azaspiro[2.5]oct-6-yl)thieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid

以6-氮杂螺[2.5]辛烷为原料，按照实施例11的方法制备2-({1-[5-(4,4-二甲基六氢吡啶-1-基)-2-甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)苯甲酸(10.5mg)，白色固体。2-({1-[5-(4,4-dimethylpiperidin-1-yl)-2-methyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)benzoic acid (10.5 mg) was prepared as a white solid using 6-azaspiro[2.5]octane as the starting material according to the method of Example 11.

MS m/z：439.1[M+H]+ MS m/z：439.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),8.42(s,1H),7.79(s,1H),7.31(d,J＝8.9Hz,1H),6.80-6.25(m,2H),5.48-5.30(m,1H),4.89(s,1H),3.68(d,J＝131.9Hz,4H),2.61(s,3H),2.22-1.93(m,2H),1.61(d,J＝7.0Hz,3H),1.38(d,J＝22.1Hz,2H),1.24(s,2H),1.10-0.74(m,2H)。 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),8.42(s,1H),7.79(s,1H),7.31(d,J＝8.9Hz,1H),6.80-6.25(m,2H),5.48-5.30(m,1H),4.89(s,1H) ,3.68(d,J＝131.9Hz,4H),2.61(s,3H),2.22-1.93(m,2H),1.61(d,J＝7.0Hz,3H),1.38(d,J＝22.1Hz,2H),1.24(s,2H),1.10-0.74(m,2H).

实施例21：2-({1-[3,6-二甲基-4-氧亚基-2-(四氢-1H-吡咯-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 21: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(tetrahydro-1H-pyrrol-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以吡咯为原料，按照实施例16的方法制备2-({1-[3,6-二甲基-4-氧亚基-2-(四氢-1H-吡咯-1-基)噻 吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(10.1mg)，白色固体。Using pyrrole as a raw material, 2-({1-[3,6-dimethyl-4-oxyylidene-2-(tetrahydro-1H-pyrrol-1-yl)thiophene] [0147] [0148] [0149] [0151] [0152] [0153] [0154] [0155] [0156] [0157] [0158] [0159] [0161] [0162] [0163] [0164] [0165] [0166] [0167] [0168] [0169] [0171] [0172] [0173] [0174] [0175] [0176] [0177] [0178] [0179] [0181] [0182] [0183] [0184] [0185] [0186] [0187] [0188] [0189] [0190] [0191] [0192] [01

MS m/z：413.1[M+H]+ MS m/z：413.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.53(s,1H),7.75(dd,J＝8.0,1.7Hz,1H),7.27(ddd,J＝8.7,7.0,1.8Hz,1H),6.66(d,J＝8.5Hz,1H),6.53-6.43(m,1H),5.00(s,1H),3.56(dtd,J＝16.6,10.8,9.7,6.0Hz,4H),3.41(s,3H),2.57(s,3H),1.89(q,J＝5.8Hz,4H),1.62(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.50(s,1H),8.53(s,1H),7.75(dd,J＝8.0,1.7Hz,1H),7.27(ddd,J＝8.7,7.0,1.8Hz,1H),6.66(d,J＝8.5Hz,1H),6.5 3-6.43(m,1H),5.00(s,1H),3.56(dtd,J＝16.6,10.8,9.7,6.0Hz,4H), 3.41 (s, 3H), 2.57 (s, 3H), 1.89 (q, J = 5.8Hz, 4H), 1.62 (d, J = 6.7Hz, 3H).

实施例22：2-({1-[2-(4,4-二甲基六氢吡啶-1-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 22: 2-({1-[2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以4,4-二甲基六氢吡啶为原料，按照实施例16的方法制备2-({1-[2-(4,4-二甲基六氢吡啶-1-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(6mg)，白色固体。Using 4,4-dimethylpiperidine as the starting material, 2-({1-[2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (6 mg) was prepared according to the method of Example 16 as a white solid.

MS m/z：455.1[M+H]+ MS m/z：455.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.51(d,J＝8.0Hz,1H),7.75(dd,J＝7.9,1.7Hz,1H),7.26(ddd,J＝8.7,7.0,1.7Hz,1H),6.66(d,J＝8.5Hz,1H),6.53-6.42(m,1H),5.03(t,J＝6.9Hz,1H),3.43(s,3H),3.20(t,J＝5.7Hz,4H),2.58(s,3H),1.63(d,J＝6.7Hz,3H),1.49(dq,J＝19.3,7.4,6.6Hz,4H),1.01(s,6H)。 1 H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.51(d,J＝8.0Hz,1H),7.75(dd,J＝7.9 ,1.7Hz,1H),7.26(ddd,J＝8.7,7.0,1.7Hz,1H),6.66(d,J＝8.5Hz,1H),6.53-6 .42(m,1H),5.03(t,J＝6.9Hz,1H),3.43(s,3H),3.20(t,J＝5.7Hz,4H),2.58( s, 3H), 1.63 (d, J = 6.7Hz, 3H), 1.49 (dq, J = 19.3, 7.4, 6.6Hz, 4H), 1.01 (s, 6H).

实施例23：2-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,4-四氢异喹啉-2-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 23: 2-({1-[3,6-dimethyl-4-oxylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以1,2,3,4-四氢异喹啉和2-氨基-5-氟苯甲酸甲酯为原料，按照实施例16的方法制备2-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,4-四氢异喹啉-2-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(5mg)，白色固体。2-({1-[3,6-dimethyl-4-oxylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (5 mg) was prepared as a white solid using 1,2,3,4-tetrahydroisoquinoline and methyl 2-amino-5-fluorobenzoate as starting materials according to the method of Example 16.

MS m/z：493.2[M+H]+ MS m/z：493.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),8.53(s,1H),7.46(dd,J＝9.8,3.2Hz,1H),7.30-7.24(m,1H),7.23-7.16(m,4H),6.67(dd,J＝9.4,4.5Hz,1H),5.00(d,J＝7.1Hz,1H),4.62-4.41(m,2H),3.59- 3.45(m,5H),3.13-2.94(m,2H),2.61(s,3H),1.60(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.53(s,1H),7.46(dd,J＝9.8,3.2Hz,1H),7.30-7.24(m,1H ),7.23-7.16(m,4H),6.67(dd,J＝9.4,4.5Hz,1H),5.00(d,J＝7.1Hz,1H),4.62-4.41(m,2H),3.59- 3.45(m,5H),3.13-2.94(m,2H),2.61(s,3H),1.60(d,J＝6.8Hz,3H).

实施例24:2-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,6-四氢吡啶-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 24: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,6-tetrahydropyridin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以1,2,3,6-四氢吡啶和2-氨基-5-氟苯甲酸甲酯为原料，按照实施例16的方法制备2-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,6-四氢吡啶-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(5mg)，白色固体。Using 1,2,3,6-tetrahydropyridine and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,6-tetrahydropyridin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (5 mg) was prepared as a white solid according to the method of Example 16.

MS m/z：443.1[M+H]+ MS m/z：443.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.37(s,1H),7.46(dd,J＝9.8,3.2Hz,1H),7.21(ddd,J＝9.3,7.9,3.2Hz,1H),6.68(dd,J＝9.4,4.5Hz,1H),5.93-5.79(m,2H),5.01(d,J＝7.2Hz,1H),3.95-3.71(m,2H),3.44(s,3H),3.39-3.23(m,2H),2.59(s,3H),2.42-2.22(m,2H),1.62(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.37(s,1H),7.46(dd,J＝9.8,3.2Hz,1H),7.21(ddd,J＝9.3,7.9,3.2Hz,1H),6.68(dd,J＝9.4,4.5Hz,1H),5. 93-5.79(m,2H),5.01(d,J＝7.2Hz,1H),3.95-3.71(m,2H),3.44(s,3H),3 .39-3.23(m,2H),2.59(s,3H),2.42-2.22(m,2H),1.62(d,J＝6.7Hz,3H).

实施例25:2-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,6-四氢吡啶-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 25: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,6-tetrahydropyridin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以1,2,3,6-四氢吡啶为原料，按照实施例16的方法制备2-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,6-四氢吡啶-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(7mg)，白色固体。Using 1,2,3,6-tetrahydropyridine as the starting material, 2-({1-[3,6-dimethyl-4-oxyylidene-2-(1,2,3,6-tetrahydropyridin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (7 mg) was prepared as a white solid according to the method of Example 16.

MS m/z：425.1[M+H]+ MS m/z：425.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.54(d,J＝8.3Hz,1H),7.75(dd,J＝8.0,1.7Hz,1H),7.27(ddd,J＝8.6,7.1,1.8Hz,1H),6.67(d,J＝8.3Hz,1H),6.54–6.45(m,1H),5.95–5.78(m,2H),5.04(q,J＝6.8Hz,1H),3.91(dt,J＝17.5,2.8Hz,1H),3.77(dt,J＝17.4,2.6Hz,1H),3.43(s,3H),3.40–3.24(m,3H),2.60(s,3H),2.33(q,J＝18.0,17.5Hz,2H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.54(d,J＝8.3Hz,1H),7.75(dd,J＝8.0,1.7Hz,1H),7 .27(ddd,J＝8.6,7.1,1.8Hz,1H),6.67(d,J＝8.3Hz,1H),6.54–6.45(m,1H),5.95–5.78(m,2H ),5.04(q,J＝6.8Hz,1H),3.91(dt,J＝17.5,2.8Hz,1H),3.77(dt,J＝17.4,2.6Hz,1H),3.43( s,3H),3.40–3.24(m,3H),2.60(s,3H),2.33(q,J＝18.0,17.5Hz,2H),1.63(d,J＝6.7Hz,3H).

实施例26:2-({1-[3,6-二甲基-4-氧亚基-2-(6-氮杂螺[2.5]辛-6-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 26: 2-({1-[3,6-dimethyl-4-oxyylidene-2-(6-azaspiro[2.5]oct-6-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以6-氮杂螺[2.5]辛烷为原料，按照实施例16的方法制备2-({1-[3,6-二甲基-4-氧亚基-2-(6-氮杂螺[2.5]辛-6-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(15mg)，白色固体。2-({1-[3,6-dimethyl-4-oxyylidene-2-(6-azaspiro[2.5]octan-6-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (15 mg) was prepared using 6-azaspiro[2.5]octane as a white solid according to the method of Example 16.

MS m/z：453.1[M+H]+ MS m/z：453.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.48(d,J＝8.1Hz,1H),7.76(dd,J＝8.0,1.7Hz,1H),7.26(ddd,J＝8.7,7.1,1.7Hz,1H),6.65(d,J＝8.5Hz,1H),6.54–6.45(m,1H),5.04(t,J＝6.7Hz,1H),3.46(s,3H),3.25(q,J＝3.6,2.8Hz,4H),2.58(s,3H),1.63(d,J＝6.8Hz,3H),1.52(dp,J＝23.5,6.1,5.0Hz,4H),0.38(s,4H)。 1 H NMR (400MHz, DMSO-d6) δ12.50 (s, 1H), 8.48 (d, J = 8.1Hz, 1H), 7.76 (dd, J = 8.0, 1.7Hz,1H),7.26(ddd,J＝8.7,7.1,1.7Hz,1H),6.65(d,J＝8.5Hz,1H),6.54–6.4 5(m,1H),5.04(t,J＝6.7Hz,1H),3.46(s,3H),3.25(q,J＝3.6,2.8Hz,4H),2.58 (s, 3H), 1.63 (d, J = 6.8 Hz, 3H), 1.52 (dp, J = 23.5, 6.1, 5.0 Hz, 4H), 0.38 (s, 4H).

实施例27:2-({1-[2-(2,3-二氢-1H-异吲哚-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 27: 2-({1-[2-(2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以2,3-二氢-1H-异吲哚及2-氨基-5-氟苯甲酸甲酯为原料，按照实施例16的方法制备2-({1-[2-(2,3-二氢-1H-异吲哚-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(5mg)，白色固体。Using 2,3-dihydro-1H-isoindole and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[2-(2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (5 mg) was prepared as a white solid according to the method of Example 16.

MS m/z：479.2[M+H]+ MS m/z：479.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),8.45(s,1H),7.47(dd,J＝9.8,3.2Hz,1H),7.40(dd,J＝5.6,3.2Hz,2H),7.32(dd,J＝5.7,3.2Hz,2H),7.17(td,J＝8.6,3.2Hz,1H),6.65(dd,J＝9.4,4.5Hz,1H),5.04(q,J＝13.7Hz,5H),3.57(s,3H),2.56(s,3H),1.62(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.45(s,1H),7.47(dd,J＝9.8,3.2Hz,1H),7.40(dd,J＝5.6,3.2Hz,2H),7.32(dd,J＝5.7,3.2Hz,2 H), 7.17 (td, J = 8.6, 3.2Hz, 1H), 6.65 (dd, J = 9.4, 4.5Hz, 1H), 5.04 (q, J = 13.7Hz, 5H), 3.57 (s, 3H), 2.56 (s, 3H), 1.62 (d, J = 6.7Hz, 3H).

实施例28:5-氟-2-({1-[2-(5-氟-2,3-二氢-1H-异吲哚-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 28: 5-Fluoro-2-({1-[2-(5-fluoro-2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以5-氟-2,3-二氢-1H-异吲哚及2-氨基-5-氟苯甲酸甲酯为原料，按照实施例16的方法制备5-氟-2- ({1-[2-(5-氟-2,3-二氢-1H-异吲哚-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(25mg)，白色固体。Using 5-fluoro-2,3-dihydro-1H-isoindole and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 5-fluoro-2- ({1-[2-(5-Fluoro-2,3-dihydro-1H-isoindol-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (25 mg), white solid.

MS m/z：497.1[M+H]+ MS m/z：497.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.38(s,1H),7.45(ddd,J＝19.1,9.1,4.2Hz,2H),7.27(dd,J＝8.9,2.5Hz,1H),7.17(dtd,J＝19.7,8.8,8.4,2.9Hz,2H),6.66(dd,J＝9.4,4.5Hz,1H),5.12–4.92(m,5H),3.56(s,3H),2.57(s,3H),1.61(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.38(s,1H),7.45(ddd,J＝19.1,9.1,4.2Hz,2H),7.27(dd,J＝8.9,2.5Hz,1H),7.17(dtd, J＝19.7,8.8,8.4,2.9Hz,2H),6.66(dd,J＝9.4,4.5Hz,1H),5.12–4.92(m,5H),3.56(s,3H),2.57(s,3H),1.61(d,J＝6.7Hz,3H).

实施例29:6-氯-3-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,4-四氢异喹啉-2-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 29: 6-Chloro-3-({1-[3,6-dimethyl-4-oxylidene-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以1,2,3,4-四氢异喹啉和3-氨基-6-氯吡啶-2-甲酸甲酯为原料，按照实施例16的方法制备6-氯-3-({1-[3,6-二甲基-4-氧亚基-2-(1,2,3,4-四氢异喹啉-2-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(9mg)，白色固体。6-Chloro-3-({1-[3,6-dimethyl-4-oxygenylidene-2-(1,2,3,4-tetrahydroisoquinoline-2-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (9 mg) was prepared as a white solid using 1,2,3,4-tetrahydroisoquinoline and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials according to the method of Example 16.

MS m/z：510.1[M+H]+ MS m/z：510.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.68(d,J＝8.5Hz,1H),7.40(d,J＝9.0Hz,1H),7.31-7.24(m,2H),7.20(d,J＝3.8Hz,3H),5.04(q,J＝7.3Hz,1H),4.61-4.42(m,2H),3.50(s,5H),3.10-2.94(m,2H),2.62(s,3H),1.61(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),8.68(d,J＝8.5Hz,1H),7.40(d,J＝9.0Hz,1H),7.31-7.24(m,2H),7.20(d,J＝3.8 Hz, 3H), 5.04 (q, J = 7.3Hz, 1H), 4.61-4.42 (m, 2H), 3.50 (s, 5H), 3.10-2.94 (m, 2H), 2.62 (s, 3H), 1.61 (d, J = 6.7Hz, 3H).

实施例30：2-{[1-(3,6-二甲基-4-氧亚基-2-苯基噻吩并[3,2-d]嘧啶-7-基)乙基]氨基}苯甲酸
Example 30: 2-{[1-(3,6-dimethyl-4-oxyylidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino}benzoic acid

步骤1：3-氨基-4-溴-5-甲基噻吩-2-甲酸
Step 1: 3-Amino-4-bromo-5-methylthiophene-2-carboxylic acid

茄形瓶中加入3-氨基-5-甲基噻吩-2-甲酸甲酯(8.0g,32.0mmol,1.0eq)，氢氧化钾(5.4g,96.0mmol, 3.0eq)和水(20mL)，甲醇(20mL)，四氢呋喃(THF)(80mL)，60℃搅拌14h，冷却至室温，浓缩，残渣中加入水(50mL)，浓盐酸调Ph＝4，过滤，滤饼水洗一次，干燥得到3-氨基-4-溴-5-甲基噻吩-2-甲酸(6.80g，收率90％)，白色固体。Add 3-amino-5-methylthiophene-2-carboxylic acid methyl ester (8.0 g, 32.0 mmol, 1.0 eq) and potassium hydroxide (5.4 g, 96.0 mmol, 3.0eq) and water (20mL), methanol (20mL), tetrahydrofuran (THF) (80mL), stirred at 60°C for 14h, cooled to room temperature, concentrated, water (50mL) was added to the residue, and Ph=4 was adjusted with concentrated hydrochloric acid, filtered, the filter cake was washed once with water, and dried to give 3-amino-4-bromo-5-methylthiophene-2-carboxylic acid (6.80g, yield 90%) as a white solid.

MS m/z：235.9/237.9[M+1]+ MS m/z：235.9/237.9[M+1] +

步骤2：3-氨基-4-溴-5,N-二甲基噻吩-2-甲酰胺
Step 2: 3-Amino-4-bromo-5,N-dimethylthiophene-2-carboxamide

茄形瓶中加入3-氨基-4-溴-5-甲基噻吩-2-甲酸(6.8g,28.8mmol,1.0eq)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(13.1g,34.6mmol,1.2eq)，甲胺盐酸盐(2.9g,43.2mmol,1.5eq)，二异丙基乙胺(11.2g,86.4mmol,3.0eq)和N,N-二甲基甲酰胺(DMF)(60mL)，氩气保护下，室温搅拌0.5h，反应液加入水(150mL)稀释，乙酸乙酯(100mL)萃取三次，合并有机相，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到3-氨基-4-溴-5,N-二甲基噻吩-2-甲酰胺(6.94g，收率96.71％)，黄色固体。3-Amino-4-bromo-5-methylthiophene-2-carboxylic acid (6.8 g, 28.8 mmol, 1.0 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (13.1 g, 34.6 mmol, 1.2 eq), methylamine hydrochloride (2.9 g, 43.2 mmol, 1.5 eq), diisopropylethylamine (11.2 g, 86.4 mmol, 3.0 eq) and N,N-dimethylformamide (DMF) (60 mL), under argon protection, stirred at room temperature for 0.5 h, the reaction solution was diluted with water (150 mL), extracted three times with ethyl acetate (100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-amino-4-bromo-5,N-dimethylthiophene-2-carboxamide (6.94 g, yield 96.71%) as a yellow solid.

MS m/z：248.9[M+1]+ MS m/z：248.9[M+1] +

1H NMR(400MHz,氘代氯仿)δ5.32(s,1H),4.62(s,2H),2.94(s,3H),2.39(s,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 5.32 (s, 1H), 4.62 (s, 2H), 2.94 (s, 3H), 2.39 (s, 3H).

步骤3：7-溴-3,6-二甲基-2-苯基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 3: 7-Bromo-3,6-dimethyl-2-phenyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

3-氨基-4-溴-5,N-二甲基噻吩-2-甲酰胺(300mg,1.2mmol,1.0eq)，苯甲醛(192mg,1.8mmol,1.5eq)，碘(460mg,1.8mmol,1.5eq)溶于乙醇(10mL)，85℃搅拌1.0小时，浓缩，残渣柱层析纯化得到7-溴-3,6-二甲基-2-苯基-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(298mg,收率74％)，白色固体。3-Amino-4-bromo-5,N-dimethylthiophene-2-carboxamide (300 mg, 1.2 mmol, 1.0 eq), benzaldehyde (192 mg, 1.8 mmol, 1.5 eq), iodine (460 mg, 1.8 mmol, 1.5 eq) were dissolved in ethanol (10 mL), stirred at 85 ° C for 1.0 hour, concentrated, and the residue was purified by column chromatography to give 7-bromo-3,6-dimethyl-2-phenyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (298 mg, yield 74%) as a white solid.

MS m/z：335.2/337.2[M+H]+ MS m/z：335.2/337.2[M+H] +

1H NMR(400MHz,氘代氯仿)δ7.60(dd,J＝6.7,3.0Hz,2H),7.57–7.52(m,3H),3.55(s,3H),2.62(s,3H)。 1 H NMR (400 MHz, deuterated chloroform) δ 7.60 (dd, J=6.7, 3.0 Hz, 2H), 7.57–7.52 (m, 3H), 3.55 (s, 3H), 2.62 (s, 3H).

步骤4,5,6,7,8参考实施例1方法制备得到2-{[1-(3,6-二甲基-4-氧亚基-2-苯基噻吩并[3,2-d]嘧啶-7-基)乙基]氨基}苯甲酸(4.6mg)，白色固体。Steps 4, 5, 6, 7, and 8 were prepared by referring to Example 1 to obtain 2-{[1-(3,6-dimethyl-4-oxyylidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino}benzoic acid (4.6 mg) as a white solid.

MS m/z：420.1[M+H]+ MS m/z：420.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.59(s,1H),8.47(d,J＝7.7Hz,1H),7.77(td,J＝7.2,2.7Hz,3H),7.58(dd,J＝5.0,1.9Hz,3H),7.26(ddd,J＝8.7,7.1,1.8Hz,1H),6.61(d,J＝8.5Hz,1H),6.54–6.48(m,1H),5.11(t,J＝7.0Hz,1H),3.40(s,3H),2.61(s,3H),1.59(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),8.47(d,J＝7.7Hz,1H),7.77(td,J＝7.2,2.7Hz,3H),7.58(dd,J＝5.0,1.9Hz,3H),7.26(ddd,J＝8 .7,7.1,1.8Hz,1H),6.61(d,J＝8.5Hz,1H),6.54–6.48(m,1H),5.11(t,J＝7.0Hz,1H),3.40(s,3H),2.61(s,3H),1.59(d,J＝6.8Hz,3H).

实施例31：2-{[1-(3,6-二甲基-4-氧亚基-2-苯基噻吩并[3,2-d]嘧啶-7-基)乙基]氨基}-5-氟苯甲酸
Example 31: 2-{[1-(3,6-dimethyl-4-oxyylidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino}-5-fluorobenzoic acid

以2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备2-{[1-(3,6-二甲基-4-氧亚基-2-苯基噻吩并[3,2-d]嘧啶-7-基)乙基]氨基}-5-氟苯甲酸(15mg)，白色固体。Using 2-amino-5-fluorobenzoic acid methyl ester as starting material, 2-{[1-(3,6-dimethyl-4-oxyylidene-2-phenylthieno[3,2-d]pyrimidin-7-yl)ethyl]amino}-5-fluorobenzoic acid (15 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：438.1[M+H]+ MS m/z：438.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),8.30(s,1H),7.76(dd,J＝6.5,3.0Hz,2H),7.58(dd,J＝5.0,1.9Hz,3H),7.49(dd,J＝9.8,3.2Hz,1H),7.20(ddd,J＝9.3,8.1,3.3Hz,1H),6.61(dd,J＝9.4,4.5Hz,1H),5.09(d,J＝7.2Hz,1H),3.40(s,3H),2.60(s,3H),1.58(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.30(s,1H),7.76(dd,J＝6.5,3.0Hz,2H),7.58(dd,J＝5.0,1.9Hz,3H),7.49(dd,J＝9.8,3.2Hz,1H) ,7.20(ddd,J＝9.3,8.1,3.3Hz,1H),6.61(dd,J＝9.4,4.5Hz,1H),5.09(d,J＝7.2Hz,1H),3.40(s,3H),2.60(s,3H),1.58(d,J＝6.8Hz,3H).

实施例32：2-({1-[2-(2-氰基苯基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 32: 2-({1-[2-(2-cyanophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以2-氰基苯甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备2-({1-[2-(2-氰基苯基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(2mg)，白色固体。Using 2-cyanobenzaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[2-(2-cyanophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (2 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：463.2[M+H]+ MS m/z：463.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.11(d,J＝7.7Hz,1H),8.02–7.88(m,2H),7.80(td,J＝7.6,1.4Hz,1H),7.48(dd,J＝9.8,3.2Hz,1H),7.03(s,1H),6.52(d,J＝7.6Hz,1H),5.11(s,1H),3.35(s,3H),2.59(s,3H),1.58(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.42(s,1H),8.11(d,J＝7.7Hz,1H),8.02–7.88(m,2H),7.80(td,J＝7.6,1.4Hz,1H),7.48(dd, J＝9.8,3.2Hz,1H),7.03(s,1H),6.52(d,J＝7.6Hz,1H),5.11(s,1H),3.35(s,3H),2.59(s,3H),1.58(d,J＝6.8Hz,3H).

实施例33：2-({1-[3,6-二甲基-4-氧亚基-2-(3-苯基氮杂环丁-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 33: 2-({1-[3,6-dimethyl-4-oxylidene-2-(3-phenylazetidin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以3-苯基氮杂环丁烷盐酸盐及2-氨基-5-氟苯甲酸甲酯为原料，按照实施例16的方法制备2-({1-[3,6-二甲基-4-氧亚基-2-(3-苯基氮杂环丁-1-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(9mg)，白色固体。Using 3-phenylazetidine hydrochloride and methyl 2-amino-5-fluorobenzoate as raw materials, 2-({1-[3,6-dimethyl-4-oxylidene-2-(3-phenylazetidin-1-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (9 mg) was prepared as a white solid according to the method of Example 16.

MS m/z：493.1[M+H]+ MS m/z：493.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝11.1Hz,1H),7.59-7.44(m,1H),7.37(d,J＝7.4Hz,2H),7.27(p,J＝6.7,6.1Hz,2H),7.21-7.02(m,1H),6.39(ddd,J＝109.7,9.3,4.3Hz,1H),5.09(d,J＝54.8Hz,1H),4.59-4.21(m,2H),3.73-3.57(m,2H),3.26(d,J＝12.7Hz,3H),2.52(s,3H),1.61(dd,J＝31.2,6.6Hz,3H)。 1 H NMR(400MHz, DMSO-d6)δ8.16(d,J＝11.1Hz,1H),7.59-7.44(m,1H),7.37(d, J＝7.4Hz,2H),7.27(p,J＝6.7,6.1Hz,2H),7.21-7.02(m,1H),6.39(ddd,J＝1 09.7,9.3,4.3Hz,1H),5.09(d,J＝54.8Hz,1H),4.59-4.21(m,2H),3.73-3.5 7(m,2H),3.26(d,J＝12.7Hz,3H),2.52(s,3H),1.61(dd,J＝31.2,6.6Hz,3H).

实施例34：2-({1-[2-(6,6-二氟-2-氮杂螺[3.3]庚-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 34: 2-({1-[2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以3-苯基氮杂环丁烷盐酸盐及2-氨基-5-氟苯甲酸甲酯为原料，按照实施例16的方法制备2-({1-[2-(6,6-二氟-2-氮杂螺[3.3]庚-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(10mg)，白色固体。Using 3-phenylazetidine hydrochloride and methyl 2-amino-5-fluorobenzoate as raw materials, 2-({1-[2-(6,6-difluoro-2-azaspiro[3.3]hept-2-yl)-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (10 mg) was prepared as a white solid according to the method of Example 16.

MS m/z：493.2[M+H]+ MS m/z：493.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.25(s,1H),7.54(dd,J＝9.6,3.2Hz,1H),7.21(d,J＝3.1Hz,1H),6.44(dd,J＝9.5,4.4Hz,1H),5.17(s,1H),4.39(d,J＝10.6Hz,1H),4.09(d,J＝10.7Hz,1H),3.48(q,J＝14.2Hz,4H),3.20(s,3H),2.79–2.54(m,3H),2.45(s,3H),2.39(d,J＝12.9Hz,1H),1.68(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.54(dd,J＝9.6,3.2Hz,1H),7.21(d,J＝3.1Hz,1H),6.44(dd,J＝9.5,4.4Hz,1H),5.17(s,1H),4.39(d,J＝10.6H z,1H),4.09(d,J＝10.7Hz,1H),3.48(q,J＝14.2Hz,4H),3.20(s,3H),2.79 –2.54(m,3H),2.45(s,3H),2.39(d,J＝12.9Hz,1H),1.68(d,J＝6.6Hz,3H).

实施例35：5-氟-2-({1-[2-(6-甲氧基吡啶-3-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 35: 5-Fluoro-2-({1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以6-甲氧基吡啶-3-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备5-氟-2-({1-[2-(6-甲氧基吡啶-3-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(3mg)，白色固体。Using 6-methoxypyridine-3-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 5-fluoro-2-({1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (3 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：469.1[M+H]+ MS m/z：469.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),8.64(d,J＝2.4Hz,1H),8.36(s,1H),8.13(dd,J＝8.6,2.5Hz,1H),7.48(dd,J＝9.8,3.2Hz,1H),7.20(td,J＝8.6,3.3Hz,1H),7.00(d,J＝8.7Hz,1H),6.64(dd,J＝9.4,4.5Hz,1H),5.09(s,1H),3.96(s,3H),3.45(s,3H),2.62(s,3H),1.59(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.64(d,J＝2.4Hz,1H),8.36(s,1H),8.13(dd,J＝8.6,2.5Hz,1H),7.48(dd,J＝9.8,3.2Hz,1H),7.20(td,J＝ 8.6, 3.3Hz, 1H), 7.00 (d, J = 8.7Hz, 1H), 6.64 (dd, J = 9.4, 4.5Hz, 1H), 5.09 (s, 1H), 3.96 (s, 3H), 3.45 (s, 3H), 2.62 (s, 3H), 1.59 (d, J = 6.8Hz, 3H).

实施例36：6-氯-3-({1-[2-(6-甲氧基吡啶-3-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 36: 6-Chloro-3-({1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以6-甲氧基吡啶-3-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[2-(6-甲氧基吡啶-3-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(3mg)，白色固体。Using 6-methoxypyridine-3-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[2-(6-methoxypyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (3 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：469.1[M+H]+ MS m/z：469.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),9.39(s,1H),8.69(s,1H),8.20(d,J＝8.6Hz,1H),7.17(d,J＝13.5Hz,1H),6.99(d,J＝8.7Hz,2H),5.10–4.98(m,1H),3.96(s,3H),3.47(s,3H),2.58(s,3H),1.57(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),9.39(s,1H),8.69(s,1H),8.20(d,J＝8.6Hz,1H),7.17(d,J＝13.5Hz,1 H),6.99(d,J＝8.7Hz,2H),5.10–4.98(m,1H),3.96(s,3H),3.47(s,3H),2.58(s,3H),1.57(d,J＝6.8Hz,3H).

实施例37：6-氯-3-({1-[3,6-二甲基-2-(1-甲基吡唑-4-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 37: 6-Chloro-3-({1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以1-甲基吡唑-4-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[3,6-二甲基-2-(1-甲基吡唑-4-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(16mg)，白色固体。Using 1-methylpyrazole-4-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (16 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：459.1[M+H]+ MS m/z：459.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.20(s,1H),7.15(d,J＝74.5Hz,3H),5.06(s,1H),3.95(s,3H),3.69(s,3H),2.60(s,3H),1.59(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ 8.61 (s, 1H), 8.20 (s, 1H), 7.15 (d, J = 74.5Hz, 3H), 5.06 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 2.60 (s, 3H), 1.59 (d, J = 6.7Hz, 3H).

实施例38：5-氟-2-({1-[2-(2-氟苯基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 38: 5-Fluoro-2-({1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以2-氟苯甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备5-氟-2-({1-[2-(2-氟苯基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(6mg)，白色固体。Using 2-fluorobenzaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 5-fluoro-2-({1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (6 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：456.1[M+H]+ MS m/z：456.1[M+H] +

实施例39：2-({1-[3,6-二甲基-2-(1-甲基吡唑-4-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 39: 2-({1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以1-甲基吡唑-4-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备2-({1-[3,6-二甲基-2-(1-甲基吡唑-4-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(15mg)，白色固体。Using 1-methylpyrazole-4-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[3,6-dimethyl-2-(1-methylpyrazol-4-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (15 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：445.2[M+H]+ MS m/z：445.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),8.49(s,2H),8.19(s,1H),7.48(dd,J＝9.8,3.2Hz,1H), 7.21(td,J＝8.7,3.3Hz,1H),6.65(dd,J＝9.3,4.5Hz,1H),5.09(d,J＝7.4Hz,1H),3.96(s,3H),3.69(s,3H),2.62(s,3H),1.61(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.96 (s, 1H), 8.49 (s, 2H), 8.19 (s, 1H), 7.48 (dd, J = 9.8, 3.2Hz, 1H), 7.21(td,J＝8.7,3.3Hz,1H),6.65(dd,J＝9.3,4.5Hz,1H),5.09(d,J＝7.4Hz,1H),3.96(s,3H),3.69(s,3H),2.62(s,3H),1.61(d,J＝6.7Hz,3H).

实施例40：6-氯-3-({1-[2-(2-氟苯基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 40: 6-Chloro-3-({1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以2-氟苯甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[2-(2-氟苯基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(4mg)，白色固体。Using 2-fluorobenzaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[2-(2-fluorophenyl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (4 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：473.2[M+H]+ MS m/z：473.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.37(s,1H),7.81(s,1H),7.73–7.64(m,1H),7.52–7.41(m,2H),7.13(s,1H),6.96(s,1H),5.04(t,J＝7.1Hz,1H),3.35(s,3H),2.58(s,3H),1.56(d,J＝6.7Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.37(s,1H),7.81(s,1H),7.73–7.64(m,1H),7.52–7.41(m,2H ),7.13(s,1H),6.96(s,1H),5.04(t,J＝7.1Hz,1H),3.35(s,3H),2.58(s,3H),1.56(d,J＝6.7Hz,3H).

实施例41：6-氯-3-({1-[2-(5-氟吡啶-3-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 41: 6-Chloro-3-({1-[2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以5-氟吡啶-3-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[2-(5-氟吡啶-3-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(16mg)，白色固体。Using 5-fluoropyridine-3-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (16 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：474.2[M+H]+ MS m/z：474.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.81(d,J＝2.8Hz,1H),8.63(d,J＝8.2Hz,1H),8.21(d,J＝9.5Hz,1H),7.40(d,J＝8.9Hz,1H),7.24(d,J＝9.0Hz,1H),5.13(t,J＝7.3Hz,1H),3.42(s,3H),2.65 (s,3H),1.60(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.81(d,J＝2.8Hz,1H),8.63(d,J＝8.2Hz,1H),8.21(d,J＝9. 5Hz,1H),7.40(d,J＝8.9Hz,1H),7.24(d,J＝9.0Hz,1H),5.13(t,J＝7.3Hz,1H),3.42(s,3H),2.65 (s,3H),1.60(d,J=6.7Hz,3H).

实施例42：5-氟-2-({1-[2-(5-氟吡啶-3-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 42: 5-Fluoro-2-({1-[2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以5-氟吡啶-3-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备5-氟-2-({1-[2-(5-氟吡啶-3-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(21mg)，白色固体。Using 5-fluoropyridine-3-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 5-fluoro-2-({1-[2-(5-fluoropyridin-3-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (21 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：457.2[M+H]+ MS m/z：457.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.96(s,1H),8.87(d,J＝2.0Hz,1H),8.81(d,J＝2.8Hz,1H),8.46(s,1H),8.22(dt,J＝9.6,2.4Hz,1H),7.48(dd,J＝9.8,3.2Hz,1H),7.16(d,J＝3.2Hz,1H),6.60(dd,J＝9.4,4.5Hz,1H),5.08(d,J＝7.0Hz,1H),3.43(s,3H),2.63(s,3H),1.58(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),8.87(d,J＝2.0Hz,1H),8.81(d,J＝2.8Hz,1H),8.46(s,1H),8.22(dt,J＝9.6,2.4Hz,1H),7.48(dd,J＝9 .8, 3.2Hz, 1H), 7.16 (d, J = 3.2Hz, 1H), 6.60 (dd, J = 9.4, 4.5Hz, 1H), 5.08 (d, J = 7.0Hz, 1H), 3.43 (s, 3H), 2.63 (s, 3H), 1.58 (d, J = 6.7Hz, 3H).

实施例43：2-({1-[3,6-二甲基-2-(1-甲基吲唑-5-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 43: 2-({1-[3,6-dimethyl-2-(1-methylindazol-5-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以1-甲基吲唑-5-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备2-({1-[3,6-二甲基-2-(1-甲基吲唑-5-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(7mg)，白色固体。Using 1-methylindazole-5-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[3,6-dimethyl-2-(1-methylindazole-5-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (7 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：492.2[M+H]+ MS m/z：492.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.38(s,1H),8.29–8.18(m,2H),7.84–7.73(m,2H),7.51(dd,J＝9.8,3.2Hz,1H),7.20(ddd,J＝11.2,8.1,3.2Hz,1H),6.62(dd,J＝9.4,4.5Hz,1H),5.09(d,J＝7.0Hz,1H),4.13(s,3H),3.45(s,3H),2.61(s,3H),1.58(d,J＝6.9Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),8.38(s,1H),8.29–8.18(m,2H),7.84–7.73(m,2H),7.51(dd,J＝9.8,3.2Hz,1H),7.20(ddd,J＝11 .2,8.1,3.2Hz,1H),6.62(dd,J＝9.4,4.5Hz,1H),5.09(d,J＝7.0Hz,1H),4.13(s,3H),3.45(s,3H),2.61(s,3H),1.58(d,J＝6.9Hz,3H).

实施例44：6-氯-3-({1-[3,6-二甲基-2-(1-甲基吲唑-5-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 44: 6-Chloro-3-({1-[3,6-dimethyl-2-(1-methylindazol-5-yl)-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以1-甲基吲唑-5-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[3,6-二甲基-2-(1-甲基吲唑-5-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(6mg)，白色固体。Using 1-methylindazole-5-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[3,6-dimethyl-2-(1-methylindazole-5-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (6 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：509.2[M+H]+ MS m/z：509.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.09(s,1H),8.23(d,J＝13.0Hz,2H),7.81(d,J＝2.0Hz,2H),7.18(d,J＝30.0Hz,1H),7.03(s,1H),5.08(d,J＝6.6Hz,1H),4.12(s,3H),3.45(s,3H),2.58(s,3H),1.57(d,J＝6.5Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.85(s,1H),9.09(s,1H),8.23(d,J＝13.0Hz,2H),7.81(d,J＝2.0Hz,2H),7.18(d,J＝3 0.0Hz,1H),7.03(s,1H),5.08(d,J＝6.6Hz,1H),4.12(s,3H),3.45(s,3H),2.58(s,3H),1.57(d,J＝6.5Hz,3H).

实施例45：2-({1-[3,6-二甲基-2-(2-甲基吲唑-5-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 45: 2-({1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以2-甲基吲唑-5-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备2-({1-[3,6-二甲基-2-(2-甲基吲唑-5-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(5mg)，白色固体。Using 2-methylindazole-5-carboxaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials, 2-({1-[3,6-dimethyl-2-(2-methylindazole-5-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (5 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：492.2[M+H]+ MS m/z：492.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.54(s,1H),8.39(s,1H),8.21–8.12(m,1H),7.74(d,J＝9.0Hz,1H),7.58(dd,J＝9.0,1.7Hz,1H),7.51(dd,J＝9.8,3.2Hz,1H),7.19(td,J＝8.6,3.2Hz,1H),6.61(dd,J＝9.4,4.5Hz,1H),5.09(d,J＝7.2Hz,1H),4.23(s,3H),3.45(s,3H),2.60(s,3H),1.58(d,J＝6.7Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.54(s,1H),8.39(s,1H),8.21–8.12( m,1H),7.74(d,J＝9.0Hz,1H),7.58(dd,J＝9.0,1.7Hz,1H),7.51(dd,J＝9.8,3 .2Hz,1H),7.19(td,J＝8.6,3.2Hz,1H),6.61(dd,J＝9.4,4.5Hz,1H),5.09(d, J＝7.2Hz,1H),4.23(s,3H),3.45(s,3H),2.60(s,3H),1.58(d,J＝6.7Hz,3H).

实施例46：5-氟-2-[(1-{2-[1-(2-甲氧基苯基)吡唑-4-基]-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]苯甲酸
Example 46: 5-Fluoro-2-[(1-{2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]benzoic acid

以1-(2-甲氧基苯基)吡唑-4-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备5-氟-2-[(1-{2-[1-(2-甲氧基苯基)吡唑-4-基]-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]苯甲酸(30mg)，白色固体。Using 1-(2-methoxyphenyl)pyrazole-4-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 5-fluoro-2-[(1-{2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]benzoic acid (30 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：534.2[M+H]+ MS m/z：534.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.95(s,1H),8.88(s,1H),8.54(s,1H),8.47(s,1H),7.71(dd,J＝7.9,1.6Hz,1H),7.55–7.40(m,2H),7.31(d,J＝8.3Hz,1H),7.23(td,J＝8.7,3.2Hz,1H),7.19–7.10(m,1H),6.70(dd,J＝9.4,4.5Hz,1H),5.11(d,J＝7.2Hz,1H),3.89(s,3H),3.74(s,3H),2.64(s,3H),1.65(d,J＝6.7Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ12.95(s,1H),8.88(s,1H),8.54(s,1H),8.47(s,1H) ,7.71(dd,J＝7.9,1.6Hz,1H),7.55–7.40(m,2H),7.31(d,J＝8.3Hz,1H),7.23( td,J＝8.7,3.2Hz,1H),7.19–7.10(m,1H),6.70(dd,J＝9.4,4.5Hz,1H),5.11(d ,J＝7.2Hz,1H),3.89(s,3H),3.74(s,3H),2.64(s,3H),1.65(d,J＝6.7Hz,3H).

实施例47：6-氯-3-({1-[3,6-二甲基-2-(2-甲基吲唑-5-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 47: 6-Chloro-3-({1-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以2-甲基吲唑-5-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[3,6-二甲基-2-(2-甲基吲唑-5-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(11mg)，白色固体。Using 2-methylindazole-5-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[3,6-dimethyl-2-(2-methylindazole-5-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (11 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：509.2[M+H]+ MS m/z：509.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.53(s,1H),8.19(s,1H),7.73(d,J＝9.0Hz,1H),7.59(d,J＝9.0Hz,1H),7.19(d,J＝34.3Hz,1H),7.01(s,1H),5.07(s,1H),4.23(s,3H),3.45(s,3H),2.58(s,3H),1.57(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.53(s,1H),8.19(s,1H),7.73(d,J＝9.0Hz,1H),7.59(d,J＝9.0Hz,1H),7 .19(d,J＝34.3Hz,1H),7.01(s,1H),5.07(s,1H),4.23(s,3H),3.45(s,3H),2.58(s,3H),1.57(d,J＝6.7Hz,3H).

实施例48：6-氯-3-[(1-{2-[1-(2-甲氧基苯基)吡唑-4-基]-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 48: 6-Chloro-3-[(1-{2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以1-(2-甲氧基苯基)吡唑-4-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-[(1-{2-[1-(2-甲氧基苯基)吡唑-4-基]-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(6mg)，白色固体。Using 1-(2-methoxyphenyl)pyrazole-4-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-[(1-{2-[1-(2-methoxyphenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (6 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：551.2[M+H]+ MS m/z：551.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.50(s,1H),8.18(s,1H),7.70(d,J＝7.8Hz,1H),7.46(t,J＝7.9Hz,1H),7.39–7.27(m,2H),7.14(t,J＝7.8Hz,2H),5.10(s,1H),3.90(s,3H),3.74(s,3H),2.62(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.50(s,1H),8.18(s,1H),7.70(d,J＝7.8Hz,1H),7.46(t,J＝7.9Hz,1H),7.3 9–7.27(m,2H),7.14(t,J＝7.8Hz,2H),5.10(s,1H),3.90(s,3H),3.74(s,3H),2.62(s,3H),1.63(d,J＝6.7Hz,3H).

实施例49：3-({1-[2-(苯并[d][1,3]二氧杂环戊熳-5-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-6-氯吡啶-2-甲酸
Example 49: 3-({1-[2-(Benzo[d][1,3]dioxolan-5-yl)-3,6-dimethyl-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-6-chloropyridine-2-carboxylic acid

以苯并[d][1,3]二氧杂环戊熳-5-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备3-({1-[2-(苯并[d][1,3]二氧杂环戊熳-5-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-6-氯吡啶-2-甲酸(6mg)，白色固体。Using benzo[d][1,3]dioxolan-5-carbaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 3-({1-[2-(Benzo[d][1,3]dioxolan-5-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-6-chloropyridine-2-carboxylic acid (6 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：499.2[M+H]+ MS m/z：499.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),7.42(s,1H),7.30(d,J＝8.0Hz,1H),7.17(d,J＝11.3Hz,1H),7.08(d,J＝8.1Hz,1H),6.97(d,J＝8.5Hz,1H),6.14(s,2H),5.05(t,J＝7.1Hz,1H),3.43(s,3H),2.55(s,3H),1.56(d,J＝6.4Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),7.42(s,1H),7.30(d,J＝8.0Hz,1H),7.17(d,J＝11.3Hz,1H),7.08(d,J＝8.1Hz ,1H),6.97(d,J＝8.5Hz,1H),6.14(s,2H),5.05(t,J＝7.1Hz,1H),3.43(s,3H),2.55(s,3H),1.56(d,J＝6.4Hz,3H).

实施例50：6-氯-3-({1-[3,6-二甲基-2-(1-甲基吲唑-6-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 50: 6-Chloro-3-({1-[3,6-dimethyl-2-(1-methylindazol-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以1-甲基吲唑-6-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[3,6-二甲基-2-(1-甲基吲唑-6-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(31mg)，白色固体。Using 1-methylindazole-6-carbaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[3,6-dimethyl-2-(1-methylindazole-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (31 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：509.2[M+H]+ MS m/z：509.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.16(d,J＝11.6Hz,2H),7.92(d,J＝8.5Hz,1H),7.49(d,J＝8.4Hz,1H),7.27(d,J＝67.5Hz,2H),5.09(s,1H),4.17(s,3H),2.64(s,3H),1.57(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.88(s,1H),8.16(d,J＝11.6Hz,2H),7.92(d,J＝8.5Hz,1H),7.49(d,J＝8 .4Hz,1H),7.27(d,J＝67.5Hz,2H),5.09(s,1H),4.17(s,3H),2.64(s,3H),1.57(d,J＝6.6Hz,3H).

实施例51：2-({1-[2-(苯并[d][1,3]二氧杂环戊熳-5-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 51: 2-({1-[2-(Benzo[d][1,3]dioxolan-5-yl)-3,6-dimethyl-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以苯并[d][1,3]二氧杂环戊熳-5-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备2-({1-[2-(苯并[d][1,3]二氧杂环戊熳-5-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(6mg)，白色固体。Using benzo[d][1,3]dioxolan-5-carbaldehyde and methyl 2-amino-5-fluorobenzoate as raw materials, 2-({1-[2-(Benzo[d][1,3]dioxolan-5-yl)-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (6 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：482.2[M+H]+ MS m/z：482.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),8.33(s,1H),7.49(dd,J＝9.8,3.2Hz,1H),7.37(d,J＝1.7Hz,1H),7.26(dd,J＝8.1,1.8Hz,1H),7.19(ddd,J＝9.2,8.1,3.2Hz,1H),7.09(d,J＝8.1Hz,1H),6.61(dd,J＝9.3,4.5Hz,1H),6.15(s,2H),5.08(d,J＝7.1Hz,1H),3.43(s,3H),2.59(s,3H),1.58(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.33(s,1H),7.49(dd,J＝9.8,3.2Hz,1H),7.37(d,J＝1.7Hz,1H),7.26(dd,J＝8.1,1.8Hz,1H),7.19(ddd,J＝9.2,8 .1,3.2Hz,1H),7.09(d,J＝8.1Hz,1H),6.61(dd,J＝9.3,4.5Hz,1H),6.15(s, 2H), 5.08 (d, J = 7.1Hz, 1H), 3.43 (s, 3H), 2.59 (s, 3H), 1.58 (d, J = 6.8Hz, 3H).

实施例52：2-({1-[3,6-二甲基-2-(2-甲基吲唑-6-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 52: 2-({1-[3,6-dimethyl-2-(2-methylindazol-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以2-甲基吲唑-6-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备2-({1-[3,6-二甲基-2-(2-甲基吲唑-6-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(8mg)，白色固体。Using 2-methylindazole-6-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[3,6-dimethyl-2-(2-methylindazole-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (8 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：492.2[M+H]+ MS m/z：492.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.43–8.22(m,1H),8.04(s,1H),7.88(d,J＝8.6Hz,1H),7.50(dd,J＝9.8,3.2Hz,1H),7.36(dd,J＝8.6,1.4Hz,1H),7.19(d,J＝2.4Hz,1H),6.62(dd,J＝9.4,4.5Hz,1H),5.11(d,J＝7.2Hz,1H),4.24(s,3H),3.45(s,3H),2.59(s,3H),1.59(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.43–8.22(m,1H),8.04(s,1H),7.88(d,J＝8.6Hz,1H),7.50(dd,J＝9.8,3.2Hz,1H),7.36(dd,J＝8.6,1.4H z,1H),7.19(d,J＝2.4Hz,1H),6.62(dd,J＝9.4,4.5Hz,1H),5.11(d,J＝7.2Hz,1H),4.24(s,3H),3.45(s,3H),2.59(s,3H),1.59(d,J＝6.7Hz,3H).

实施例53：6-氯-3-({1-[2-(3-氟吡啶-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 53: 6-Chloro-3-({1-[2-(3-fluoropyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以3-氟吡啶-2-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[2-(3-氟吡啶-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(11mg)，白色固体。Using 3-fluoropyridine-2-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[2-(3-fluoropyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (11 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：474.2[M+H]+ MS m/z：474.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.65(d,J＝4.6Hz,1H),8.07(t,J＝9.1Hz,1H),7.78(dt,J＝8.7,4.4Hz,1H),7.08(d,J＝8.6Hz,1H),6.89(d,J＝8.7Hz,1H),5.05(p,J＝6.8Hz,1H),3.40(s,3H),2.57(s,3H),1.56(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.35(s,1H),8.65(d,J＝4.6Hz,1H),8.07(t,J＝9.1Hz,1H),7.78(dt,J＝8.7,4.4Hz,1H),7. 08(d,J＝8.6Hz,1H),6.89(d,J＝8.7Hz,1H),5.05(p,J＝6.8Hz,1H),3.40(s,3H),2.57(s,3H),1.56(d,J＝6.8Hz,3H).

实施例54：5-氟-2-({1-[2-(3-氟吡啶-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 54: 5-Fluoro-2-({1-[2-(3-fluoropyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以3-氟吡啶-2-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备5-氟-2-({1-[2-(3-氟吡啶-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(19mg)，白色固体。Using 3-fluoropyridine-2-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 5-fluoro-2-({1-[2-(3-fluoropyridin-2-yl)-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (19 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：457.2[M+H]+ MS m/z：457.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.63(dt,J＝4.7,1.4Hz,1H),8.33(s,1H),8.05(ddd,J＝9.8,8.6,1.3Hz,1H),7.77(dt,J＝8.6,4.4Hz,1H),7.48(dd,J＝9.8,3.2Hz,1H),7.10(td,J＝8.6,3.2Hz,1H),6.53(dd,J＝9.4,4.5Hz,1H),5.07(s,1H),3.38(s,3H),2.61(s,3H),1.57(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.63(dt,J＝4.7,1.4Hz,1H),8.33(s,1H),8.05(ddd,J＝9.8,8.6,1.3Hz,1H),7.77(dt,J＝8.6,4.4Hz,1H),7. 48(dd,J＝9.8,3.2Hz,1H),7.10(td,J＝8.6,3.2Hz,1H),6.53(dd,J＝9.4,4 .5Hz,1H),5.07(s,1H),3.38(s,3H),2.61(s,3H),1.57(d,J＝6.8Hz,3H).

实施例55：6-氯-3-({1-[3,6-二甲基-2-(2-甲基吲唑-6-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 55: 6-Chloro-3-({1-[3,6-dimethyl-2-(2-methylindazol-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以2-甲基吲唑-6-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[3,6-二甲基-2-(2-甲基吲唑-6-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(2mg)，白色固体。Using 2-methylindazole-6-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[3,6-dimethyl-2-(2-methylindazole-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (2 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：509.2[M+H]+ MS m/z：509.2[M+H] +

实施例56：2-({1-[3,6-二甲基-2-(1-甲基吲唑-6-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸
Example 56: 2-({1-[3,6-dimethyl-2-(1-methylindazol-6-yl)-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid

以1-甲基吲唑-6-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备2-({1-[3,6-二甲基-2-(1-甲基吲唑-6-基)-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-5-氟苯甲酸(11mg)，白色固体。Using 1-methylindazole-6-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 2-({1-[3,6-dimethyl-2-(1-methylindazole-6-yl)-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-5-fluorobenzoic acid (11 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：492.2[M+H]+ MS m/z：492.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.19(s,1H),8.12–8.03(m,1H),7.93(d,J＝8.3Hz,1H),7.58–7.44(m,2H),7.23–7.13(m,1H),6.63(dd,J＝9.3,4.5Hz,1H),5.09(d,J＝7.0Hz,1H),4.14(s,3H),3.43(s,3H),2.62(s,3H),1.58(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.19(s,1H),8.12–8.03(m,1H),7.93(d,J＝8.3Hz,1H),7.58–7.44(m,2H),7.23–7.13 (m,1H),6.63(dd,J＝9.3,4.5Hz,1H),5.09(d,J＝7.0Hz,1H),4.14(s,3H),3.43(s,3H),2.62(s,3H),1.58(d,J＝6.7Hz,3H).

实施例57：6-氯-3-({1-[2-(1H-吡咯并[2,3-b]吡啶-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 57: 6-Chloro-3-({1-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以1H-吡咯并[2,3-b]吡啶-2-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[2-(1H-吡咯并[2,3-b]吡啶-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(7mg)，白色固体。Using 1H-pyrrolo[2,3-b]pyridine-2-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (7 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：494.2[M+H]+ MS m/z：494.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.43(dd,J＝4.7,1.7Hz,1H),8.15(dd,J＝8.0,1.6Hz,1H),7.50(dd,J＝9.9,3.3Hz,1H),7.29(d,J＝2.1Hz,1H),7.25–7.02(m,2H),6.70(dd,J＝9.4,4.5Hz,1H),5.38(s,1H),3.81(s,3H),2.58(s,3H),1.60(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.43(dd,J＝4.7,1.7Hz,1H),8.15(dd,J＝8.0,1.6Hz,1H),7.50(dd,J＝9.9,3.3Hz,1H),7.29(d,J＝ 2.1Hz,1H),7.25–7.02(m,2H),6.70(dd,J＝9.4,4.5Hz,1H),5.38(s,1H),3.81(s,3H),2.58(s,3H),1.60(d,J＝6.8Hz,3H).

实施例58：5-氟-2-({1-[2-(1H-吡咯并[2,3-b]吡啶-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸
Example 58: 5-Fluoro-2-({1-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dimethyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid

以1H-吡咯并[2,3-b]吡啶-2-甲醛及2-氨基-5-氟苯甲酸甲酯为原料，参照实施例30的方法制备5-氟-2-({1-[2-(1H-吡咯并[2,3-b]吡啶-2-基)-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)苯甲酸(3mg)，白色固体。Using 1H-pyrrolo[2,3-b]pyridine-2-carboxaldehyde and 2-amino-5-fluorobenzoic acid methyl ester as raw materials, 5-fluoro-2-({1-[2-(1H-pyrrolo[2,3-b]pyridin-2-yl)-3,6-dimethyl-4-oxydithieno[3,2-d]pyrimidin-7-yl]ethyl}amino)benzoic acid (3 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：478.2[M+H]+ MS m/z：478.2[M+H] +

实施例59：6-氯-3-[(1-{2-[1-(3-氰基苯基)吡唑-4-基]-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 59: 6-Chloro-3-[(1-{2-[1-(3-cyanophenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以3-(4-甲酰基吡唑-1-基)苯-1-甲腈及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-[(1-{2-[1-(3-氰基苯基)吡唑-4-基]-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(2mg)，白色固体。Using 3-(4-formylpyrazol-1-yl)benzene-1-carbonitrile and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-[(1-{2-[1-(3-cyanophenyl)pyrazol-4-yl]-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (2 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：546.2[M+H]+ MS m/z：546.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.81(s,1H),8.58(d,J＝9.8Hz,1H),8.53(d,J＝10.6Hz,1H),8.37(d,J＝8.0Hz,1H),7.97–7.86(m,1H),7.80(t,J＝8.0Hz,1H),7.42(d,J＝8.8Hz,1H),7.29(d,J＝9.0Hz,1H),5.16(t,J＝7.4Hz,1H),3.78(d,J＝2.9Hz,3H),2.66(s,3H),1.64(d,J＝6.7Hz,3H)。 1 H NMR(400MHz, DMSO-d6)δ9.32(s,1H),8.81(s,1H),8.58(d,J＝9.8Hz,1H),8.53(d,J＝10.6Hz,1H),8.37(d,J＝8.0Hz,1H),7.97–7.86(m,1H),7.80 (t,J＝8.0Hz,1H),7.42(d,J＝8.8Hz,1H),7.29(d,J＝9.0Hz,1H),5.16(t,J＝7.4Hz,1H),3.78(d,J＝2.9Hz,3H),2.66(s,3H),1.64(d,J＝6.7Hz,3H).

实施例60：6-氯-3-[(1-{2,6-二甲基-5-[4-(1-甲基吡唑-4-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸
Example 60: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(1-methylpyrazol-4-yl)phenyl]-7-oxydithieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

以4-(1-甲基吡唑-4-基)苯甲酰氯及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，按照实施例1方法制备6-氯-3-[(1-{2,6-二甲基-5-[4-(1-甲基吡唑-4-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸(8mg)，白色固体。Using 4-(1-methylpyrazol-4-yl)benzoyl chloride and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-[(1-{2,6-dimethyl-5-[4-(1-methylpyrazol-4-yl)phenyl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (8 mg) was prepared as a white solid according to the method of Example 1.

MS m/z:535.2[M+H]+ MS m/z:535.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.99(s,1H),7.78–7.64(m,4H),7.38(d,J＝8.9Hz,1H),7.12(d,J＝9.0Hz,1H),5.00(t,J＝6.8Hz,1H),3.90(s,3H),2.63(s,3H),2.06(s,3H),1.60(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),7.99(s,1H),7.78–7.64(m,4H),7.38(d,J＝8.9Hz,1H),7.12(d ,J＝9.0Hz,1H),5.00(t,J＝6.8Hz,1H),3.90(s,3H),2.63(s,3H),2.06(s,3H),1.60(d,J＝6.7Hz,3H).

实施例61：6-氯-3-[(1-{2,6-二甲基-5-[6-(1-甲基吡唑-4-基)吡啶-3-基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸
Example 61: 6-Chloro-3-[(1-{2,6-dimethyl-5-[6-(1-methylpyrazol-4-yl)pyridin-3-yl]-7-oxydithieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

以6-(1-甲基吡唑-4-基)吡啶-3-甲酰氯及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，按照实施例1方法制备6-氯-3-[(1-{2,6-二甲基-5-[6-(1-甲基吡唑-4-基)吡啶-3-基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸(3mg)，白色固体。Using 6-(1-methylpyrazol-4-yl)pyridine-3-carbonyl chloride and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-[(1-{2,6-dimethyl-5-[6-(1-methylpyrazol-4-yl)pyridin-3-yl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (3 mg) was prepared as a white solid according to the method of Example 1.

MS m/z:536.2[M+H]+ MS m/z:536.2[M+H] +

实施例62：6-氯-3-[(1-{3,6-二甲基-2-[4-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)苯基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 62: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)phenyl]-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以4-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)苯-1-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-[(1-{3,6-二甲基-2-[4-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)苯基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(4mg)，白色固体。Using 4-(3-methyl-1,2,4-oxadiazacyclopentyl)benzene-1-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(3-methyl-1,2,4-oxadiazacyclopentyl)phenyl]-4-oxyidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (4 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：537.2[M+H]+ MS m/z：537.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ11.88(s,1H),8.26(d,J＝7.8Hz,2H),8.06(d,J＝8.0Hz,2H),7.42–7.34(m,1H),7.27–7.19(m,1H),6.90(s,1H),5.08–5.01(m,1H),3.43(s,3H),2.59(s,3H),2.47(s,3H),1.57(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ11.88(s,1H),8.26(d,J＝7.8Hz,2H),8.06(d,J＝8.0Hz,2H),7.42–7.34(m,1H),7.27 –7.19(m,1H),6.90(s,1H),5.08–5.01(m,1H),3.43(s,3H),2.59(s,3H),2.47(s,3H),1.57(d,J＝6.7Hz,3H).

实施例63：6-氯-3-[(1-{3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 63: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

步骤1：7-乙酰基-3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 1: 7-Acetyl-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

以5-甲基-2-(哌嗪-1-基)嘧啶为原料，按照实施例16的方法制备得到7-乙酰基-3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(449mg)，黄色固体。 Using 5-methyl-2-(piperazin-1-yl)pyrimidine as raw material, 7-acetyl-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (449 mg) was prepared as a yellow solid according to the method of Example 16.

MS m/z:399.3[M+H]+ MS m/z:399.3[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.22(s,2H),4.04–3.96(m,4H),3.67(s,3H),3.37–3.29(m,4H),2.80(s,6H),2.17(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.22(s,2H),4.04–3.96(m,4H),3.67(s,3H),3.37–3.29(m,4H),2.80(s,6H),2.17(s,3H).

步骤2：7-(1-氨基乙基)-3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 2: 7-(1-aminoethyl)-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

7-乙酰基-3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(260mg,0.65mmol,1.0eq)溶于异丙醇(10mL)中，加入醋酸铵(503mg,6.5mmol,10.0eq)和氰基硼氢化钠(82mg,1.3mmol,2.0eq)，氩气保护，85℃反应5小时，冷却至室温，反应液加入水(50mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到7-(1-氨基乙基)-3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(115mg,收率44.1％)，白色固体。7-Acetyl-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (260 mg, 0.65 mmol, 1.0 eq) was dissolved in isopropanol (10 mL), and ammonium acetate (503 mg, 6.5 mmol, 10.0 eq) and sodium cyanoborohydride (82 mg, 1.3 mmol, 2.0 eq) were added. The mixture was reacted at 85 °C for 5 hours under argon protection and cooled to room temperature. The reaction solution was diluted with water (50 mL) and extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-(1-aminoethyl)-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (115 mg, yield 44.1%) as a white solid.

MS m/z:400.3[M+H]+ MS m/z:400.3[M+H] +

步骤3：6-氯-3-[(1-{3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸甲酯
Step 3: 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid methyl ester

7-(1-氨基乙基)-3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(500mg,1.25mmol,1.0eq)溶于DMSO(10mL)中，加入6-氯-3-氟吡啶-2-甲酸甲酯(285mg,1.5mmol,1.0eq)和二异丙基乙胺(DIPEA)(323mg,2.5mmol,2.0eq)，氩气保护，120℃反应5小时，冷却至室温，反应液加入水(50mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到6-氯-3-[(1-{3,6-二甲基 -2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸甲酯(567mg,收率79.61％)，黄色固体。7-(1-aminoethyl)-3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (500 mg, 1.25 mmol, 1.0 eq) was dissolved in DMSO (10 mL), and methyl 6-chloro-3-fluoropyridine-2-carboxylate (285 mg, 1.5 mmol, 1.0 eq) and diisopropylethylamine (DIPEA) (323 mg, 2.5 mmol, 2.0 eq) were added. The mixture was reacted at 120 ° C for 5 hours under argon protection, cooled to room temperature, and diluted with water (50 mL). The reaction solution was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 6-chloro-3-[(1-{3,6-dimethyl -2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid methyl ester (567 mg, yield 79.61%), yellow solid.

MS m/z:569.3[M+H]+ MS m/z:569.3[M+H] +

步骤4：6-氯-3-[(1-{3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸Step 4: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

6-氯-3-[(1-{3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸甲酯(567mg,1.00mmol,1.0eq)溶于四氢呋喃(10mL)、甲醇(2mL)和水(1mL)中，加入一水氢氧化锂(83mg,1.99mmol,2.0eq)，室温反应3小时，1mol/L盐酸调节PH值为7左右，反应液加入水(50mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到6-氯-3-[(1-{3,6-二甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(345mg,收率62.3％)，白色固体。6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid methyl ester (567 mg, 1.00 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), methanol (2 mL) and water (1 mL), and lithium hydroxide monohydrate (83 mg, 1.99 mmol, 2.0 eq) was added. The mixture was reacted at room temperature for 3 hours, and the pH was adjusted to 1 mol/L hydrochloric acid. 7, the reaction solution was diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (345 mg, yield 62.3%) as a white solid.

MS m/z：555.2[M+H]+ MS m/z：555.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.22(s,2H),7.19–6.98(m,2H),4.92(s,1H),3.90(s,7H),3.46(s,3H),3.28(s,4H),2.06(s,3H),1.56(d,J＝8.3Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.22(s,2H),7.19–6.98(m,2H),4.92(s,1H),3.90(s,7H),3.46(s,3H),3.28(s,4H),2.06(s,3H),1.56(d,J＝8.3Hz,3H).

实施例64：6-氯-3-[(1-{3,6-二甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 64: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以2-甲基-5-(哌嗪-1-基)吡嗪为原料，参照实施例63的方法制备6-氯-3-[(1-{3,6-二甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(11mg)，黄色固体。Using 2-methyl-5-(piperazin-1-yl)pyrazine as starting material, 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (11 mg) was prepared as a yellow solid by referring to the method of Example 63.

MS m/z：555.2[M+H]+ MS m/z：555.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.44(s,1H),8.29(s,1H),8.04(s,1H),7.22(s,1H),7.08(d,J＝8.3Hz,1H),5.00(t,J＝7.5Hz,1H),4.16(s,1H),3.70(d,J＝9.3Hz,4H),3.51(s,3H),3.39(q,J＝6.9,6.3Hz,4H),2.57(s,3H),2.34(s,3H),1.61(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.44(s,1H),8.29(s,1H),8.04(s,1H),7.22(s,1H),7.08(d,J＝8.3Hz,1H),5.00(t,J＝7.5Hz ,1H),4.16(s,1H),3.70(d,J＝9.3Hz,4H),3.51(s,3H),3.39(q,J＝6.9,6.3Hz,4H),2.57(s,3H),2.34(s,3H),1.61(d,J＝6.7Hz,3H).

实施例65：6-氯-3-[(1-{3,6-二甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 65: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以2-(哌嗪-1-基)嘧啶为原料，参照实施例63的方法制备6-氯-3-[(1-{3,6-二甲基-4-氧亚基-2-[4-(嘧啶-2-基)哌嗪-1-基]噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(25mg)，白色固体。Using 2-(piperazin-1-yl)pyrimidine as starting material, 6-chloro-3-[(1-{3,6-dimethyl-4-oxyylidene-2-[4-(pyrimidin-2-yl)piperazin-1-yl]thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (25 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：541.2[M+H]+ MS m/z：541.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ13.42(s,1H),9.55(d,J＝214.4Hz,1H),8.41(d,J＝4.7Hz,2H),7.17(s,1H),7.02(d,J＝8.7Hz,1H),6.68(t,J＝4.7Hz,1H),4.99(s,1H),3.94(dt,J＝13.3,7.7Hz,4H),3.51(s,3H),3.35(t,J＝5.2Hz,4H),2.55(s,3H),1.59(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ13.42(s,1H),9.55(d,J＝214.4Hz,1H),8.41(d,J＝4.7Hz,2H),7.17(s,1H),7.02(d,J＝8.7Hz,1H),6.68(t ,J＝4.7Hz,1H),4.99(s,1H),3.94(dt,J＝13.3,7.7Hz,4H),3.51(s,3H),3.35(t,J＝5.2Hz,4H),2.55(s,3H),1.59(d,J＝6.7Hz,3H).

实施例66：6-氯-3-[(1-{3,6-二甲基-2-[4-(6-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 66: 6-Chloro-3-[(1-{3,6-dimethyl-2-[4-(6-methylpyrazin-2-yl)piperazin-1-yl]-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以6-甲基-2-(哌嗪-1-基)吡嗪为原料，参照实施例63的方法制备6-氯-3-[(1-{3,6-二甲基-2-[4-(6-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(81mg)，黄色固体。Using 6-methyl-2-(piperazin-1-yl)pyrazine as starting material, 6-chloro-3-[(1-{3,6-dimethyl-2-[4-(6-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (81 mg) was prepared as a yellow solid by referring to the method of Example 63.

MS m/z：555.2[M+H]+ MS m/z：555.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),9.19(s,1H),8.18(s,1H),7.79(s,1H),7.28(s,1H),7.15(d,J＝8.8Hz,1H),5.02(t,J＝7.4Hz,1H),3.74(q,J＝6.1Hz,4H),3.51(s,3H),3.42–3.34(m,4H),2.58(s,3H),2.33(s,3H),1.62(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),9.19(s,1H),8.18(s,1H),7.79(s,1H),7.28(s,1H),7.15(d,J＝8.8Hz,1H),5.02( t,J＝7.4Hz,1H),3.74(q,J＝6.1Hz,4H),3.51(s,3H),3.42–3.34(m,4H),2.58(s,3H),2.33(s,3H),1.62(d,J＝6.7Hz,3H).

实施例67：6-氯-3-[(1-{3,6-二甲基-2-[1-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-3-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 67: 6-Chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

步骤1：1-(7-乙酰基-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-2-基)双环[1.1.1]戊烷-3-甲酸甲酯
Step 1: 1-(7-acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester

以1-(氧亚基甲基)双环[1.1.1]戊烷-3-甲酸甲酯为原料，参照实施例30的方法制备1-(7-乙酰基-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-2-基)双环[1.1.1]戊烷-3-甲酸甲酯(220mg)，黄色固体。Using 1-(oxyylidenemethyl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester as starting material, 1-(7-acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (220 mg) was prepared as a yellow solid according to the method of Example 30.

MS m/z：347.2[M+H]+ MS m/z：347.2[M+H] +

步骤2：1-(7-乙酰基-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-2-基)双环[1.1.1]戊烷-3-甲酸
Step 2: 1-(7-acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid

1-(7-乙酰基-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-2-基)双环[1.1.1]戊烷-3-甲酸甲酯(220mg,0.64mmol,1.0eq)溶于四氢呋喃(1mL)、甲醇(1mL)和水(4mL)中，加入一水氢氧化锂(53mg,1.27mmol,2.0eq)，50℃反应3小时，1mol/L盐酸调节PH值为7左右，反应液加入水(50mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(50mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到1-(7-乙酰基-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-2-基)双环[1.1.1]戊烷-3-甲酸(209mg,收率99％)，白色固体。1-(7-Acetyl-3,6-dimethyl-4-oxythieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (220 mg, 0.64 mmol, 1.0 eq) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL) and water (4 mL), and lithium hydroxide monohydrate (53 mg, 1.27 mmol, 2.0 eq) was added. The mixture was reacted at 50 ° C for 3 hours, and the pH was adjusted with 1 mol/L hydrochloric acid. The value was about 7. Water (50 mL) was added to the reaction solution for dilution, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1-(7-acetyl-3,6-dimethyl-4-oxythieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (209 mg, yield 99%) as a white solid.

MS m/z：333.2[M+H]+ MS m/z：333.2[M+H] +

步骤3：O-{[1-(7-乙酰基-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-2-基)双环[1.1.1]戊-3-基]羰基}-N- (1-氮亚基乙基)羟胺
Step 3: O-{[1-(7-acetyl-3,6-dimethyl-4-oxyidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentan-3-yl]carbonyl}-N- (1-Azolylideneethyl)hydroxylamine

1-(7-乙酰基-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-2-基)双环[1.1.1]戊烷-3-甲酸(200mg,0.6mmol,1.0eq)溶于二氧六环(10mL)中，加入N-(1-氮亚基乙基)羟胺(53mg,0.72mmol,1.2eq)，二异丙基乙胺(DIPEA)(233mg,1.8mmol,3.0eq)和三吡咯烷基溴化鏻六氟磷酸盐(336mg,0.72mmol,1.2eq)，氩气保护，50℃反应5小时，冷却至室温，反应液加入饱和碳酸氢钠水溶液(50mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物直接用于下一步反应。1-(7-Acetyl-3,6-dimethyl-4-oxyylidenethieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (200 mg, 0.6 mmol, 1.0 eq) was dissolved in dioxane (10 mL), and N-(1-nitrogenylideneethyl)hydroxylamine (53 mg, 0.72 mmol, 1.2 eq), diisopropylethylamine (DIPEA) (233 mg, 1.8 mmol, 3.0 eq) and tripyrrolidinylphosphonium bromide hexafluorophosphate (336 mg, 0.72 mmol, 1.2 eq) were added. The mixture was protected by argon and reacted at 50 °C for 5 hours. The mixture was cooled to room temperature, and the reaction solution was diluted with saturated sodium bicarbonate aqueous solution (50 mL). The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was directly used for the next reaction.

MS m/z:389.2[M+H]+ MS m/z:389.2[M+H] +

步骤4：7-乙酰基-3,6-二甲基-2-[3-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 4: 7-Acetyl-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

O-{[1-(7-乙酰基-3,6-二甲基-4-氧亚基噻吩并[3,2-d]嘧啶-2-基)双环[1.1.1]戊-3-基]羰基}-N-(1-氮亚基乙基)羟胺(230mg,0.6mmol,1.0eq)溶于四氢呋喃(10mL)中，加入四丁基氟化铵(0.6mL,0.6mmol,1.0eq),室温反应5小时，反应液加入水(50mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到7-乙酰基-3,6-二甲基-2-[3-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(219mg,收率99％)，白色固体。O-{[1-(7-acetyl-3,6-dimethyl-4-oxythieno[3,2-d]pyrimidin-2-yl)bicyclo[1.1.1]pentan-3-yl]carbonyl}-N-(1-nitrogenylideneethyl)hydroxylamine (230 mg, 0.6 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (0.6 mL, 0.6 mmol, 1.0 eq) was added, and the mixture was reacted at room temperature for 5 hours. Water (50 mL) was added to dilute the reaction solution, and ethyl acetate was added. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-acetyl-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (219 mg, yield 99%) as a white solid.

1H NMR(400MHz,DMSO-d6)δ3.78(s,3H),2.87(s,6H),2.84(s,3H),2.82(s,3H),2.44(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ3.78(s,3H), 2.87(s,6H), 2.84(s,3H), 2.82(s,3H), 2.44(s,3H).

步骤5：7-(1-氨基乙基)-3,6-二甲基-2-[3-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 5: 7-(1-aminoethyl)-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

7-乙酰基-3,6-二甲基-2-[3-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(110mg,0.3mmol,1.0eq)溶于异丙醇(10mL)中，加入醋酸铵(229mg,2.97mmol,10.0eq)和氰基硼氢化钠(37mg,0.59mmol,2.0eq)，氩气保护，85℃反应5小时，冷却至室温，反应液加入水(50mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(50mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到7-(1-氨基乙基)-3,6-二甲基-2-[3-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(53mg,收率48.1％)，黄色固体。7-Acetyl-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (110 mg, 0.3 mmol, 1.0 eq) was dissolved in isopropanol (10 mL), and ammonium acetate (229 mg, 2.97 mmol, 10.0 eq) and sodium cyanoborohydride (37 mg, 0.59 mmol, 2.0 eq) were added. The mixture was protected by argon and reacted at 85 °C for 5 hours. The mixture was cooled. The mixture was cooled to room temperature, and water (50 mL) was added to dilute the reaction solution. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-(1-aminoethyl)-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (53 mg, yield 48.1%) as a yellow solid.

MS m/z:372.3[M+H]+ MS m/z:372.3[M+H] +

步骤6：6-氯-3-[(1-{3,6-二甲基-2-[1-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-3-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸甲酯
Step 6: 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid methyl ester

7-(1-氨基乙基)-3,6-二甲基-2-[3-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-1-基]-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(53mg,0.14mmol,1.0eq)溶于DMSO(6mL)中，加入6-氯-3-氟吡啶-2-甲酸甲酯(33mg,0.17mmol,1.1eq)和二异丙基乙胺(DIPEA)(55mg,0.43mmol,3.0eq)，氩气保护，120℃反应5小时，冷却至室温，反应液加入水(20mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(50mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到6-氯-3-[(1-{3,6-二甲基-2-[1-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-3-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸甲酯(65mg,收率84.2％)，黄色固体。7-(1-Aminoethyl)-3,6-dimethyl-2-[3-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-1-yl]-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (53 mg, 0.14 mmol, 1.0 eq) was dissolved in DMSO (6 mL), methyl 6-chloro-3-fluoropyridine-2-carboxylate (33 mg, 0.17 mmol, 1.1 eq) and diisopropylethylamine (DIPEA) (55 mg, 0.43 mmol, 3.0 eq) were added, and the mixture was reacted at 120 °C for 5 hours under argon protection. The reaction mixture was cooled to room temperature, and water (20 mL) was added to dilute the reaction solution. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give methyl 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylate (65 mg, yield 84.2%) as a yellow solid.

MS m/z:541.3[M+H]+ MS m/z:541.3[M+H] +

步骤7：6-氯-3-[(1-{3,6-二甲基-2-[1-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-3-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸 Step 7: 6-Chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentan-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

6-氯-3-[(1-{3,6-二甲基-2-[1-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-3-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸甲酯(65mg,0.12mmol,1.0eq)溶于四氢呋喃(4mL)、甲醇(1mL)和水(1mL)中，加入一水氢氧化锂(10.1mg,0.24mmol,2.0eq)，室温反应3小时，1mol/L盐酸调节PH值为5左右，反应液中加入水(20mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到6-氯-3-[(1-{3,6-二甲基-2-[1-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-3-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(36mg,收率55.7％)，白色固体。6-Chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid methyl ester (65 mg, 0.12 mmol, 1.0 eq) was dissolved in tetrahydrofuran (4 mL), methanol (1 mL) and water (1 mL), and lithium hydroxide monohydrate (10.1 mg, 0.24 mmol, 2.0 eq) was added. The reaction was carried out at room temperature for 3 hours, and the pH value was adjusted with 1 mol/L hydrochloric acid. The reaction mixture was diluted with water (20 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (36 mg, yield 55.7%) as a white solid.

MS m/z：527.2[M+H]+ MS m/z：527.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),9.28(d,J＝449.7Hz,1H),7.44–7.03(m,2H),5.08(s,1H),3.61(s,3H),2.93–2.85(m,3H),2.81–2.72(m,3H),2.65(s,3H),2.36(s,3H),1.65(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.87 (s, 1H), 9.28 (d, J = 449.7Hz, 1H), 7.44–7.03 (m, 2H), 5.08 (s, 1H), 3. 61(s,3H),2.93–2.85(m,3H),2.81–2.72(m,3H),2.65(s,3H),2.36(s,3H),1.65(d,J＝6.6Hz,3H).

实施例68：6-氯-3-[(1-{2,6-二甲基-5-[4-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸
Example 68: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

步骤1：4-(3-乙酰基-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-5-基)苯甲酸甲酯
Step 1: Methyl 4-(3-acetyl-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)benzoate

以4-(氯羰基)苯甲酸甲酯为原料，按照实施例1方法制备4-(3-乙酰基-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-5-基)苯甲酸甲酯(456mg)。Using methyl 4-(chlorocarbonyl)benzoate as raw material, methyl 4-(3-acetyl-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)benzoate (456 mg) was prepared according to the method of Example 1.

MS m/z:357.2[M+H]+ MS m/z:357.2[M+H] +

步骤2：6-氯-3-[(1-{2,6-二甲基-5-[4-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸 Step 2: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

以4-(3-乙酰基-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-5-基)苯甲酸甲酯为原料，按照实施例67方法制备6-氯-3-[(1-{2,6-二甲基-5-[4-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸(2mg)，白色固体。6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-7-oxythieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (2 mg) was prepared as a white solid using methyl 4-(3-acetyl-2,6-dimethyl-7-oxythieno[3,2-b]pyran-5-yl)benzoate as a starting material according to the method of Example 67.

MS m/z:537.2[M+H]+ MS m/z:537.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),8.27(d,J＝8.1Hz,2H),8.05(d,J＝8.0Hz,2H),7.29–7.18(m,1H),6.99(t,J＝12.7Hz,1H),4.98–4.83(m,1H),3.08(s,3H),2.63(s,3H),2.07(s,3H),1.56(d,J＝6.7Hz,3H)。 1 H NMR(400MHz, DMSO-d6)δ9.82(s,1H),8.27(d,J＝8.1Hz,2H),8.05(d,J＝8.0Hz,2H),7.29–7.18(m,1H),6 .99(t,J＝12.7Hz,1H),4.98–4.83(m,1H),3.08(s,3H),2.63(s,3H),2.07(s,3H),1.56(d,J＝6.7Hz,3H).

实施例69：6-氯-3-[(1-{5-[1-(2-甲氧基苯基)吡唑-4-基]-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸
Example 69: 6-Chloro-3-[(1-{5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

步骤1：3-乙酰基-5-[1-(2-甲氧基苯基)吡唑-4-基]-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 1: 3-Acetyl-5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

以1-(2-甲氧基苯基)吡唑-4-甲酰氯为原料，按照实施例1方法制备3-乙酰基-5-[1-(2-甲氧基苯基)吡唑-4-基]-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(78mg)，黄色固体。Using 1-(2-methoxyphenyl)pyrazole-4-carbonyl chloride as starting material, 3-acetyl-5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (78 mg) was prepared as a yellow solid according to the method of Example 1.

MS m/z:395.2[M+H]+ MS m/z:395.2[M+H] +

步骤2：6-氯-3-[(1-{5-[1-(2-甲氧基苯基)吡唑-4-基]-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸Step 2: 6-Chloro-3-[(1-{5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

以3-乙酰基-5-[1-(2-甲氧基苯基)吡唑-4-基]-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮为原料，按照实施例67方法制备6-氯-3-[(1-{5-[1-(2-甲氧基苯基)吡唑-4-基]-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸(5mg)，白色固体。6-Chloro-3-[(1-{5-[1-(2-methoxyphenyl)pyrazol-4-yl]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one)-3-yl]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one)-3-yl]-4-thieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (5 mg) was prepared as a white solid according to the method of Example 67.

MS m/z:551.1[M+H]+ MS m/z:551.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.91(d,J＝68.9Hz,1H),8.90(s,1H),8.45(s,1H),7.71(dd,J＝7.9,1.7Hz,1H),7.46(t,J＝7.5Hz,1H),7.30(d,J＝8.3Hz,1H),7.20–6.96(m,3H),5.05–4.94(m,1H),3.88 (s,3H),2.61(s,3H),2.19(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ9.91(d,J＝68.9Hz,1H),8.90(s,1H),8.45(s,1H),7.71(dd,J＝7.9,1.7H z,1H),7.46(t,J＝7.5Hz,1H),7.30(d,J＝8.3Hz,1H),7.20–6.96(m,3H),5.05–4.94(m,1H),3.88 (s,3H),2.61(s,3H),2.19(s,3H),1.63(d,J=6.7Hz,3H).

实施例70：6-氯-3-[(1-{5-[1-(3-氰基苯基)吡唑-4-基]-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸
Example 70: 6-Chloro-3-[(1-{5-[1-(3-cyanophenyl)pyrazol-4-yl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

以1-(3-氰基苯基)吡唑-4-甲酰氯为原料，按照实施例69方法制备6-氯-3-[(1-{5-[1-(3-氰基苯基)吡唑-4-基]-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸(3mg)，白色固体。6-Chloro-3-[(1-{5-[1-(3-cyanophenyl)pyrazol-4-yl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (3 mg) was prepared as a white solid using 1-(3-cyanophenyl)pyrazole-4-carbonyl chloride as starting material according to the method of Example 69.

MS m/z:546.1[M+H]+ MS m/z:546.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),9.18(s,1H),8.66(s,1H),8.56(d,J＝2.2Hz,1H),8.44(s,1H),8.39(d,J＝8.3Hz,1H),7.89(d,J＝7.6Hz,1H),7.80(t,J＝8.0Hz,1H),7.43(d,J＝8.9Hz,1H),7.18(d,J＝9.0Hz,1H),5.12(t,J＝7.0Hz,1H),2.66(s,3H),2.22(s,3H),1.68(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ13.12(s,1H),9.18(s,1H),8.66(s,1H),8.56(d,J＝2.2Hz,1H),8.44(s,1H),8.39(d,J＝8.3Hz,1H),7.89(d,J＝7.6Hz,1 H), 7.80 (t, J = 8.0Hz, 1H), 7.43 (d, J = 8.9Hz, 1H), 7.18 (d, J = 9.0Hz, 1H), 5.12 (t, J = 7.0Hz, 1H), 2.66 (s, 3H), 2.22 (s, 3H), 1.68 (d, J = 6.7Hz, 3H).

实施例71：6-氯-3-[(1-{2,6-二甲基-5-[4-(1,4-氧杂氮杂环己-4-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸
Example 71: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(1,4-oxazepan-4-yl)phenyl]-7-oxydithieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

以4-(1,4-氧杂氮杂环己-4-基)苯甲酰氯为原料，按照实施例69方法制备6-氯-3-[(1-{2,6-二甲基-5-[4-(1,4-氧杂氮杂环己-4-基)苯基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸(1.9mg)，淡黄色固体。6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(1,4-oxazepine-4-yl)phenyl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (1.9 mg) was prepared as a light yellow solid using 4-(1,4-oxazepine-4-yl)benzoyl chloride as starting material according to the method of Example 69.

MS m/z:540.1[M+H]+ MS m/z:540.1[M+H] +

实施例72：6-氯-3-({1-[5-(4-氰基苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)吡啶-2-甲酸
Example 72: 6-Chloro-3-({1-[5-(4-cyanophenyl)-2,6-dimethyl-7-oxydethieno[3,2-b]pyran-3-yl]ethyl}amino)pyridine-2-carboxylic acid

以4-氰基苯甲酰氯为原料，按照实施例69方法制备6-氯-3-({1-[5-(4-氰基苯基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)吡啶-2-甲酸(10mg)，白色固体。6-Chloro-3-({1-[5-(4-cyanophenyl)-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)pyridine-2-carboxylic acid (10 mg) was prepared as a white solid using 4-cyanobenzoyl chloride as the starting material according to the method of Example 69.

MS m/z:480.1[M+H]+ MS m/z:480.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),8.34(d,J＝7.2Hz,1H),8.04(d,J＝8.5Hz,2H),7.87(d,J＝6.5Hz,2H),7.41(d,J＝8.9Hz,1H),7.13(d,J＝9.0Hz,1H),5.02(p,J＝6.7Hz,1H),2.66(s,3H),1.99(s,3H),1.59(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.34(d,J＝7.2Hz,1H),8.04(d,J＝8.5Hz,2H),7.87(d,J＝6.5Hz,2H),7.41 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 5.02 (p, J = 6.7 Hz, 1H), 2.66 (s, 3H), 1.99 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H).

实施例73：6-氯-3-[(1-{3,6-二甲基-2-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 73: 6-Chloro-3-[(1-{3,6-dimethyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以5-甲基-2-[(2S)-2-甲基哌嗪-1-基]嘧啶为原料，参照实施例63的方法制备6-氯-3-[(1-{3,6-二甲基-2-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(9mg)，白色固体。Using 5-methyl-2-[(2S)-2-methylpiperazin-1-yl]pyrimidine as starting material, 6-chloro-3-[(1-{3,6-dimethyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxythylenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (9 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：569.2[M+H]+ MS m/z：569.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.26(s,1H),8.59(s,1H),8.30(s,2H),7.49–7.16(m,2H),4.98(d,J＝58.5Hz,2H),4.48(t,J＝11.5Hz,1H),3.85–3.60(m,5H),3.35(p,J＝12.5Hz,1H),3.15(t,J＝15.9Hz,1H),3.07–2.84(m,1H),2.62(s,3H),2.11(s,3H),1.63(d,J＝6.6Hz,3H),1.26(dd,J＝25.0,6.5Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ12.26(s,1H),8.59(s,1H),8.30(s,2H),7.49–7.1 6(m,2H),4.98(d,J＝58.5Hz,2H),4.48(t,J＝11.5Hz,1H),3.85–3.60(m,5H ),3.35(p,J＝12.5Hz,1H),3.15(t,J＝15.9Hz,1H),3.07–2.84(m,1H),2.62 (s,3H),2.11(s,3H),1.63(d,J＝6.6Hz,3H),1.26(dd,J＝25.0,6.5Hz,3H).

实施例74：6-氯-3-[(1-{6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(74)
Example 74: 6-Chloro-3-[(1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (74)

以氘代甲胺盐酸盐为原料，参照实施例63的方法制备6-氯-3-[(1-{6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(74，13mg)，白色固体。Using deuterated methylamine hydrochloride as starting material, 6-chloro-3-[(1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (74, 13 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：558.2[M+H]+ MS m/z：558.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.59(d,J＝8.5Hz,1H),8.29(s,2H),7.41(d,J＝9.0Hz,1H),7.28(d,J＝9.1Hz,1H),5.12–4.98(m,1H),3.86(ddt,J＝17.9,12.9,6.4Hz,4H),3.31–3.16(m,4H),2.61(s,3H),2.11(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.59(d,J＝8.5Hz,1H),8.29(s,2H),7.41(d,J＝9.0Hz,1H),7.28(d,J＝9.1Hz,1H),5. 12–4.98(m,1H),3.86(ddt,J＝17.9,12.9,6.4Hz,4H),3.31–3.16(m,4H),2.61(s,3H),2.11(s,3H),1.63(d,J＝6.7Hz,3H).

6-氯-3-{[(1S)-1-{6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(74-P1和74-P2)
6-Chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (74-P1 and 74-P2)

实施例74化合物通过超临界流体色谱(SFC)分离制备得到6-氯-3-{[(1S)-1-{6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(310mg,白色固体)和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(275mg,白色固体),74-P1先于74-P2出峰。The compound of Example 74 was separated and prepared by supercritical fluid chromatography (SFC) to give 6-chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (310 mg, white solid) and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (275 mg, white solid), 74-P1 eluted before 74-P2.

手性分离方法：Chiral separation method:

仪器:SFC-150(Waters)Instrument: SFC-150 (Waters)

手性柱:AD 25*250mm,10μm(Daicel)Chiral column: AD 25*250mm, 10μm (Daicel)

柱温:35℃Column temperature: 35°C

流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50 Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50

流速:100mL/minFlow rate: 100mL/min

检测波长:214nm。Detection wavelength: 214nm.

实施例75：6-氯-3-[(1-{6-甲基-2-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(75)
Example 75: 6-Chloro-3-[(1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (75)

以氘代甲胺盐酸盐及5-甲基-2-[(2S)-2-甲基哌嗪-1-基]嘧啶为原料，参照实施例63的方法制备6-氯-3-[(1-{6-甲基-2-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(75，12mg)，白色固体。Using deuterated methylamine hydrochloride and 5-methyl-2-[(2S)-2-methylpiperazin-1-yl]pyrimidine as raw materials, 6-chloro-3-[(1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (75, 12 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：572.2[M+H]+ MS m/z：572.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.59(t,J＝8.3Hz,1H),8.29(d,J＝3.0Hz,2H),7.41(dd,J＝8.9,2.6Hz,1H),7.26(dd,J＝9.1,7.0Hz,1H),5.05(dt,J＝10.9,3.7Hz,1H),4.89(d,J＝7.5Hz,1H),4.48(dd,J＝13.0,10.1Hz,1H),3.71–3.47(m,2H),3.28(dd,J＝12.8,3.1Hz,1H),3.17–2.85(m,2H),2.62(d,J＝2.3Hz,3H),2.11(s,3H),1.64(dd,J＝6.7,2.0Hz,3H),1.25(dd,J＝25.9,6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.59(t,J＝8.3Hz,1H),8.29(d,J＝3.0Hz,2H),7.41(dd,J＝8 .9,2.6Hz,1H),7.26(dd,J＝9.1,7.0Hz,1H),5.05(dt,J＝10.9,3.7Hz,1H),4.89(d,J＝7.5Hz,1H), 4.48(dd,J＝13.0,10.1Hz,1H),3.71–3.47(m,2H),3.28(dd,J＝12.8,3.1Hz,1H),3.17–2.85(m,2H ), 2.62 (d, J = 2.3Hz, 3H), 2.11 (s, 3H), 1.64 (dd, J = 6.7, 2.0Hz, 3H), 1.25 (dd, J = 25.9, 6.7Hz, 3H).

6-氯-3-{[(1S)-1-{6-甲基-2-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-{6-甲基-2-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(75-P1和75-P2)
6-Chloro-3-{[(1S)-1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (75-P1 and 75-P2)

实施例75化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-{6-甲基-2-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(301mg,白色 固体)和6-氯-3-{[(1R)-1-{6-甲基-2-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(317mg,白色固体),75-P1先于75-P2出峰。Example 75 The compound was separated by SFC to obtain 6-chloro-3-{[(1S)-1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (301 mg, white Solid) and 6-chloro-3-{[(1R)-1-{6-methyl-2-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (317 mg, white solid), 75-P1 eluted before 75-P2.

手性分离方法同实施例74。The chiral separation method is the same as Example 74.

实施例76：2-[(1-{6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]苯甲酸
Example 76: 2-[(1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]benzoic acid

以氘代甲胺盐酸盐及2-氟苯甲酸甲酯为原料，参照实施例63的方法制备2-[(1-{6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]苯甲酸(5mg)，黄色固体。Using deuterated methylamine hydrochloride and methyl 2-fluorobenzoate as raw materials, 2-[(1-{6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]benzoic acid (5 mg) was prepared as a yellow solid according to the method of Example 63.

MS m/z：523.2[M+H]+ MS m/z：523.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.56(s,1H),8.53(s,1H),8.29(s,2H),7.74(dd,J＝7.9,1.7Hz,1H),7.27(ddd,J＝8.7,7.1,1.8Hz,1H),6.66(d,J＝8.5Hz,1H),6.49(t,J＝7.8Hz,1H),5.02(s,1H),3.88(dtd,J＝18.2,12.9,4.8Hz,4H),3.33(t,J＝5.1Hz,4H),2.61(s,3H),2.11(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.56(s,1H),8.53(s,1H),8.29(s,2H),7.74(dd,J＝7.9,1.7Hz,1H),7.27(ddd,J＝8.7,7.1,1.8Hz,1H),6.66(d,J＝8.5Hz,1 H),6.49(t,J＝7.8Hz,1H),5.02(s,1H),3.88(dtd,J＝18.2,12.9,4.8Hz,4H ), 3.33 (t, J = 5.1Hz, 4H), 2.61 (s, 3H), 2.11 (s, 3H), 1.63 (d, J = 6.7Hz, 3H).

实施例77：6-氯-3-{[1-(5-{4-[3-(二甲基氨基)氮杂环丁-1-基]苯基}-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}吡啶-2-甲酸
Example 77: 6-Chloro-3-{[1-(5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid

步骤1：3-溴-5-(4-甲氧基苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 1: 3-Bromo-5-(4-methoxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

以4-甲氧基苯甲酰氯为原料，按照实施例69方法制备3-溴-5-(4-甲氧基苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(4.2g)，黄色固体。3-Bromo-5-(4-methoxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (4.2 g) was prepared from 4-methoxybenzoyl chloride as a yellow solid according to the method of Example 69.

MS m/z:365.1/367.1[M+H]+MS m/z:365.1/367.1[M+H]+

步骤2：3-溴-5-(4-羟基苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 2: 3-Bromo-5-(4-hydroxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

3-溴-5-(4-甲氧基苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(1.5g,4.1mmol,1.0eq)溶于二氯甲烷(20mL)中，-78℃下缓慢加入三溴化硼(5.2g,20.5mmol,5.0eq)，氩气保护，-78°℃反应1小时，加入甲醇淬灭反应，升至室温，减压浓缩，残留物柱层析纯化得到3-溴-5-(4-羟基苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(750mg,收率52％)，土黄色固体。3-Bromo-5-(4-methoxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (1.5 g, 4.1 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and boron tribromide (5.2 g, 20.5 mmol, 5.0 eq) was slowly added at -78°C, with argon protection, and the mixture was reacted at -78°C for 1 hour. Methanol was added to quench the reaction, and the mixture was warmed to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-bromo-5-(4-hydroxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (750 mg, yield 52%) as a khaki solid.

MS m/z:351.3/353.3[M+H]+ MS m/z:351.3/353.3[M+H] +

步骤3：三氟甲烷磺酸-4-(3-溴-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-5-基)苯基酯
Step 3: 4-(3-bromo-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)phenyl trifluoromethanesulfonate

3-溴-5-(4-羟基苯基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(800mg,2.3mmol,1.0eq)溶于氮，氮-二甲基甲酰胺(20mL)中，室温下加入三乙胺(230mg,2.3mmol,1.0eq)和三氟甲磺酸酐(976mg,2.73mmol,1.2eq)，氩气保护，室温反应2小时，加入水(50mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，减压浓缩，残留物柱层析纯化得到三氟甲烷磺酸-4-(3-溴-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-5-基)苯基酯(950mg,收率86.36％)。3-Bromo-5-(4-hydroxyphenyl)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (800 mg, 2.3 mmol, 1.0 eq) was dissolved in nitrogen-dimethylformamide (20 mL), and triethylamine (230 mg, 2.3 mmol, 1.0 eq) and trifluoromethanesulfonic anhydride (976 mg, 2.73 mmol, 1.2 eq) were added at room temperature. The mixture was protected by argon and reacted at room temperature for 2 hours. Water (50 mL) was added for dilution, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give trifluoromethanesulfonic acid-4-(3-bromo-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)phenyl ester (950 mg, yield 86.36%).

MS m/z:483.3[M+H]+ MS m/z:483.3[M+H] +

步骤4：3-溴-5-{4-[3-(二甲基氨基)氮杂环丁-1-基]苯基}-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 4: 3-Bromo-5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

三氟甲烷磺酸-4-(3-溴-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-5-基)苯基酯(191mg,0.4mmol,1.0eq)溶于二氧六环(20mL)中，加入碳酸铯(386mg,1.19mmol,3.0eq)、3-(二甲基氨基)氮杂环丁烷盐酸盐(88mg,0.51mmol,1.3eq)、S-(-)-1,1'-联萘-2,2'-双二苯膦(36mg,0.06mmol,0.1eq)和醋酸钯(8.9mg,0.04mmol,0.1eq)，氩气保护，100℃反应16小时，冷却至室温，加入水(40mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，减压浓缩，残留物柱层析纯化得到3-溴-5-{4-[3-(二甲基氨基)氮杂环丁-1-基]苯基}-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(81mg,收率47.6％)。4-(3-bromo-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-5-yl)phenyl trifluoromethanesulfonate (191 mg, 0.4 mmol, 1.0 eq) was dissolved in dioxane (20 mL), and cesium carbonate (386 mg, 1.19 mmol, 3.0 eq), 3-(dimethylamino)azetidine hydrochloride (88 mg, 0.51 mmol, 1.3 eq), S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (36 mg, 0.06 mmol, 0.1 eq) and ester were added. Palladium chloride (8.9 mg, 0.04 mmol, 0.1 eq), argon protection, reaction at 100 ° C for 16 hours, cooled to room temperature, added water (40 mL) to dilute, extracted three times with ethyl acetate (20 mL), combined organic phases, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give 3-bromo-5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (81 mg, yield 47.6%).

MS m/z:433.3/435.3[M+H]+ MS m/z:433.3/435.3[M+H] +

步骤5：6-氯-3-{[1-(5-{4-[3-(二甲基氨基)氮杂环丁-1-基]苯基}-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}吡啶-2-甲酸Step 5: 6-Chloro-3-{[1-(5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid

以3-溴-5-{4-[3-(二甲基氨基)氮杂环丁-1-基]苯基}-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮为原料，参照实施例63的方法制备6-氯-3-{[1-(5-{4-[3-(二甲基氨基)氮杂环丁-1-基]苯基}-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}吡啶-2-甲酸(2mg)，白色固体。Using 3-bromo-5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one as starting material, 6-chloro-3-{[1-(5-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-2,6-dimethyl-7-oxydithieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid (2 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：553.2[M+H]+ MS m/z：553.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.80(d,J＝34.9Hz,1H),7.66(d,J＝8.2Hz,2H),7.13(d,J＝8.6Hz,1H),6.98(s,1H),6.54(d,J＝8.3Hz,2H),4.86(s,1H),3.99(q,J＝6.9Hz,2H),3.68(dq,J＝8.2,4.4,3.9Hz,2H),3.23(d,J＝6.2Hz,1H),2.73(d,J＝7.0Hz,1H),2.58(s,3H),2.13(s,6H),2.06(s,3H),1.56(d,J＝6.7Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ9.80(d,J＝34.9Hz,1H),7.66(d,J＝8.2Hz,2H),7.13( d,J＝8.6Hz,1H),6.98(s,1H),6.54(d,J＝8.3Hz,2H),4.86(s,1H),3.99(q,J＝ 6.9Hz,2H),3.68(dq,J＝8.2,4.4,3.9Hz,2H),3.23(d,J＝6.2Hz,1H),2.73(d, J＝7.0Hz,1H),2.58(s,3H),2.13(s,6H),2.06(s,3H),1.56(d,J＝6.7Hz,3H).

实施例78：6-氯-3-{[1-(5-{4-[4-(二甲基氨基)六氢吡啶-1-基]苯基}-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}吡啶-2-甲酸
Example 78: 6-Chloro-3-{[1-(5-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid

以4-(二甲基氨基)六氢吡啶为原料，参照实施例77的方法制备6-氯-3-{[1-(5-{4-[4-(二甲基氨基)六氢吡啶-1-基]苯基}-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基)乙基]氨基}吡啶-2-甲酸(1.6mg)，白色固体。Using 4-(dimethylamino)piperidine as starting material, 6-chloro-3-{[1-(5-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl)ethyl]amino}pyridine-2-carboxylic acid (1.6 mg) was prepared as a white solid by referring to the method of Example 77.

MS m/z：581.2[M+H]+ MS m/z：581.2[M+H] +

实施例79：6-氯-3-({1-[2-(5-氟吡啶-2-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 79: 6-Chloro-3-({1-[2-(5-fluoropyridin-2-yl)-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以5-氟吡啶-2-甲醛及3-氨基-6-氯吡啶-2-甲酸甲酯为原料，参照实施例30的方法制备6-氯-3-({1-[2-(5-氟吡啶-2-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(23mg)，白色固体。Using 5-fluoropyridine-2-carboxaldehyde and 3-amino-6-chloropyridine-2-carboxylic acid methyl ester as raw materials, 6-chloro-3-({1-[2-(5-fluoropyridin-2-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (23 mg) was prepared as a white solid according to the method of Example 30.

MS m/z：477.2[M+H]+ MS m/z：477.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),8.73(d,J＝2.7Hz,1H),8.60(d,J＝7.5Hz,1H),8.14(dd,J＝8.8,4.5Hz,1H),7.98(td,J＝8.7,2.9Hz,1H),7.31(dd,J＝58.0,9.0Hz,2H),5.13(t,J＝7.1Hz,1H),2.65(s,3H),1.60(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.92(s,1H),8.73(d,J＝2.7Hz,1H),8.60(d,J＝7.5Hz,1H),8.14(dd,J＝8.8,4.5Hz,1H),7. 98(td,J＝8.7,2.9Hz,1H),7.31(dd,J＝58.0,9.0Hz,2H),5.13(t,J＝7.1Hz,1H),2.65(s,3H),1.60(d,J＝6.7Hz,3H).

实施例80：6-氯-3-({1-[5-(5-氟吡啶-2-基)-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)吡啶-2-甲酸
Example 80: 6-Chloro-3-({1-[5-(5-fluoropyridin-2-yl)-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl]ethyl}amino)pyridine-2-carboxylic acid

以5-氟吡啶-2-甲酰氯为原料，按照实施例69方法制备6-氯-3-({1-[5-(5-氟吡啶-2-基)-2,6-二甲基- 7-氧亚基噻吩并[3,2-b]吡喃-3-基]乙基}氨基)吡啶-2-甲酸(5mg)，白色固体。5-Fluoropyridine-2-carbonyl chloride was used as the starting material to prepare 6-chloro-3-({1-[5-(5-fluoropyridin-2-yl)-2,6-dimethyl- 7-Oxylidenethieno[3,2-b]pyran-3-yl]ethyl}amino)pyridine-2-carboxylic acid (5 mg), white solid.

MS m/z:474.1[M+H]+ MS m/z:474.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.79(d,J＝2.8Hz,1H),8.43(d,J＝7.1Hz,1H),8.10–7.90(m,2H),7.40(d,J＝8.9Hz,1H),7.14(d,J＝9.0Hz,1H),5.05(p,J＝7.0Hz,1H),2.66(s,3H),2.14(s,3H),1.63(d,J＝6.8Hz,3H)。 1 H NMR(400MHz, DMSO-d6)δ8.79(d,J＝2.8Hz,1H),8.43(d,J＝7.1Hz,1H),8.10–7.90(m,2H),7.40(d,J＝8.9 Hz, 1H), 7.14 (d, J = 9.0Hz, 1H), 5.05 (p, J = 7.0Hz, 1H), 2.66 (s, 3H), 2.14 (s, 3H), 1.63 (d, J = 6.8Hz, 3H).

实施例81：3-[(1-{5-[4-(4-乙酰基哌嗪-1-基)苯基]-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]-6-氯吡啶-2-甲酸
Example 81: 3-[(1-{5-[4-(4-acetylpiperazin-1-yl)phenyl]-2,6-dimethyl-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid

以1-(哌嗪-1-基)乙-1-酮为原料，参照实施例77的方法制备3-[(1-{5-[4-(4-乙酰基哌嗪-1-基)苯基]-2,6-二甲基-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]-6-氯吡啶-2-甲酸(16mg)，淡黄色固体。Using 1-(piperazin-1-yl)ethan-1-one as starting material, 3-[(1-{5-[4-(4-acetylpiperazin-1-yl)phenyl]-2,6-dimethyl-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid (16 mg) was prepared as a light yellow solid according to the method of Example 77.

MS m/z：581.2[M+H]+ MS m/z：581.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.59(d,J＝8.4Hz,2H),7.39(d,J＝8.9Hz,1H),7.09(t,J＝11.3Hz,3H),4.99(s,1H),3.59(q,J＝5.8Hz,4H),3.29(d,J＝5.4Hz,3H),2.62(s,3H),2.05(d,J＝3.6Hz,6H),1.59(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),7.59(d,J＝8.4Hz,2H),7.39(d,J＝8.9Hz,1H),7.09(t,J＝11.3Hz,3H),4.99 (s, 1H), 3.59 (q, J = 5.8Hz, 4H), 3.29 (d, J = 5.4Hz, 3H), 2.62 (s, 3H), 2.05 (d, J = 3.6Hz, 6H), 1.59 (d, J = 6.7Hz, 3H).

实施例82：6-氯-3-[(1-{2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸
Example 82: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

步骤1：3-溴-2,6-二甲基-5-巯基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 1: 3-Bromo-2,6-dimethyl-5-mercapto-7H-thieno[3,2-b]pyran-7-one

1-(4-溴-3-羟基-5-甲基噻吩-2-基)丙-1-酮(2.0g，8.03mmol,1.0eq)溶于干燥四氢呋喃(10mL)中，氩气保护，-50℃下滴加2mol/L双(三甲基硅基)氨基钠(14mL,28.1mmol,3.5eq)，0℃反应1小时，冷却至-45℃，滴加二硫化碳(0.6g，8.03mmol,1.0eq),室温搅拌过夜，冷却至-50℃，滴加15％稀硫酸调节PH值为7左右，反应液中加入水(50mL)稀释，乙酸乙酯(50mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩得到粗品3-溴-2,6-二甲基-5-巯基-7H-噻吩并[3,2-b]吡喃-7-酮(1.6g,收率68.4％)，黄色固体。1-(4-Bromo-3-hydroxy-5-methylthiophen-2-yl)propan-1-one (2.0 g, 8.03 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (10 mL) under argon protection, 2 mol/L sodium bis(trimethylsilyl)amide (14 mL, 28.1 mmol, 3.5 eq) was added dropwise at -50 °C, reacted at 0 °C for 1 hour, cooled to -45 °C, carbon disulfide (0.6 g, 8.03 mmol, 1.0 eq) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The mixture was stirred overnight at room temperature, cooled to -50°C, 15% dilute sulfuric acid was added dropwise to adjust the pH value to about 7, water (50 mL) was added to the reaction solution to dilute it, and ethyl acetate (50 mL) was used for extraction three times. The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 3-bromo-2,6-dimethyl-5-mercapto-7H-thieno[3,2-b]pyran-7-one (1.6 g, yield 68.4%) as a yellow solid.

MS m/z：291.2/293.2[M+H]+ MS m/z：291.2/293.2[M+H] +

步骤2：3-溴-5-(乙基硫基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 2: 3-Bromo-5-(ethylthio)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

3-溴-2,6-二甲基-5-巯基-7H-噻吩并[3,2-b]吡喃-7-酮(1.6g，5.49mmol,1.0eq)溶于氮，氮-二甲基甲酰胺(10mL)中，氩气保护下加入硫酸二乙酯(0.85g,5.49mmol,1.0eq)和碳酸钾(0.76g,5.49mmol,1.0eq)，室温反应5小时，反应液中加入水(30mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(50mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物纯化得到3-溴-5-(乙基硫基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(1.0g,收率57.1％)，黄色固体。3-Bromo-2,6-dimethyl-5-mercapto-7H-thieno[3,2-b]pyran-7-one (1.6 g, 5.49 mmol, 1.0 eq) was dissolved in nitrogen-dimethylformamide (10 mL). Diethyl sulfate (0.85 g, 5.49 mmol, 1.0 eq) and potassium carbonate (0.76 g, 5.49 mmol, 1.0 eq) were added under argon protection. The reaction mixture was reacted at room temperature for 5 hours. Water (30 mL) was added to the reaction mixture for dilution. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 3-bromo-5-(ethylthio)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (1.0 g, yield 57.1%) as a yellow solid.

MS m/z：319.2/321.2[M+H]+ MS m/z：319.2/321.2[M+H] +

步骤3：3-溴-5-[乙基(氧亚基)-λ4-硫基]-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮
Step 3: 3-Bromo-5-[ethyl(oxyylidene)-λ4-thio]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one

3-溴-5-(乙基硫基)-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(0.5g，1.57mmol,1.0eq)溶于二氯甲烷(10mL)中，氩气保护下加入3-氯过氧苯甲酸(0.4g,2.35mmol,1.5eq)，室温反应6小时，反应液中加入水(10mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物纯化得到3-溴-5-[乙基(氧亚基)-λ4-硫基]-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(370mg,收率70.1％)，类白色固体。3-Bromo-5-(ethylthio)-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (0.5 g, 1.57 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), 3-chloroperoxybenzoic acid (0.4 g, 2.35 mmol, 1.5 eq) was added under argon protection, and the reaction was allowed to react at room temperature for 6 hours. Water (10 mL) was added to the reaction solution for dilution, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 3-bromo-5-[ethyl(oxyylidene)-λ4-thio]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (370 mg, yield 70.1%) as an off-white solid.

MS m/z：335.2/337.2[M+H]+ MS m/z：335.2/337.2[M+H] +

步骤4：3-溴-2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7H-噻吩并[3,2-b]吡喃-7-酮
Step 4: 3-Bromo-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one

3-溴-5-[乙基(氧亚基)-λ4-硫基]-2,6-二甲基-7H-噻吩并[3,2-b]吡喃-7-酮(30mg，0.09mmol,1.0eq)溶于DMSO(5mL)中，氩气保护下加入5-甲基-2-(哌嗪-1-基)嘧啶(32mg,0.18mmol,2.0eq)，室温反应4小时，反应液加入水(10mL)稀释，二氯甲烷(10mL)萃取三次，合并有机相，饱和食盐水(30mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到3-溴-2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7H-噻吩并[3,2-b]吡喃-7-酮(10mg,收率25.7％)，类白色固体。3-Bromo-5-[ethyl(oxyylidene)-λ4-thio]-2,6-dimethyl-7H-thieno[3,2-b]pyran-7-one (30 mg, 0.09 mmol, 1.0 eq) was dissolved in DMSO (5 mL), and 5-methyl-2-(piperazin-1-yl)pyrimidine (32 mg, 0.18 mmol, 2.0 eq) was added under argon protection. The reaction mixture was reacted at room temperature for 4 hours. Water (10 mL) was added to dilute the reaction solution, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-bromo-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one (10 mg, yield 25.7%) as an off-white solid.

MS m/z：435.2/437.2[M+H]+ MS m/z：435.2/437.2[M+H] +

步骤5：3-乙酰基-2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7H-噻吩并[3,2-b]吡喃-7-酮
Step 5: 3-Acetyl-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one

以3-溴-2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7H-噻吩并[3,2-b]吡喃-7-酮为原料，按照实施例16的方法制备得到3-乙酰基-2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7H-噻吩并[3,2-b]吡喃-7-酮(49mg)，类白色固体。Using 3-bromo-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one as raw material, 3-acetyl-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one (49 mg) was prepared as an off-white solid according to the method of Example 16.

MS m/z：399.2/401.2[M+H]+ MS m/z：399.2/401.2[M+H] +

步骤6：6-氯-3-[(1-{2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸Step 6: 6-Chloro-3-[(1-{2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

以3-乙酰基-2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7H-噻吩并[3,2-b]吡喃-7-酮为原料，按照实施例63的方法制备得到6-氯-3-[(1-{2,6-二甲基-5-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸(3mg)，白色固体。Using 3-acetyl-2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7H-thieno[3,2-b]pyran-7-one as starting material, 6-chloro-3-[(1-{2,6-dimethyl-5-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxyylidenethieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (3 mg) was prepared as a white solid according to the method of Example 63.

MS m/z：555.2/557.2[M+H]+ MS m/z：555.2/557.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ13.21(s,1H),8.83(s,1H),8.29(s,2H),7.33(d,J＝11.4Hz,1H),7.05(d,J＝8.8Hz,1H),4.93(s,1H),3.93–3.77(m,4H),3.41(d,J＝5.2Hz,4H),2.61(s,3H),2.12(s,3H),1.91(s,3H),1.62(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),8.83(s,1H),8.29(s,2H),7.33(d,J＝11.4Hz,1H),7.05(d,J＝8.8Hz,1H),4. 93(s,1H),3.93–3.77(m,4H),3.41(d,J＝5.2Hz,4H),2.61(s,3H),2.12(s,3H),1.91(s,3H),1.62(d,J＝6.7Hz,3H).

实施例83：6-氯-3-[(1-{2-[4-(咪唑并[2,3-f][1,2]二氮杂环己熳-6-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 83: 6-Chloro-3-[(1-{2-[4-(imidazo[2,3-f][1,2]diazepin-6-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteromethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺盐酸盐及6-(哌嗪-1-基)咪唑并[2,3-f][1,2]二氮杂环己熳为原料，参照实施例63的方法制备6-氯-3-[(1-{2-[4-(咪唑并[2,3-f][1,2]二氮杂环己熳-6-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(10mg)，白色固体。Using deuterated methylamine hydrochloride and 6-(piperazin-1-yl)imidazo[2,3-f][1,2]diazepine as starting materials, 6-chloro-3-[(1-{2-[4-(imidazo[2,3-f][1,2]diazepine-6-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (10 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：583.2[M+H]+ MS m/z：583.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),7.96(s,1H),7.89(d,J＝9.9Hz,1H),7.52(s,1H),7.25(d,J＝10.0Hz,1H),7.16–6.94(m,2H),5.00–4.90(m,1H),3.66(d,J＝12.2Hz,4H),3.50–3.38(m,4H),2.56(s,3H),1.61(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.70(s,1H),7.96(s,1H),7.89(d,J＝9.9Hz,1H),7.52(s,1H),7.25(d,J＝10.0Hz,1H),7.1 6–6.94(m,2H),5.00–4.90(m,1H),3.66(d,J＝12.2Hz,4H),3.50–3.38(m,4H),2.56(s,3H),1.61(d,J＝6.7Hz,3H).

实施例84：6-氯-3-[(1-{3,6-二甲基-2-[1-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-3-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 84: 6-Chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentyl-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺盐酸盐及1-(甲氧基羰基)双环[2.2.2]辛烷-4-甲酸为原料，参照实施例67的方法制备6-氯-3-[(1-{3,6-二甲基-2-[1-(3-甲基-1,2,4-氧杂二氮杂环戊熳-5-基)双环[1.1.1]戊-3-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(12mg)，白色固体。Using deuterated methylamine hydrochloride and 1-(methoxycarbonyl)bicyclo[2.2.2]octane-4-carboxylic acid as starting materials, 6-chloro-3-[(1-{3,6-dimethyl-2-[1-(3-methyl-1,2,4-oxadiazacyclopentane-5-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (12 mg) was prepared as a white solid by referring to the method of Example 67.

MS m/z：572.1[M+H]+ MS m/z：572.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),7.07(d,J＝23.5Hz,2H),5.04(t,J＝7.3Hz,1H),2.33(s,6H),2.24–2.15(m,3H),2.04(t,J＝7.8Hz,6H),1.62(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 7.07 (d, J = 23.5Hz, 2H), 5.04 (t, J = 7.3Hz, 1 H), 2.33 (s, 6H), 2.24–2.15 (m, 3H), 2.04 (t, J = 7.8Hz, 6H), 1.62 (d, J = 6.7Hz, 3H).

实施例85：6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[1.1.1]戊-3-基}噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(85)
Example 85: 6-Chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-3-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (85)

以氘代甲胺盐酸盐及N-(1-氮亚基-2,2,2-三氘基乙基)羟胺为原料，参照实施例67的方法制备6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[1.1.1]戊-3-基}噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(85，2mg)，白色固体。Using deuterated methylamine hydrochloride and N-(1-nitrogenylidene-2,2,2-trideuterioethyl)hydroxylamine as raw materials, 6-chloro-3-({1-[6-methyl-4-oxygenylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-3-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (85,2 mg) was prepared as a white solid by referring to the method of Example 67.

MS m/z：533.1[M+H]+ MS m/z：533.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.77–8.66(m,1H),7.39(d,J＝8.9Hz,1H),7.25(d,J＝9.1Hz,1H),5.08(q,J＝7.2Hz,1H),2.88(dd,J＝9.4,1.9Hz,3H),2.77(dd,J＝9.4,1.9Hz,3H),2.66(s,3H),1.66(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.77–8.66(m,1H),7.39(d,J＝8.9Hz,1H),7.25(d,J＝9.1Hz,1H),5.08(q,J＝7. 2Hz, 1H), 2.88 (dd, J = 9.4, 1.9Hz, 3H), 2.77 (dd, J = 9.4, 1.9Hz, 3H), 2.66 (s, 3H), 1.66 (d, J = 6.7Hz, 3H).

6-氯-3-{[(1S)-1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{3-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[1.1.1]戊-1-基}噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{3-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[1.1.1]戊-1-基}噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(85-P1和85-P2)
6-Chloro-3-{[(1S)-1-[6-methyl-4-oxo-3-(trideuteriomethyl)-2-{3-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3- {[(1R)-1-[6-methyl-4-oxo-3-(trideuteriomethyl)-2-{3-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (85-P1 and 85-P2)

实施例85化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{3-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[1.1.1]戊-1-基}噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(300mg,白色固体)和6-氯-3-{[(1R)-1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{3-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[1.1.1]戊-1-基}噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(310mg,白色固体),85-P1先于85-P2出峰。The compound of Example 85 was separated by SFC to obtain 6-chloro-3-{[(1S)-1-[6-methyl-4-oxylidene-3-(trideuteriomethyl)-2-{3-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentane-5-yl]bicyclo[1.1.1]pentan-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (300 mg, white solid) ) and 6-chloro-3-{[(1R)-1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{3-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[1.1.1]pentan-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (310 mg, white solid), 85-P1 eluted before 85-P2.

手性分离方法：Chiral separation method:

仪器:SFC-150(Waters) Instrument: SFC-150 (Waters)

手性柱:AD 25*250mm,10μm(Daicel)Chiral column: AD 25*250mm, 10μm (Daicel)

柱温:35℃Column temperature: 35°C

流动相:CO2/甲醇＝40/60Mobile phase: CO 2 /methanol=40/60

流速:100mL/minFlow rate: 100mL/min

检测波长:214nm。Detection wavelength: 214nm.

实施例86：6-氯-3-({1-[2-(1-乙炔基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 86: 6-Chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxyylidene-3-(trideuterated methyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

步骤1：3-(羟基甲基)双环[1.1.1]戊烷-1-甲酸甲酯
Step 1: Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate

1-(甲氧基羰基)双环[1.1.1]戊烷-3-甲酸(1.5g，8.82mmol,1.0eq)溶于干燥四氢呋喃(10mL)中，氩气保护，0℃下滴加硼烷二甲硫醚(0.97mL,9.7mmol,1.1eq)，室温反应3小时，冷却至0℃，加入甲醇淬灭,减压浓缩得到3-(羟基甲基)双环[1.1.1]戊烷-1-甲酸甲酯(1.26g,收率92％)，无色油状物，直接用于下一步反应。1-(Methoxycarbonyl)bicyclo[1.1.1]pentane-3-carboxylic acid (1.5 g, 8.82 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (10 mL) and argon was protected. Borane dimethyl sulfide (0.97 mL, 9.7 mmol, 1.1 eq) was added dropwise at 0°C. The mixture was reacted at room temperature for 3 hours, cooled to 0°C, and methanol was added to quench the reaction. The mixture was concentrated under reduced pressure to give 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (1.26 g, yield 92%). The colorless oil was used directly in the next step.

步骤2：1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊烷-3-甲酸甲酯
Step 2: 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester

3-(羟基甲基)双环[1.1.1]戊烷-1-甲酸甲酯(1.26g，8.11mmol,1.0eq)溶于二氯甲烷(10mL)中，氩气保护下加入4-二甲氨基吡啶(99mg,0.81mmol,0.1eq),咪唑(0.83g,12.2mmol,1.5eq)，冷却至0℃，加入氯(2-甲基丙-2-基)二苯基甲硅烷(2.67mg,9.73mmol,1.2eq)，室温反应5小时，反应液加入水(50 mL)稀释，二氯甲烷(50mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，得到粗品1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊烷-3-甲酸甲酯(2.94g,收率92％)，无色油状物，直接用于下一步反应。3-(Hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (1.26 g, 8.11 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). 4-dimethylaminopyridine (99 mg, 0.81 mmol, 0.1 eq) and imidazole (0.83 g, 12.2 mmol, 1.5 eq) were added under argon protection. The mixture was cooled to 0°C and chloro(2-methylprop-2-yl)diphenylsilane (2.67 mg, 9.73 mmol, 1.2 eq) was added. The mixture was reacted at room temperature for 5 hours. Water (50 The organic phase was combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product of 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanopentan-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (2.94 g, yield 92%) as a colorless oil, which was directly used in the next step.

1H NMR(400MHz,DMSO-d6)δ7.69–7.64(m,4H),7.48–7.37(m,6H),3.70(s,3H),3.68(s,2H),1.98(s,6H),1.08(s,9H)。 1 H NMR (400MHz, DMSO-d6) δ7.69–7.64(m,4H),7.48–7.37(m,6H),3.70(s,3H),3.68(s,2H),1.98(s,6H),1.08(s,9H).

步骤3：1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊烷-3-甲酸
Step 3: 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid

1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊烷-3-甲酸甲酯(2.94g，7.46mmol,1.0eq)溶于四氢呋喃(20mL)、水(4mL)和甲醇(10mL)中，加入氢氧化锂一水合物(0.94g,22.4mmol,3.0eq)，40℃反应2.5小时，1.0mol/L盐酸调节PH至4，加入水(50mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物纯化得到1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊烷-3-甲酸(2.83g,收率99.1％)，白色固体。1-(4,4-Dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (2.94 g, 7.46 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), water (4 mL) and methanol (10 mL), and lithium hydroxide monohydrate (0.94 g, 22.4 mmol, 3.0 eq) was added, and the reaction was carried out at 40 ° C for 2.5 hours, and 1.0 mol/ L hydrochloric acid to adjust the pH to 4, add water (50 mL) to dilute, extract three times with dichloromethane (20 mL), combine the organic phases, wash with saturated brine (100 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified to give 1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanopentan-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (2.83 g, yield 99.1%) as a white solid.

MS m/z：335.2/337.2[M+H]+ MS m/z：335.2/337.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),7.69–7.63(m,4H),7.46–7.38(m,6H),3.68(s,2H),2.00(s,6H),1.08(s,9H)。 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),7.69–7.63(m,4H),7.46–7.38(m,6H),3.68(s,2H),2.00(s,6H),1.08(s,9H).

步骤4：[1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊-3-基]甲醇
Step 4: [1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol

1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊烷-3-甲酸(2.83g，7.43mmol,1.0eq)溶于干燥四氢呋喃(30mL)中，氩气保护下，0℃加入硼烷二甲硫醚(0.82mL,8.17mmol,1.0eq)，室温反应1.5小时，冷却至0℃，加入甲醇淬灭反应，减压浓缩，得到粗品[1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊-3-基]甲醇(2.69g,收率98.9％)，无色油状物。1-(4,4-Dimethyl-3,3-diphenyl-2-oxa-3-silanopentan-1-yl)bicyclo[1.1.1]pentane-3-carboxylic acid (2.83 g, 7.43 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (30 mL). Under argon protection, borane dimethyl sulfide (0.82 mL, 8.17 mmol, 1.0 eq) was added at 0°C. The mixture was reacted at room temperature for 1.5 hours, cooled to 0°C, and methanol was added to quench the reaction. The mixture was concentrated under reduced pressure to obtain a crude product [1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanopentan-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol (2.69 g, yield 98.9%) as a colorless oil.

1H NMR(400MHz,Chloroform-d)δ7.69–7.67(m,4H),7.40(dd,J＝6.5,4.5Hz,6H),3.69(s,2H),3.67(s,2H),1.63(s,6H),1.08(s,9H) 1 H NMR(400MHz,Chloroform-d)δ7.69–7.67(m,4H),7.40(dd,J＝6.5,4.5Hz,6H),3.69(s,2H),3.67(s,2H),1.63(s,6H),1.08(s,9H)

步骤5：[1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊-3-基]甲烷醛
Step 5: [1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanopentan-1-yl)bicyclo[1.1.1]pentan-3-yl]methanal

[1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊-3-基]甲醇(2.69g，7.35mmol,1.0eq)溶于二氯甲烷(40mL)中，加入氯铬酸吡啶(3.17g,14.7mmol,2.0eq)，室温反应2小时，反应液过滤，减压浓缩，残留物柱层析纯化得到[1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊-3-基]甲烷醛(2.12g,收率79.4％)，无色油状物。[1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentan-3-yl]methanol (2.69 g, 7.35 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL), and pyridinium chlorochromate (3.17 g, 14.7 mmol, 2.0 eq) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give [1-(4,4-dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pentan-3-yl]methanal (2.12 g, yield 79.4%) as a colorless oil.

1H NMR(400MHz,Chloroform-d)δ9.60(s,1H),7.69–7.66(m,4H),7.46–7.40(m,6H),3.70(s,2H),1.96(s,6H),1.09(s,9H)。 1 H NMR (400MHz, Chloroform-d) δ9.60(s,1H),7.69–7.66(m,4H),7.46–7.40(m,6H),3.70(s,2H),1.96(s,6H),1.09(s,9H).

步骤6：1-(3-乙炔基双环[1.1.1]戊-1-基)-4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊烷
Step 6: 1-(3-ethynylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethyl-3,3-diphenyl-2-oxa-3-silapentane

[1-(4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊-1-基)双环[1.1.1]戊-3-基]甲烷醛(500mg，1.37mmol,1.0eq)溶于甲醇(10mL)中，加入(1Z)-1-(乙氮炔-1-正离子基自由基)-1-[二甲氧基(氧亚基)-λ5-甲磷基]丙-1-烯-2-醇根离子(317mg,1.65mmol,1.2eq)和碳酸钾(473mg,3.43mmol,2.5eq)，氩气保护下，室温反应4小时，加入水(50mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物纯化得到1-(3-乙炔基双环[1.1.1]戊-1-基)-4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊烷(287mg,收率58.1％)，无色油状物。[1-(4,4-Dimethyl-3,3-diphenyl-2-oxa-3-silanol-1-yl)bicyclo[1.1.1]pent-3-yl]methanal (500 mg, 1.37 mmol, 1.0 eq) was dissolved in methanol (10 mL), and (1Z)-1-(ethazin-1-yl radical)-1-[dimethoxy(oxyylidene)-λ5-methylphosphino]prop-1-en-2-ol anion (317 mg, 1.65 mmol, 1.2 eq) and potassium carbonate (473 mg, 3.43mmol, 2.5eq), react at room temperature for 4 hours under argon protection, add water (50mL) to dilute, extract three times with dichloromethane (20mL), combine the organic phases, wash with saturated brine (100mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified to obtain 1-(3-ethynylbicyclo[1.1.1]pent-1-yl)-4,4-dimethyl-3,3-diphenyl-2-oxa-3-silapentane (287mg, yield 58.1%) as a colorless oil.

步骤7：4,4-二甲基-3,3-二苯基-1-(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)-2-氧杂-3-硅杂戊烷
Step 7: 4,4-dimethyl-3,3-diphenyl-1-(3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)-2-oxa-3-silapentane

1-(3-乙炔基双环[1.1.1]戊-1-基)-4,4-二甲基-3,3-二苯基-2-氧杂-3-硅杂戊烷(283mg，0.78mmol,1.0eq)溶于干燥四氢呋喃(10mL)中，氩气保护下，-78℃滴加正丁基锂(0.54mL,0.86mmol,1.1eq)，搅拌20分钟，加入三异丙基氯硅烷(166mg,0.86mmol,1.1eq)，室温反应过夜，1.0mmol/L稀盐酸调 节PH至4，加入水(50mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物纯化得到4,4-二甲基-3,3-二苯基-1-(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)-2-氧杂-3-硅杂戊烷(351mg,收率86.5％)，无色油状物。1-(3-Ethynylbicyclo[1.1.1]pent-1-yl)-4,4-dimethyl-3,3-diphenyl-2-oxa-3-silapentane (283 mg, 0.78 mmol, 1.0 eq) was dissolved in dry tetrahydrofuran (10 mL). Under argon protection, n-butyl lithium (0.54 mL, 0.86 mmol, 1.1 eq) was added dropwise at -78 °C. The mixture was stirred for 20 minutes. Triisopropylsilyl chloride (166 mg, 0.86 mmol, 1.1 eq) was added and the mixture was reacted at room temperature overnight. The mixture was adjusted with 1.0 mmol/L dilute hydrochloric acid. The pH value was adjusted to 4, water (50 mL) was added to dilute, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified to give 4,4-dimethyl-3,3-diphenyl-1-(3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pent-1-yl)-2-oxa-3-silapentane (351 mg, yield 86.5%) as a colorless oil.

步骤8：(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)甲醇
Step 8: (3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanol

4,4-二甲基-3,3-二苯基-1-(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)-2-氧杂-3-硅杂戊烷(306mg，0.59mmol,1.0eq)溶于甲醇(10mL)中，室温加入乙酰氯(0.084mL,1.18mmol,2.0eq)，室温搅拌2小时，1.0mmol/L氢氧化钠调节PH至9，加入水(50mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(100mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，得到(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)甲醇(146mg,收率89％)，无色油状物。4,4-Dimethyl-3,3-diphenyl-1-(3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)-2-oxa-3-silapentane (306 mg, 0.59 mmol, 1.0 eq) was dissolved in methanol (10 mL), acetyl chloride (0.084 mL, 1.18 mmol, 2.0 eq) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The pH was adjusted to 9 with 1.0 mmol/L sodium hydroxide, and water (50 mL) was added for dilution. The mixture was extracted with dichloromethane (20 mL) three times, and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanol (146 mg, yield 89%) as a colorless oil.

步骤9：(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)甲烷醛
Step 9: (3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanal

(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)甲醇(146mg，0.52mmol,1.0eq)溶于二氯甲烷(5mL)中，加入氯铬酸吡啶(169mg,0.79mmol,1.5eq)，室温反应2小时，反应液过滤，减压浓缩，残留物柱层析纯化得到(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)甲烷醛(110mg,收率75.4％)，无色油状物。(3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanol (146 mg, 0.52 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and pyridinium chlorochromate (169 mg, 0.79 mmol, 1.5 eq) was added. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give (3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanal (110 mg, yield 75.4%) as a colorless oil.

步骤10：6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-(1-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-3-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸甲酯
Step 10: 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-(1-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-3-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid methyl ester

以氘代甲胺盐酸盐及(3-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-1-基)甲烷醛为原料，参照实施例67的方法制备6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-(1-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-3-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸甲酯(49.5mg)，白色固体。Using deuterated methylamine hydrochloride and (3-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-1-yl)methanal as raw materials, the method of Example 67 was used to prepare methyl 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-(1-{[tri(propan-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-3-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate (49.5 mg) as a white solid.

MS m/z：642.1[M+H]+ MS m/z：642.1[M+H] +

步骤11：6-氯-3-({1-[2-(1-乙炔基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸甲酯
Step 11: 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxoylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid methyl ester

6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-(1-{[三(丙-2-基)甲硅基]乙炔基}双环[1.1.1]戊-3-基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸甲酯(49.5mg，0.08mmol,1.0eq)溶于四氢呋喃(5mL)中，加入四丁基氟化铵溶液(0.077mL,0.08mmol,1.0eq)，室温反应过夜，加水(10mL)稀释，二氯甲烷(10mL)萃取三次，合并有机相，饱和食盐水(10mL)洗涤,有机相无水硫酸钠干燥，减压浓缩，残留物柱层析纯化得到6-氯-3-({1-[2-(1-乙炔基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸甲酯(24mg,收率64％)，黄色油状物。Methyl 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuterylmethyl)-2-(1-{[tri(propyl-2-yl)methylsilyl]ethynyl}bicyclo[1.1.1]pentan-3-yl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate (49.5 mg, 0.08 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride solution (0.077 mL, 0.08 mmol, 1.0 eq) was added, and the mixture was reacted at room temperature overnight. , diluted with water (10 mL), extracted three times with dichloromethane (10 mL), combined the organic phases, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give methyl 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxyylidene-3-(trideuteratedmethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate (24 mg, yield 64%) as a yellow oil.

MS m/z：486.2[M+H]+ MS m/z：486.2[M+H] +

步骤12：6-氯-3-({1-[2-(1-乙炔基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸Step 12: 6-Chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxoylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

6-氯-3-({1-[2-(1-乙炔基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸甲酯(24mg,0.05mmol,1.0eq)溶于四氢呋喃(4mL)、甲醇(2mL)和水(0.5mL)中，加入一水氢氧化锂(6.22mg,0.15mmol,3.0eq)，室温反应2小时，1mol/L盐酸调节PH值为5左右，反应液加入水(10mL)稀释，乙酸乙酯(10mL)萃取三次，合并有机相，饱和食盐水(10mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到6-氯-3-({1-[2-(1-乙炔基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(7.2mg,收率31％)，白色固体。Methyl 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylate (24 mg, 0.05 mmol, 1.0 eq) was dissolved in tetrahydrofuran (4 mL), methanol (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (6.22 mg, 0.15 mmol, 3.0 eq) was added. The mixture was reacted at room temperature for 2 hours. 1 mol/L hydrochloric acid was used to adjust the pH. The H value was about 5. Water (10 mL) was added to the reaction solution for dilution. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-chloro-3-({1-[2-(1-ethynylbicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxyylidene-3-(trideuteratedmethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (7.2 mg, yield 31%) as a white solid.

MS m/z：472.2[M+H]+ MS m/z：472.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),7.12(d,J＝59.1Hz,2H),5.01(q,J＝7.3Hz,1H),3.21(s,1H),2.65(d,J＝9.5Hz,3H),2.59(s,3H),2.55(s,3H),1.61(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 7.12 (d, J = 59.1Hz, 2H), 5.01 (q, J = 7.3Hz, 1H), 3.21(s,1H),2.65(d,J＝9.5Hz,3H),2.59(s,3H),2.55(s,3H),1.61(d,J＝6.7Hz,3H).

实施例87：6-氯-3-[(1-{6-甲基-2-[4-(6-甲基-1,2-二氮杂环己熳-3-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 87: 6-Chloro-3-[(1-{6-methyl-2-[4-(6-methyl-1,2-diazacyclohexan-3-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺盐酸盐及6-甲基-3-(哌嗪-1-基)-1,2-二氮杂环己熳为原料，参照实施例63的方法制备6-氯-3-[(1-{6-甲基-2-[4-(6-甲基-1,2-二氮杂环己熳-3-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(2mg)，白色固体。Using deuterated methylamine hydrochloride and 6-methyl-3-(piperazin-1-yl)-1,2-diazacyclohexine as starting materials, 6-chloro-3-[(1-{6-methyl-2-[4-(6-methyl-1,2-diazacyclohexine-3-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (2 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：558.2[M+H]+ MS m/z：558.2[M+H] +

实施例88：6-氯-3-[(1-{2,6-二甲基-5-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸
Example 88: 6-Chloro-3-[(1-{2,6-dimethyl-5-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxydithieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺盐酸盐及5-甲基-2-[(2S)-2-甲基哌嗪-1-基]嘧啶为原料，参照实施例82的方法制备6-氯-3-[(1-{2,6-二甲基-5-[(3S)-3-甲基-4-(5-甲基嘧啶-2-基)哌嗪-1-基]-7-氧亚基噻吩并[3,2-b]吡喃-3-基}乙基)氨基]吡啶-2-甲酸(1.5mg)，白色固体。Using deuterated methylamine hydrochloride and 5-methyl-2-[(2S)-2-methylpiperazin-1-yl]pyrimidine as raw materials, 6-chloro-3-[(1-{2,6-dimethyl-5-[(3S)-3-methyl-4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-7-oxothieno[3,2-b]pyran-3-yl}ethyl)amino]pyridine-2-carboxylic acid (1.5 mg) was prepared as a white solid by referring to the method of Example 82.

MS m/z：569.1[M+H]+。MS m/z: 569.1 [M+H] + .

实施例89：6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[2.2.2]辛-4-基}噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(89)
Example 89: 6-Chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (89)

6-氯-3-{[(1S)-1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[2.2.2]辛-4-基}噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[2.2.2]辛-4-基}噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(89-P1和89-P2)
6-Chloro-3-{[(1S)-1-[6-methyl-4-oxylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentyl-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3- {[(1R)-1-[6-methyl-4-oxo-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentan-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (89-P1 and 89-P2)

以N-(1-氮亚基-2,2,2-三氘基乙基)羟胺为原料，参照实施例84的方法制备得到6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[2.2.2]辛-4-基}噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(89，714mg)，黄色固体。Using N-(1-nitrogenylidene-2,2,2-trideuterioethyl)hydroxylamine as raw material, referring to the method of Example 84, 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentane-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (89, 714 mg) was prepared as a yellow solid.

MS m/z：575.2[M+H]+ MS m/z：575.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.80(s,1H),9.93–8.63(m,1H),7.35(d,J＝9.0Hz,1H),7.20(d,J＝8.8Hz,1H),5.08(d,J＝8.8Hz,1H),2.61(s,3H),2.38–2.26(m,3H),2.25–2.12(m,3H),2.05(t,J＝7.8Hz,6H),1.64(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),9.93–8.63(m,1H),7.35(d,J＝9.0Hz,1H),7.20(d,J＝8.8Hz,1H),5.08(d, J＝8.8Hz,1H),2.61(s,3H),2.38–2.26(m,3H),2.25–2.12(m,3H),2.05(t,J＝7.8Hz,6H),1.64(d,J＝6.7Hz,3H).

实施例89化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[2.2.2]辛-4-基}噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(278mg,白色固体)和6-氯-3-{[(1R)-1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]双环[2.2.2]辛-4-基}噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(225mg，白色固体),89-P1先于89-P2出峰。The compound of Example 89 was separated by SFC to obtain 6-chloro-3-{[(1S)-1-[6-methyl-4-oxylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentane-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (278 mg, white solid) ) and 6-chloro-3-{[(1R)-1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentane-5-yl]bicyclo[2.2.2]oct-4-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (225 mg, white solid), 89-P1 eluted before 89-P2.

手性分离方法同实施例85。The chiral separation method is the same as Example 85.

实施例90：6-氯-3-[(1-{6-甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(90)
Example 90: 6-Chloro-3-[(1-{6-methyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (90)

6-氯-3-{[(1S)-1-{6-甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(90-P1和90-P2)
6-Chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (90-P1 and 90-P2)

以氘代甲胺为原料，参照实施例64的方法制备得到6-氯-3-[(1-{6-甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(90，1.03g)，淡黄色固体。Using deuterated methylamine as raw material, refer to the method of Example 64 to prepare 6-chloro-3-[(1-{6-methyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (90, 1.03 g) as a light yellow solid.

MS m/z：558.2[M+H]+ MS m/z：558.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝8.5Hz,1H),8.30(d,J＝1.5Hz,1H),8.04(s,1H),7.39(d,J＝8.9Hz,1H),7.28(d,J＝9.0Hz,1H),5.06(t,J＝7.5Hz,1H),3.68(q,J＝4.9Hz,4H),3.38(dq,J＝11.6,5.6,4.7Hz,4H),2.61(s,3H),2.34(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.65(d,J＝8.5Hz,1H),8.30(d,J＝1.5Hz,1H),8.04(s,1H),7.39(d,J＝8.9Hz,1H),7.28(d,J＝9.0Hz,1H), 5.06(t,J＝7.5Hz,1H),3.68(q,J＝4.9Hz,4H),3.38(dq,J＝11.6,5.6,4.7Hz,4H),2.61(s,3H),2.34(s,3H),1.63(d,J＝6.7Hz,3H).

实施例90化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-{6-甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(462mg,白色固体)和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(5-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(431mg,白色固体),90-P1先于90-P2出峰。The compound of Example 90 was prepared by SFC separation to give 6-chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (462 mg, white solid) and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (431 mg, white solid), 90-P1 eluted before 90-P2.

手性分离方法同实施例74。The chiral separation method is the same as Example 74.

实施例91：6-氯-3-[(1-{6-甲基-2-[4-(6-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 91: 6-Chloro-3-[(1-{6-methyl-2-[4-(6-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺为原料，参照实施例66的方法制备得到6-氯-3-[(1-{6-甲基-2-[4-(6-甲基吡嗪-2-基)哌嗪-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(20mg)，黄色固体。Using deuterated methylamine as starting material, refer to the method of Example 66 to prepare 6-chloro-3-[(1-{6-methyl-2-[4-(6-methylpyrazin-2-yl)piperazin-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (20 mg) as a yellow solid.

MS m/z：558.2[M+H]+ MS m/z：558.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),8.62(d,J＝8.5Hz,1H),8.20(s,1H),7.81(s,1H),7.42(d,J＝9.0Hz,1H),7.31(d,J＝9.1Hz,1H),5.12–5.03(m,1H),3.73(d,J＝6.6Hz,4H),3.40(q,J＝6.7,5.0Hz,4H),2.61(s,3H),2.34(s,3H),1.64(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),8.62(d,J＝8.5Hz,1H),8.20(s,1H),7.81(s,1H),7.42(d,J＝9.0Hz,1H),7.31(d,J＝9.1H z,1H),5.12–5.03(m,1H),3.73(d,J＝6.6Hz,4H),3.40(q,J＝6.7,5.0Hz,4H),2.61(s,3H),2.34(s,3H),1.64(d,J＝6.7Hz,3H).

实施例92：6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{4-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]哌嗪-1-基}噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 92: 6-Chloro-3-({1-[6-methyl-4-oxylidene-3-(trideuteriomethyl)-2-{4-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentane-5-yl]piperazin-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以氘代甲胺和1-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]哌嗪为原料，参照实施例63的方法制备得到6-氯-3-({1-[6-甲基-4-氧亚基-3-(三氘基甲基)-2-{4-[3-(三氘基甲基)-1,2,4-氧杂二氮杂环戊熳-5-基]哌嗪-1-基}噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(6mg)，白色固体。Using deuterated methylamine and 1-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentane-5-yl]piperazine as raw materials, 6-chloro-3-({1-[6-methyl-4-oxyylidene-3-(trideuteriomethyl)-2-{4-[3-(trideuteriomethyl)-1,2,4-oxadiazacyclopentane-5-yl]piperazin-1-yl}thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (6 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：551.2[M+H]+ MS m/z：551.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.84(d,J＝8.1Hz,1H),7.08(d,J＝8.7Hz,1H),6.89(d,J＝8.7Hz,1H),4.96–4.87(m,1H),3.71–3.68(m,2H),3.37–3.31(m,2H),3.20(d,J＝20.8Hz,4H),2.55(d,J＝1.8Hz,3H),1.58(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.84(d,J＝8.1Hz,1H),7.08(d,J＝8.7Hz,1H),6.89(d,J＝8.7Hz,1H),4.96–4.87(m,1H ),3.71–3.68(m,2H),3.37–3.31(m,2H),3.20(d,J＝20.8Hz,4H),2.55(d,J＝1.8Hz,3H),1.58(d,J＝6.7Hz,3H).

实施例93：6-氯-3-[(1-{6-甲基-4-氧亚基-2-[4-([1,2,4]三氮杂环戊熳并[3,4-f][1,2]二氮杂环己熳-6-基)哌嗪-1-基]-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 93: 6-Chloro-3-[(1-{6-methyl-4-oxo-2-[4-([1,2,4]triazacyclopentano[3,4-f][1,2]diazepin-6-yl)piperazin-1-yl]-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺和6-(哌嗪-1-基)[1,2,4]三氮杂环戊熳并[3,4-f][1,2]二氮杂环己熳为原料，参照实施例63的方法制备得到6-氯-3-[(1-{6-甲基-4-氧亚基-2-[4-([1,2,4]三氮杂环戊熳并[3,4-f][1,2]二氮杂环己熳-6-基)哌嗪-1-基]-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(11mg)，白色固体。Using deuterated methylamine and 6-(piperazin-1-yl)[1,2,4]triazacyclopentano[3,4-f][1,2]diazepine as raw materials, 6-chloro-3-[(1-{6-methyl-4-oxylidene-2-[4-([1,2,4]triazacyclopentano[3,4-f][1,2]diazepine-6-yl)piperazin-1-yl]-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (11 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：584.2[M+H]+ MS m/z：584.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),9.27(s,1H),8.65(d,J＝8.4Hz,1H),8.14(d,J＝10.2Hz,1H),7.44(dd,J＝24.1,9.6Hz,2H),7.31(d,J＝9.0Hz,1H),5.07(p,J＝6.8Hz,1H),3.73(d,J＝6.0Hz,4H),3.52–3.38(m,4H),2.61(s,3H),1.64(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),9.27(s,1H),8.65(d,J＝8.4Hz,1H),8.14(d,J＝10.2Hz,1H),7.44(dd,J＝24.1,9.6Hz,2H ), 7.31 (d, J = 9.0Hz, 1H), 5.07 (p, J = 6.8Hz, 1H), 3.73 (d, J = 6.0Hz, 4H), 3.52–3.38 (m, 4H), 2.61 (s, 3H), 1.64 (d, J = 6.6Hz, 3H).

实施例94：6-氯-3-[(1-{6-甲基-2-[3-(2-甲基吡唑-3-基)-8-氮杂双环[3.2.1]辛-8-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 94: 6-Chloro-3-[(1-{6-methyl-2-[3-(2-methylpyrazol-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺和3-(2-甲基吡唑-3-基)-8-氮杂双环[3.2.1]辛烷为原料，参照实施例63的方法制备得到6-氯-3-[(1-{6-甲基-2-[3-(2-甲基吡唑-3-基)-8-氮杂双环[3.2.1]辛-8-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(2mg)，白色固体。Using deuterated methylamine and 3-(2-methylpyrazol-3-yl)-8-azabicyclo[3.2.1]octane as raw materials, refer to the method of Example 63 to prepare 6-chloro-3-[(1-{6-methyl-2-[3-(2-methylpyrazol-3-yl)-8-azabicyclo[3.2.1]oct-8-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (2 mg) as a white solid.

MS m/z：571.2[M+H]+ MS m/z：571.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),7.27(dd,J＝19.5,1.9Hz,2H),7.07(s,1H),6.20(d,J＝1.9Hz,1H),4.99(s,1H),4.62(s,1H),4.28(t,J＝7.3Hz,1H),3.94(s,1H),3.75(s,3H),3.21(s,1H),2.73–2.62(m,1H),2.55(s,3H),2.39(d,J＝13.8Hz,1H),2.20(dd,J＝17.2,11.8Hz,1H),1.97(s,1H),1.71(s,1H),1.59(d,J＝6.8Hz,3H),1.34(s,1H),0.82(dt,J＝14.6,7.0Hz,1H)。 1 H NMR(400MHz, DMSO-d6)δ8.89(s,1H),7.27(dd,J＝19.5,1.9Hz,2H),7.07(s,1H),6.20(d,J＝1 .9Hz,1H),4.99(s,1H),4.62(s,1H),4.28(t,J＝7.3Hz,1H),3.94(s,1H),3.75(s,3H),3.21(s ,1H),2.73–2.62(m,1H),2.55(s,3H),2.39(d,J＝13.8Hz,1H),2.20(dd,J＝17.2,11.8Hz,1H) ,1.97(s,1H),1.71(s,1H),1.59(d,J＝6.8Hz,3H),1.34(s,1H),0.82(dt,J＝14.6,7.0Hz,1H).

实施例95：6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(95)
Example 95: 6-Chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]oct-4-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (95)

步骤1：1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯
Step 1: 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester

以氘代甲胺和1-(氧亚基甲基)双环[2.2.2]辛烷-4-甲酸甲酯为原料，参照实施例30的方法制备得到1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯(624mg)，黄色固体。Using deuterated methylamine and 1-(oxyylidenemethyl)bicyclo[2.2.2]octane-4-carboxylic acid methyl ester as raw materials, refer to the method of Example 30 to prepare 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester (624 mg) as a yellow solid.

MS m/z：428.2/430.2[M+H]+ MS m/z：428.2/430.2[M+H] +

步骤2：1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸
Step 2: 1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid

1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯(624mg,1.46mmol,1.0eq)溶于四氢呋喃(5mL)、水(1mL)和甲醇(1mL)中，50℃下反应3小时，冷却至室温，1mol/L盐酸调节PH值为7左右，反应液加入水(10mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸(567mg,收率94％)，黄色固体。1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriummethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester (624 mg, 1.46 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL), water (1 mL) and methanol (1 mL), reacted at 50 ° C for 3 hours, cooled to room temperature, 1 mol/L hydrochloric acid was used to adjust the pH value to about 7, and water was added to the reaction solution. The mixture was diluted with 1% paraformaldehyde (10 mL), extracted with dichloromethane (20 mL) for three times, the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteromethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid (567 mg, yield 94%) as a yellow solid.

MS m/z:414.2/416.2[M+H]+ MS m/z:414.2/416.2[M+H] +

步骤3：N'-乙酰基-1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酰肼
Step 3: N'-acetyl-1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid hydrazide

1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸(400mg,0.97mmol,1.0eq)溶于氮，氮-二甲基甲酰胺(10mL)中，加入乙酰肼(86mg,1.16mmol,1.2eq)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(440mg,1.16mmol,1.2eq)和三乙胺(0.4mL,2.9mmol,3.0eq)，室温下反应4小时，反应液加入水(40mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到N'-乙酰基-1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酰肼(182mg,收率40％)，白色固体。1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid (400 mg, 0.97 mmol, 1.0 eq) was dissolved in nitrogen-dimethylformamide (10 mL), and acetic acid hydrazide (86 mg, 1.16 mmol, 1.2 eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (440 mg, 1.16 mmol, 1.2 eq) and triethylamine (0.4 mL, 2.9 mmol, 3.0 eq), reacted at room temperature for 4 hours, the reaction solution was diluted with water (40 mL), extracted with ethyl acetate (20 mL) three times, the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain N'-acetyl-1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid hydrazide (182 mg, yield 40%) as a white solid.

MS m/z:470.2/472.2[M+H]+ MS m/z:470.2/472.2[M+H] +

步骤4：7-溴-6-甲基-2-[4-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 4: 7-Bromo-6-methyl-2-[4-(5-methyl-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

N'-乙酰基-1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酰肼(182mg,0.38mmol,1.0eq)溶于吡啶(6mL)中，加入对甲苯磺酰氯(110mg,1.16mmol,3.0eq)，115℃下反应4小时，反应液冷至室温，减压浓缩，残留物柱层析纯化得到7-溴-6-甲基-2-[4-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(170mg,收率97％)，黄色固体。N'-acetyl-1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid hydrazide (182 mg, 0.38 mmol, 1.0 eq) was dissolved in pyridine (6 mL), p-toluenesulfonyl chloride (110 mg, 1.16 mmol, 3.0 eq) was added, and the mixture was heated at 115 °C. The reaction mixture was reacted for 4 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to give 7-bromo-6-methyl-2-[4-(5-methyl-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (170 mg, yield 97%) as a yellow solid.

MS m/z:452.2/454.2[M+H]+ MS m/z:452.2/454.2[M+H] +

步骤5：6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(95)Step 5: 6-Chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (95)

以7-溴-6-甲基-2-[4-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，按照实施例63的方法制备得到6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(3mg)Using 7-bromo-6-methyl-2-[4-(5-methyl-1,3,4-oxadiazacyclopentan-2-yl)bicyclo[2.2.2]oct-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as a raw material, 6-chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,3,4-oxadiazacyclopentan-2-yl)bicyclo[2.2.2]oct-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (3 mg) was prepared according to the method of Example 63.

MS m/z:572.2[M+H]+ MS m/z:572.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),7.23–7.03(m,2H),5.05(t,J＝7.4Hz,1H),2.58(s,3H),2.48(s,3H),2.36–2.27(m,3H),2.18(ddt,J＝13.0,9.2,4.8Hz,3H),2.01(t,J＝7.8Hz,6H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 7.23–7.03 (m, 2H), 5.05 (t, J = 7.4Hz, 1H), 2.58 (s, 3H), 2.48 (s, 3H) ),2.36–2.27(m,3H),2.18(ddt,J＝13.0,9.2,4.8Hz,3H),2.01(t,J＝7.8Hz,6H),1.63(d,J＝6.7Hz,3H).

6-氯-3-{[(1S)-1-{6-甲基-2-[4-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(95-P1和95-P2)
6-Chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methyl-1,3,4-oxadiazacyclopentan-2-yl)bicyclo[2.2.2]oct-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methyl-1,3,4-oxadiazacyclopentan-2-yl)bicyclo[2.2.2]oct-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (95-P1 and 95-P2)

实施例95化合物通过超临界流体色谱(SFC)分离制备得到6-氯-3-{[(1S)-1-{6-甲基-2-[4-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(516mg,白色固体)和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(5-甲基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(501mg,白色固体),95-P1先于95-P2出峰。Example 95 The compound was separated by supercritical fluid chromatography (SFC) to obtain 6-chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methyl-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]oct-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (516 mg) , white solid) and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methyl-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]octan-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (501 mg, white solid), 95-P1 eluted before 95-P2.

手性分离方法：Chiral separation method:

仪器:SFC-150(Waters)Instrument: SFC-150 (Waters)

手性柱:AD 25*250mm,10μm(Daicel)Chiral column: AD 25*250mm, 10μm (Daicel)

柱温:35℃Column temperature: 35°C

流动相:CO2/[甲醇:乙腈＝1:1]＝50/50Mobile phase: CO 2 /[methanol:acetonitrile＝1:1]＝50/50

流速:100mL/minFlow rate: 100mL/min

检测波长:214nmDetection wavelength: 214nm

实施例96：6-氯-3-({1-[2-(1-氰基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(96)
Example 96: 6-Chloro-3-({1-[2-(1-cyanobicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (96)

步骤1：1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酸
Step 1: 1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxylic acid

以氘代甲胺和1-(氧亚基甲基)双环[1.1.1]戊烷-3-甲酸甲酯为原料，参照实施例95的方法制备得到1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酸(350mg)，黄色固体。Using deuterated methylamine and 1-(oxyylidenemethyl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester as raw materials, 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxylic acid (350 mg) was prepared as a yellow solid according to the method of Example 95.

MS m/z：372.2/374.2[M+H]+ MS m/z：372.2/374.2[M+H] +

步骤2：1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酰胺
Step 2: 1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxamide

1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酸(350mg,0.94mmol,1.0eq)溶于四氢呋喃(6mL)中，加入草酰氯(239mg,1.88mmol,2.0eq)和氮，氮-二甲基甲酰胺(76uL,0.94mmol,1.0eq),室温下反应1小时，减压浓缩，残渣中加入四氢呋喃(6mL)，0℃下滴加30％氨水(3mL)，搅拌30分钟，反应液加入水(10mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酰胺(264mg,收率80％)，白色固体。1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriummethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxylic acid (350 mg, 0.94 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6 mL), and oxalyl chloride (239 mg, 1.88 mmol, 2.0 eq) and nitrogen, nitrogen-dimethylformamide (76 uL, 0.94 mmol, 1.0 eq) were added. The mixture was reacted at room temperature for 1 hour, and concentrated under reduced pressure. Tetrahydrofuran (6 mL) was added to the residue. , 30% aqueous ammonia (3 mL) was added dropwise at 0°C and stirred for 30 minutes. The reaction solution was diluted with water (10 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteromethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxamide (264 mg, yield 80%) as a white solid.

MS m/z:371.2/373.2[M+H]+ MS m/z:371.2/373.2[M+H] +

步骤3：1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲腈
Step 3: 1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carbonitrile

1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酰胺(264mg,0.71mmol,1.0eq)溶于氯化亚砜(5mL)中，氩气保护，90℃下搅拌4小时，冷却至室温，反应液浓缩，加水(20mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲腈(215mg,收率86％)，白色固体。1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxamide (264 mg, 0.71 mmol, 1.0 eq) was dissolved in thionyl chloride (5 mL) and stirred at 90 °C for 4 hours under argon protection. The reaction solution was concentrated and diluted with water (20 mL). The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carbonitrile (215 mg, yield 86%) as a white solid.

MS m/z:353.2/355.2[M+H]+ MS m/z:353.2/355.2[M+H] +

步骤4：6-氯-3-({1-[2-(1-氰基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(96)Step 4: 6-Chloro-3-({1-[2-(1-cyanobicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (96)

以1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲腈为原料，按照实施例63的方法制备得到6-氯-3-({1-[2-(1-氰基双环[1.1.1]戊-3-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(33mg)Using 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carbonitrile as raw material, 6-chloro-3-({1-[2-(1-cyanobicyclo[1.1.1]pentan-3-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (33 mg) was prepared according to the method of Example 63.

MS m/z:473.2[M+H]+ MS m/z:473.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.94(s,1H),9.32(d,J＝396.1Hz,1H),7.37–7.03(m,2H),5.04(s,1H),2.97–2.84(m,3H),2.77(d,J＝9.2Hz,3H),2.64(s,3H),1.62(d,J＝6.7Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ12.94(s,1H),9.32(d,J＝396.1Hz,1H),7.37–7.03(m,2H),5.0 4(s,1H),2.97–2.84(m,3H),2.77(d,J＝9.2Hz,3H),2.64(s,3H),1.62(d,J＝6.7Hz,3H).

6-氯-3-{[(1S)-1-[2-(3-氰基双环[1.1.1]戊-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-[2-(3-氰基双环[1.1.1]戊-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(96-P1和96-P2)
6-Chloro-3-{[(1S)-1-[2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-[2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (96-P1 and 96-P2)

实施例96化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-[2-(3-氰基双环[1.1.1]戊-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(480mg,白色固体)和6-氯-3-{[(1R)-1-[2-(3-氰基双环[1.1.1]戊-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(420mg,白色固体),96-P1先于96-P2出峰。 The compound of Example 96 was separated by SFC to give 6-chloro-3-{[(1S)-1-[2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (480 mg, white solid) and 6-chloro-3-{[(1R)-1-[2-(3-cyanobicyclo[1.1.1]pentan-1-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (420 mg, white solid), 96-P1 eluted before 96-P2.

手性分离方法：Chiral separation method:

仪器:SFC-150(Waters)Instrument: SFC-150 (Waters)

手性柱:AD 25*250mm,10μm(Daicel)Chiral column: AD 25*250mm, 10μm (Daicel)

柱温:35℃Column temperature: 35°C

流动相:CO2/甲醇＝50/50Mobile phase: CO 2 /methanol = 50/50

流速:100mL/minFlow rate: 100mL/min

检测波长:214nmDetection wavelength: 214nm

实施例97：6-氯-3-[(1-{2-[4-(5-氰基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(97)
Example 97: 6-Chloro-3-[(1-{2-[4-(5-cyanopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (97)

以氘代甲胺和2-(哌嗪-1-基)嘧啶-5-甲腈为原料，参照实施例63的方法制备得到6-氯-3-[(1-{2-[4-(5-氰基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(7mg)，白色固体。Using deuterated methylamine and 2-(piperazine-1-yl)pyrimidine-5-carbonitrile as raw materials, refer to the method of Example 63 to prepare 6-chloro-3-[(1-{2-[4-(5-cyanopyrimidin-2-yl)piperazine-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (7 mg) as a white solid.

MS m/z：569.2[M+H]+ MS m/z：569.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.81(s,2H),7.08(d,J＝33.4Hz,2H),4.96(s,1H),4.14–3.94(m,4H),3.39(d,J＝4.8Hz,4H),2.57(s,3H),1.60(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ9.80 (s, 1H), 8.81 (s, 2H), 7.08 (d, J = 33.4Hz, 2H), 4.96 (s, 1H), 4.14–3.94 (m, 4H), 3.39 (d, J = 4.8Hz, 4H), 2.57 (s, 3H), 1.60 (d, J = 6.7Hz, 3H).

6-氯-3-{[(1S)-1-{2-[4-(5-氰基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-{2-[4-(5-氰基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(97-P1和97-P2)
6-Chloro-3-{[(1S)-1-{2-[4-(5-cyanopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{2-[4-(5-cyanopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (97-P1 and 97-P2)

实施例97化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-{2-[4-(5-氰基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(520mg,白色固体)和6- 氯-3-{[(1R)-1-{2-[4-(5-氰基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(517mg,白色固体),97-P1先于97-P2出峰。The compound of Example 97 was separated by SFC to give 6-chloro-3-{[(1S)-1-{2-[4-(5-cyanopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (520 mg, white solid) and 6- Chloro-3-{[(1R)-1-{2-[4-(5-cyanopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (517 mg, white solid), 97-P1 eluted before 97-P2.

手性分离方法同实施例74。The chiral separation method is the same as Example 74.

实施例98：6-氯-3-({1-[2-(1-氰基双环[2.2.2]辛-4-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(98)
Example 98: 6-Chloro-3-({1-[2-(1-cyanobicyclo[2.2.2]octan-4-yl)-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (98)

以氘代甲胺和1-(氧亚基甲基)双环[2.2.2]辛烷-4-甲酸甲酯为原料，参照实施例96的方法制备得到6-氯-3-({1-[2-(1-氰基双环[2.2.2]辛-4-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸，淡黄色固体。Using deuterated methylamine and 1-(oxyylidenemethyl)bicyclo[2.2.2]octane-4-carboxylic acid methyl ester as raw materials, refer to the method of Example 96 to prepare 6-chloro-3-({1-[2-(1-cyanobicyclo[2.2.2]octan-4-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid as a light yellow solid.

MS m/z：515.2[M+H]+ MS m/z：515.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.84(s,1H),8.47(d,J＝7.7Hz,1H),7.45–7.21(m,2H),5.10(t,J＝7.3Hz,1H),2.62(s,3H),2.55(s,1H),2.29–2.17(m,3H),2.11–2.00(m,8H),1.64(d,J＝6.5Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),8.47(d,J＝7.7Hz,1H),7.45–7.21(m,2H),5.10(t,J＝7.3 Hz,1H),2.62(s,3H),2.55(s,1H),2.29–2.17(m,3H),2.11–2.00(m,8H),1.64(d,J＝6.5Hz,3H).

6-氯-3-{[(1S)-1-[2-(4-氰基双环[2.2.2]辛-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-[2-(4-氰基双环[2.2.2]辛-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(98-P1和98-P2)
6-Chloro-3-{[(1S)-1-[2-(4-cyanobicyclo[2.2.2]octan-1-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-[2-(4-cyanobicyclo[2.2.2]octan-1-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (98-P1 and 98-P2)

实施例98化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-[2-(4-氰基双环[2.2.2]辛-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(590mg,白色固体)和6-氯-3-{[(1R)-1-[2-(4-氰基双环[2.2.2]辛-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基]氨基}吡啶-2-甲酸(580mg,白色固体),98-P1先于98-P2出峰。The compound of Example 98 was prepared by SFC separation to give 6-chloro-3-{[(1S)-1-[2-(4-cyanobicyclo[2.2.2]octan-1-yl)-6-methyl-4-oxyylidene-3-(trideuteromethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (590 mg, white solid) and 6-chloro-3-{[(1R)-1-[2-(4-cyanobicyclo[2.2.2]octan-1-yl)-6-methyl-4-oxyylidene-3-(trideuteromethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl]amino}pyridine-2-carboxylic acid (580 mg, white solid), 98-P1 eluted before 98-P2.

手性分离方法：Chiral separation method:

仪器:SFC-150(Waters) Instrument: SFC-150 (Waters)

手性柱:AD 25*250mm,10μm(Daicel)Chiral column: AD 25*250mm, 10μm (Daicel)

柱温:35℃Column temperature: 35°C

流动相:CO2/甲醇＝50/50Mobile phase: CO 2 /methanol = 50/50

流速:100mL/minFlow rate: 100mL/min

检测波长:214nmDetection wavelength: 214nm

实施例99：6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(99)
Example 99: 6-Chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (99)

步骤1：7-溴-6-甲基-2-[4-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 1: 7-Bromo-6-methyl-2-[4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

N'-乙酰基-1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酰肼(370mg,0.79mmol,1.0eq)溶于乙酸乙酯(25mL)中，加入五硫化二磷(700mg,3.15mmol,4.0eq)，氩气保护，80℃下反应3小时，反应液冷至室温，减压浓缩，加入饱和碳酸钠溶液，过滤，滤饼甲醇打浆，过滤，滤饼干燥得到7-溴-6-甲基-2-[4-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(350mg,收率95％)，白色固体。N'-acetyl-1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid hydrazide (370 mg, 0.79 mmol, 1.0 eq) was dissolved in ethyl acetate (25 mL), phosphorus pentasulfide (700 mg, 3.15 mmol, 4.0 eq) was added, and the mixture was reacted at 80°C for 3 hours under argon protection. The reaction solution was cooled to room temperature, concentrated under reduced pressure, saturated sodium carbonate solution was added, filtered, the filter cake was slurried with methanol, filtered, and the filter cake was dried to obtain 7-bromo-6-methyl-2-[4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (350 mg, yield 95%) as a white solid.

MS m/z：468.2/470.2[M+H]+ MS m/z：468.2/470.2[M+H] +

1H NMR(400MHz,CHCl3-d6)δ2.78(s,3H),2.58(s,3H),2.34(dd,J＝9.9,5.7Hz,6H),2.18(dd,J＝9.9,5.7Hz,6H)。 1 H NMR (400MHz, CHCl 3 -d6) δ 2.78 (s, 3H), 2.58 (s, 3H), 2.34 (dd, J = 9.9, 5.7Hz, 6H), 2.18 (dd, J = 9.9, 5.7Hz, 6H).

步骤2：6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(99)Step 2: 6-Chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (99)

以7-溴-6-甲基-2-[4-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，按照实施例63的方法制备得到6-氯-3-[(1-{6-甲基-2-[1-(5-甲基- 1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(29mg)，白色固体。Using 7-bromo-6-methyl-2-[4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as raw material, 6-chloro-3-[(1-{6-methyl-2-[1-(5-methyl- [0147] [0149] The product was 3-(1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-4-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (29 mg), a white solid.

MS m/z：588.2[M+H]+ MS m/z：588.2[M+H] +

1H NMR(400MHz,CHCl3-d6)δ12.87(s,1H),8.50(d,J＝8.3Hz,1H),7.43(d,J＝8.9Hz,1H),7.29(d,J＝9.0Hz,1H),5.11(t,J＝7.3Hz,1H),2.70(s,3H),2.63(s,3H),2.33(d,J＝7.7Hz,3H),2.20(d,J＝7.9Hz,3H),2.07(t,J＝7.8Hz,6H),1.67(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, CHCl 3 -d6) δ12.87(s,1H),8.50(d,J＝8.3Hz,1H),7.43(d,J＝8.9Hz,1H),7.29(d,J＝9.0Hz,1H),5.11(t,J＝7.3Hz,1H),2. 70 (s, 3H), 2.63 (s, 3H), 2.33 (d, J = 7.7Hz, 3H), 2.20 (d, J = 7.9Hz, 3H), 2.07 (t, J = 7.8Hz, 6H), 1.67 (d, J = 6.6Hz, 3H).

6-氯-3-{[(1S)-1-{6-甲基-2-[4-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(99-P1和99-P2)
6-Chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methyl-1,3,4-thiadiazolidin-2-yl)bicyclo[2.2.2]octan-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methyl-1,3,4-thiadiazolidin-2-yl)bicyclo[2.2.2]octan-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (99-P1 and 99-P2)

实施例99化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-{6-甲基-2-[4-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(543mg,白色固体)和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(515mg,白色固体),99-P1先于99-P2出峰。Example 99 The compound was separated by SFC to obtain 6-chloro-3-{[(1S)-1-{6-methyl-2-[4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]oct-1-yl]-4-oxyylidene-3-(trideuterated methyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (543 mg, white solid) ) and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (515 mg, white solid), 99-P1 eluted before 99-P2.

手性分离方法同实施例98。The chiral separation method is the same as Example 98.

实施例100：6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(100)
Example 100: 6-Chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (100)

步骤1：7-溴-2-[4-(羟基甲基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮和7-溴-2-[4-(羟基甲基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-1,2,3,4-四氢噻吩并[3,2-d] 嘧啶-4-酮
Step 1: 7-bromo-2-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one and 7-bromo-2-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteriomethyl)-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-4-one Pyrimidin-4-one

1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯(500mg,1.17mmol,1.0eq)溶于四氢呋喃(10mL)中，0℃下加入四氢铝锂(0.47mL,1.17mmol,1.0eq)，氩气保护，0℃下反应1小时，反应液中加水(1mL)，15％的氢氧化钠水溶液(1mL)和水(3mL)，室温搅拌0.5小时，硅藻土过滤，减压浓缩得到7-溴-2-[4-(羟基甲基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮和7-溴-2-[4-(羟基甲基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-1,2,3,4-四氢噻吩并[3,2-d]嘧啶-4-酮混合物(460mg,收率98％)，黄色固体。1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuterylmethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester (500 mg, 1.17 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), lithium aluminum tetrahydride (0.47 mL, 1.17 mmol, 1.0 eq) was added at 0°C, argon was protected, and the reaction was carried out at 0°C for 1 hour. Water (1 mL), 15% sodium hydroxide aqueous solution (1 mL) and water (3 mL) were added to the reaction solution, and the mixture was heated to room temperature. The mixture was stirred for 0.5 h, filtered through celite, and concentrated under reduced pressure to give a mixture of 7-bromo-2-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one and 7-bromo-2-[4-(hydroxymethyl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteriomethyl)-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-4-one (460 mg, yield 98%) as a yellow solid.

MS m/z：400.2/402.2和402/404.2[M+H]+ MS m/z：400.2/402.2 and 402/404.2[M+H] +

步骤2：{1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛-4-基}甲烷醛
Step 2: {1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octan-4-yl}methanal

步骤1混合物(460mg,1.17mmol,1.0eq)溶于二氯甲烷(40mL)中，加入戴斯马丁试剂(987mg,1.17mmol,1.0eq)，室温下反应过夜，过滤，减压浓缩，残留物柱层析纯化得到{1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛-4-基}甲烷醛(301mg,收率65％)，黄色固体。The mixture of step 1 (460 mg, 1.17 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL), and Dess-Martin reagent (987 mg, 1.17 mmol, 1.0 eq) was added. The mixture was reacted overnight at room temperature, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give {1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteratedmethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octan-4-yl}methanal (301 mg, yield 65%) as a yellow solid.

MS m/z：398.2/400.2[M+H]+ MS m/z：398.2/400.2[M+H] +

步骤3：7-溴-2-(4-乙炔基双环[2.2.2]辛-1-基)-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 3: 7-Bromo-2-(4-ethynylbicyclo[2.2.2]octan-1-yl)-6-methyl-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

{1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛-4-基}甲烷醛(301mg,0.76mmol,1.0eq)溶于甲醇(10mL)中，加入(1-重氮基-2-氧代丙基)膦酸二甲酯(189mg,0.98mmol,1.3eq)和碳酸钾(261mg,1.98mmol,2.5eq)，氩气保护，室温下反应5小时，加水(20mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到得到7-溴-2-(4-乙炔基双环[2.2.2]辛-1-基)-6-甲基-3-(三氘 基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(117mg,收率39.3％)，黄色固体。{1-[7-bromo-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octan-4-yl}methanal (301 mg, 0.76 mmol, 1.0 eq) was dissolved in methanol (10 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (189 mg, 0.98 mmol, 1.3 eq) and potassium carbonate (261 mg, 1.98mmol, 2.5eq), argon protection, reaction at room temperature for 5 hours, dilution with water (20mL), extraction with ethyl acetate (20mL) three times, organic phases combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 7-bromo-2-(4-ethynylbicyclo[2.2.2]octan-1-yl)-6-methyl-3-(trideuterated 4-dihydrothieno[3,2-d]pyrimidin-4-one (117 mg, yield 39.3%), yellow solid.

MS m/z：394.2/396.2[M+H]+ MS m/z：394.2/396.2[M+H] +

步骤4：7-溴-6-甲基-3-(三氘基甲基)-2-(4-{1-[(三甲基甲硅基)甲基]-1,2,3-三氮杂环戊熳-4-基}双环[2.2.2]辛-1-基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 4: 7-Bromo-6-methyl-3-(trideuteriomethyl)-2-(4-{1-[(trimethylsilyl)methyl]-1,2,3-triazacyclopentan-4-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

7-溴-2-(4-乙炔基双环[2.2.2]辛-1-基)-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(107mg,0.27mmol,1.0eq)溶于氮，氮-二甲基甲酰胺(5mL)中，加入三甲基硅基叠氮甲烷(140mg,1.09mmol,1.3eq)和碘化亚铜(5.2mg,0.03mmol,0.1eq)，氩气保护，室温下反应过夜，加水(10mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到得到7-溴-6-甲基-3-(三氘基甲基)-2-(4-{1-[(三甲基甲硅基)甲基]-1,2,3-三氮杂环戊熳-4-基}双环[2.2.2]辛-1-基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(111mg,收率78.3％)，白色固体。7-Bromo-2-(4-ethynylbicyclo[2.2.2]octan-1-yl)-6-methyl-3-(trideuterylmethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (107 mg, 0.27 mmol, 1.0 eq) was dissolved in nitrogen-dimethylformamide (5 mL), trimethylsilylazide (140 mg, 1.09 mmol, 1.3 eq) and cuprous iodide (5.2 mg, 0.03 mmol, 0.1 eq) were added, and the mixture was reacted at room temperature overnight under argon protection. Water (10 m L), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 7-bromo-6-methyl-3-(trideuteriomethyl)-2-(4-{1-[(trimethylsilyl)methyl]-1,2,3-triazacyclopentane-4-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (111 mg, yield 78.3%) as a white solid.

MS m/z：523.2/525.2[M+H]+ MS m/z：523.2/525.2[M+H] +

步骤5：7-溴-6-甲基-2-[4-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 5: 7-Bromo-6-methyl-2-[4-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

7-溴-6-甲基-3-(三氘基甲基)-2-(4-{1-[(三甲基甲硅基)甲基]-1,2,3-三氮杂环戊熳-4-基}双环[2.2.2]辛-1-基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(100mg,0.19mmol,1.0eq)溶于四氢呋喃(6mL)中，加入四丁基氟化铵(0.19mL,0.19mmol,1.0eq)，氩气保护，70℃下反应2.5小时，反应冷却至室温，加水(10mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩得到7-溴-6-甲基-2-[4-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮粗品(80mg,收率92％)，黄色固体。7-Bromo-6-methyl-3-(trideuterylmethyl)-2-(4-{1-[(trimethylsilyl)methyl]-1,2,3-triazacyclopentan-4-yl}bicyclo[2.2.2]octan-1-yl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (100 mg, 0.19 mmol, 1.0 eq) was dissolved in tetrahydrofuran (6 mL), tetrabutylammonium fluoride (0.19 mL, 0.19 mmol, 1.0 eq) was added, and the mixture was reacted at 70°C for 2.5 hours under argon protection. The reaction mixture was cooled to room temperature, diluted with water (10 mL), extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-6-methyl-2-[4-(1-methyl-1,2,3-triazacyclopentane-4-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one crude product (80 mg, yield 92%) as a yellow solid.

MS m/z：451.2/453.2[M+H]+ MS m/z：451.2/453.2[M+H] +

步骤6：6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(100)Step 6: 6-Chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteromethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (100)

以7-溴-6-甲基-2-[4-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，按照实施例63方法制备得到6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(5mg)，白色固体。Using 7-bromo-6-methyl-2-[4-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as starting material, 6-chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (5 mg) was prepared as a white solid according to the method of Example 63.

MS m/z:571.2[M+H]+ MS m/z:571.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.82(s,1H),7.21–7.03(m,2H),5.06(t,J＝7.4Hz,1H),4.00(s,3H),2.57(s,3H),2.36–2.13(m,6H),1.93(t,J＝7.9Hz,6H),1.63(d,J＝6.7Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.82(s,1H),7.21–7.03(m,2H),5.06(t,J＝7.4Hz,1H) ,4.00(s,3H),2.57(s,3H),2.36–2.13(m,6H),1.93(t,J＝7.9Hz,6H),1.63(d,J＝6.7Hz,3H).

6-氯-3-{[(1S)-1-{6-甲基-2-[4-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(100-P1和100-P2)
6-Chloro-3-{[(1S)-1-{6-methyl-2-[4-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[2.2.2]oct-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[2.2.2]oct-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (100-P1 and 100-P2)

实施例100化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-{6-甲基-2-[4-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(424mg,白色固体)和6-氯-3-{[(1R)-1-{6-甲基-2-[4-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[2.2.2]辛-1-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(460mg,白色固体),100-P1先于100-P2出峰。The compound of Example 100 was separated by SFC to obtain 6-chloro-3-{[(1S)-1-{6-methyl-2-[4-(1-methyl-1,2,3-triazacyclopentane-4-yl)bicyclo[2.2.2]oct-1-yl]-4-oxyylidene-3-(trideuteratedmethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (424 mg, white solid) ) and 6-chloro-3-{[(1R)-1-{6-methyl-2-[4-(1-methyl-1,2,3-triazacyclopentane-4-yl)bicyclo[2.2.2]octan-1-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (460 mg, white solid), 100-P1 eluted before 100-P2.

手性分离方法同实施例98。The chiral separation method is the same as Example 98.

实施例101：6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[1.1.1]戊-3-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 101: 6-Chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

步骤1：1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酸甲酯
Step 1: 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester

以氘代甲胺和1-(氧亚基甲基)双环[1.1.1]戊烷-3-甲酸甲酯为原料，参照实施例95的方法制备得到1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酸甲酯(547mg),白色固体。Using deuterated methylamine and 1-(oxyylidenemethyl)bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester as raw materials, referring to the method of Example 95, 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester (547 mg) was prepared as a white solid.

MS m/z:386.2/388.2[M+H]+ MS m/z:386.2/388.2[M+H] +

步骤2：6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[1.1.1]戊-3-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸Step 2: 6-Chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[1.1.1]戊烷-3-甲酸甲酯为原料，参照实施例100的方法制备得到6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3-三氮杂环戊熳-4-基)双环[1.1.1]戊-3-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(1.5mg),白色固体。Using 1-[7-bromo-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[1.1.1]pentane-3-carboxylic acid methyl ester as raw material, referring to the method of Example 100, 6-chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3-triazacyclopentan-4-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (1.5 mg) was prepared as a white solid.

MS m/z:529.2[M+H]+ MS m/z:529.2[M+H] +

实施例102：6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,2,4-氧杂二氮杂环戊熳-3-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 102: 6-Chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,2,4-oxadiazacyclopentyl-3-yl)bicyclo[2.2.2]oct-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

步骤1：1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲腈
Step 1: 1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carbonitrile

以1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯为原料，参照实施例96的方法制备得到1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲腈(800mg)，类白色固体。Using 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester as starting material, referring to the method of Example 96 to prepare 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carbonitrile (800 mg) as an off-white solid.

MS m/z:395.1/397.1[M+H]+ MS m/z:395.1/397.1[M+H] +

步骤2：2-{4-[氮亚基(羟基氨基)甲基]双环[2.2.2]辛-1-基}-7-溴-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 2: 2-{4-[Azolylidene(hydroxyamino)methyl]bicyclo[2.2.2]octan-1-yl}-7-bromo-6-methyl-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲腈(360mg,0.91mmol,1.0eq)溶于乙醇(10mL)中，加入羟胺盐酸盐(316mg,4.55mmol,5.0eq)和碳酸钾(628mg,4.55mmol,5.0eq)，氩气保护,80℃下反应5小时，反应冷却至室温，加水(10mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩得到2-{4-[氮亚基(羟基氨基)甲基]双环[2.2.2]辛-1-基}-7-溴-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(390mg,收率99％)，类白色固体。1-[7-Bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carbonitrile (360 mg, 0.91 mmol, 1.0 eq) was dissolved in ethanol (10 mL), hydroxylamine hydrochloride (316 mg, 4.55 mmol, 5.0 eq) and potassium carbonate (628 mg, 4.55 mmol, 5.0 eq) were added, and the reaction was carried out at 80 ° C for 5 hours under argon protection. The mixture was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (20 mL) three times, the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-{4-[nitrogenylidene(hydroxyamino)methyl]bicyclo[2.2.2]octan-1-yl}-7-bromo-6-methyl-3-(trideuteratedmethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (390 mg, yield 99%) as an off-white solid.

MS m/z：428.1/430.1[M+H]+ MS m/z：428.1/430.1[M+H] +

步骤3：O-乙酰基-N-(氮亚基{1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛-4-基}甲基)羟胺
Step 3: O-acetyl-N-(nitrogenylidene{1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octan-4-yl}methyl)hydroxylamine

2-{4-[氮亚基(羟基氨基)甲基]双环[2.2.2]辛-1-基}-7-溴-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(390mg,0.93mmol,1.0eq)溶于二氯甲烷(10mL)中，加入乙酰氯(66μL,0.93mmol,1.0eq)和三乙胺(94.3mg,0.93mmol,1.0eq)，氩气保护,室温下反应1小时，加水(10mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩得到O-乙酰基-N-(氮亚基{1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛-4-基}甲基)羟胺(430mg,收率98％)，类白色固体。2-{4-[Azolylidene(hydroxyamino)methyl]bicyclo[2.2.2]octan-1-yl}-7-bromo-6-methyl-3-(trideuterylmethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (390 mg, 0.93 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), acetyl chloride (66 μL, 0.93 mmol, 1.0 eq) and triethylamine (94.3 mg, 0.93 mmol, 1.0 eq) were added, and the mixture was stirred at room temperature under argon protection. The mixture was reacted at room temperature for 1 hour, diluted with water (10 mL), extracted three times with dichloromethane (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give O-acetyl-N-(nitrogen substituent {1-[7-bromo-6-methyl-4-oxysubstituent-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octan-4-yl}methyl)hydroxylamine (430 mg, yield 98%) as an off-white solid.

MS m/z：470.1/472.1[M+H]+ MS m/z：470.1/472.1[M+H] +

步骤4：7-溴-6-甲基-2-[4-(5-甲基-1,2,4-氧杂二氮杂环戊熳-3-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 4: 7-Bromo-6-methyl-2-[4-(5-methyl-1,2,4-oxadiazacyclopentyl-3-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

O-乙酰基-N-(氮亚基{1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛-4-基}甲基)羟胺(430mg,0.91mmol,1.0eq)溶于四氢呋喃(10mL)中，加入四丁基氟化铵(1.5mL,1.5mmol,1.6eq)，氩气保护,60℃下反应4小时，加水(10mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩得到7-溴-6-甲基-2-[4-(5-甲基-1,2,4-氧杂二氮杂环戊熳-3-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(279mg,收率68％)，白色固体。O-acetyl-N-(nitrogenylidene{1-[7-bromo-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octan-4-yl}methyl)hydroxylamine (430 mg, 0.91 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1.5 mL, 1.5 mmol, 1.6 eq) was added, and the mixture was reacted at 60 °C for 4 hours under argon protection. Water (10 mL) was added. ), extracted three times with ethyl acetate (20 mL), combined the organic phases, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-6-methyl-2-[4-(5-methyl-1,2,4-oxadiazacyclopentyl-3-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (279 mg, yield 68%) as a white solid.

MS m/z：452.1/454.1[M+H]+ MS m/z：452.1/454.1[M+H] +

步骤5：6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,2,4-氧杂二氮杂环戊熳-3-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸Step 5: 6-chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,2,4-oxadiazacyclopentyl-3-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以7-溴-6-甲基-2-[4-(5-甲基-1,2,4-氧杂二氮杂环戊熳-3-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，参照实施例63的方法制备得到6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,2,4-氧杂二氮杂环戊熳-3-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(6mg),白色固体。Using 7-bromo-6-methyl-2-[4-(5-methyl-1,2,4-oxadiazacyclopentan-3-yl)bicyclo[2.2.2]oct-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as starting material, 6-chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,2,4-oxadiazacyclopentan-3-yl)bicyclo[2.2.2]oct-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (6 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z:572.1[M+H]+ MS m/z:572.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),8.52(s,1H),7.42(d,J＝9.0Hz,1H),7.27(d,J＝9.0Hz,1H),5.11(t,J＝7.4Hz,1H),2.63(s,3H),2.57(s,3H),2.55(m,1H),2.30(dt,J＝14.8,8.0Hz,3H),2.22–2.12(m,3H),1.98(d,J＝8.0Hz,5H),1.67(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),8.52(s,1H),7.42(d,J＝9.0Hz,1H),7.27(d,J＝9.0Hz,1H),5.11(t,J＝7.4Hz,1H),2.63(s ,3H),2.57(s,3H),2.55(m,1H),2.30(dt,J＝14.8,8.0Hz,3H),2.22–2.12(m,3H),1.98(d,J＝8.0Hz,5H),1.67(d,J＝6.7Hz,3H).

实施例103：6-氯-3-[(1-{2-[4-(5-氰基吡嗪-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(103)
Example 103: 6-Chloro-3-[(1-{2-[4-(5-cyanopyrazin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (103)

以氘代甲胺和5-(哌嗪-1-基)吡嗪-2-甲腈为原料，参照实施例63的方法制备得到6-氯-3-[(1-{2-[4-(5-氰基吡嗪-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(8mg)，白色固体。Using deuterated methylamine and 5-(piperazine-1-yl)pyrazine-2-carbonitrile as raw materials, refer to the method of Example 63 to prepare 6-chloro-3-[(1-{2-[4-(5-cyanopyrazine-2-yl)piperazine-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (8 mg) as a white solid.

MS m/z：569.2[M+H]+ MS m/z：569.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.67(d,J＝8.6Hz,1H),8.62(s,1H),8.52(s,1H),7.39(d,J＝8.9Hz,1H),7.27(d,J＝9.0Hz,1H),5.06(t,J＝7.4Hz,1H),3.95(t,J＝5.5Hz,4H),3.42(d,J＝5.7Hz,4H),2.61(s,3H),1.62(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.67(d,J＝8.6Hz,1H),8.62(s,1H),8.52(s,1H),7.39(d,J＝8.9Hz,1H),7.27(d,J＝9.0H z, 1H), 5.06 (t, J = 7.4Hz, 1H), 3.95 (t, J = 5.5Hz, 4H), 3.42 (d, J = 5.7Hz, 4H), 2.61 (s, 3H), 1.62 (d, J = 6.6Hz, 3H).

6-氯-3-{[(1S)-1-{2-[4-(5-氰基吡嗪-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸和6-氯-3-{[(1R)-1-{2-[4-(5-氰基吡嗪-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(103-P1和103-P2)
6-Chloro-3-{[(1S)-1-{2-[4-(5-cyanopyrazin-2-yl)piperazin-1-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid and 6-chloro-3-{[(1R)-1-{2-[4-(5-cyanopyrazin-2-yl)piperazin-1-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (103-P1 and 103-P2)

实施例103化合物通过SFC分离制备得到6-氯-3-{[(1S)-1-{2-[4-(5-氰基吡嗪-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(520mg,白色固体)和6-氯-3-{[(1R)-1-{2-[4-(5-氰基吡嗪-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基]氨基}吡啶-2-甲酸(517mg,白色固体),103-P1先于103-P2出峰。The compound of Example 103 was separated by SFC to give 6-chloro-3-{[(1S)-1-{2-[4-(5-cyanopyrazin-2-yl)piperazin-1-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (520 mg, white solid) and 6-chloro-3-{[(1R)-1-{2-[4-(5-cyanopyrazin-2-yl)piperazin-1-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl]amino}pyridine-2-carboxylic acid (517 mg, white solid), 103-P1 eluted before 103-P2.

手性分离方法同实施例74。The chiral separation method is the same as Example 74.

实施例104 3-{[1-(2-{4-[5-(氨基甲基)嘧啶-2-基]哌嗪-1-基}-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基)乙基]氨基}-6-氯吡啶-2-甲酸
Example 104 3-{[1-(2-{4-[5-(aminomethyl)pyrimidin-2-yl]piperazin-1-yl}-6-methyl-4-oxydeoxy-3-(trideuteromethyl)thieno[3,2-d]pyrimidin-7-yl)ethyl]amino}-6-chloropyridine-2-carboxylic acid

以氘代甲胺和({[2-(哌嗪-1-基)嘧啶-5-基]甲基}氨基)甲烷酸-2-甲基丙-2-基酯为原料，参照实施例63的方法制备得到3-{[1-(2-{4-[5-(氨基甲基)嘧啶-2-基]哌嗪-1-基}-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基)乙基]氨基}-6-氯吡啶-2-甲酸(16mg)，白色固体。Using deuterated methylamine and ({[2-(piperazin-1-yl)pyrimidin-5-yl]methyl}amino)methane-2-methylpropan-2-yl ester as raw materials, refer to the method of Example 63 to prepare 3-{[1-(2-{4-[5-(aminomethyl)pyrimidin-2-yl]piperazin-1-yl}-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl)ethyl]amino}-6-chloropyridine-2-carboxylic acid (16 mg) as a white solid.

MS m/z：573.1[M+H]+ MS m/z：573.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),8.46(s,2H),7.35(d,J＝8.9Hz,1H),7.21(d,J＝9.0Hz,1H),5.02(s,1H),3.93(d,J＝9.6Hz,5H),2.61(s,3H),1.62(d,J＝6.5Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),8.46(s,2H),7.35(d,J＝8.9Hz,1H),7.21(d,J＝ 9.0Hz, 1H), 5.02 (s, 1H), 3.93 (d, J = 9.6Hz, 5H), 2.61 (s, 3H), 1.62 (d, J = 6.5Hz, 3H).

实施例105 3-[(1-{2-[4-(5-甲酰胺基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸
Example 105 3-[(1-{2-[4-(5-formamidopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxydeoxy-3-(trideuteromethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid

步骤1：3-[(1-{2-[4-(5-甲酰胺基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸甲酯
Step 1: 3-[(1-{2-[4-(5-formamidopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid methyl ester

制备实施例97化合物得到副产物3-[(1-{2-[4-(5-甲酰胺基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸甲酯(54mg)，白色固体。The compound of Example 97 was prepared to give the by-product 3-[(1-{2-[4-(5-formamidopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropicolinic acid methyl ester (54 mg) as a white solid.

MS m/z：601.1[M+H]+ MS m/z：601.1[M+H] +

步骤2：3-[(1-{2-[4-(5-甲酰胺基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸Step 2: 3-[(1-{2-[4-(5-formamidopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid

参照实施例63步骤4的方法制备得到3-[(1-{2-[4-(5-甲酰胺基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸(45mg，收率81％),白色固体。Referring to the method of step 4 of Example 63, 3-[(1-{2-[4-(5-formamidopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid (45 mg, yield 81%) was prepared as a white solid.

MS m/z：587.1[M+H]+ MS m/z：587.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.84(s,2H),8.58(d,J＝8.5Hz,1H),7.90(s,1H),7.41(s,1H),7.35(s,1H),7.29(s,1H),5.06(t,J＝7.5Hz,1H),4.02(dt,J＝9.7,5.1Hz,4H),3.34(d,J＝5.2Hz,4H),2.62(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.84(s,2H),8.58(d,J＝8.5Hz,1H),7.90(s,1H),7.41(s,1H),7.35(s,1H),7.29 (s, 1H), 5.06 (t, J = 7.5Hz, 1H), 4.02 (dt, J = 9.7, 5.1Hz, 4H), 3.34 (d, J = 5.2Hz, 4H), 2.62 (s, 3H), 1.63 (d, J = 6.7Hz, 3H).

实施例106 6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 106 6-Chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]oct-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

步骤1：7-乙酰基-2-[4-(4H-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 1: 7-acetyl-2-[4-(4H-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲腈(300mg,0.84mmol,1.0eq)溶于二甲苯(5mL)中，加入叠氮三丁基-λ4-锡烷(416mg,1.26mmol,1.5eq)，氩气保护，110℃下搅拌过夜小时，冷却至室温，反应液浓缩，加水(20mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到7-乙酰基-2-[4-(4H-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(100mg,收率30％)，类白色固体。1-[7-Acetyl-6-methyl-4-oxyylidene-3-(trideuteriummethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carbonitrile (300 mg, 0.84 mmol, 1.0 eq) was dissolved in xylene (5 mL), and tributylazide-λ4-stannane (416 mg, 1.26 mmol, 1.5 eq) was added. The mixture was stirred at 110°C overnight under argon protection for 24 hours, cooled to room temperature, concentrated, and diluted with water (20 mL). , extracted three times with ethyl acetate (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-acetyl-2-[4-(4H-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteratedmethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (100 mg, yield 30%) as an off-white solid.

MS m/z:402.1[M+H]+ MS m/z:402.1[M+H] +

步骤2：7-乙酰基-6-甲基-2-[4-(1-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-3-(三氘基甲 基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮和7-乙酰基-6-甲基-2-[4-(2-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 2: 7-acetyl-6-methyl-2-[4-(1-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuterio)methoxy 7-Acetyl-6-methyl-2-[4-(2-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

7-乙酰基-2-[4-(4H-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(400mg,1.00mmol,1.0eq)溶于乙腈(10mL)中，加入碘甲烷(0.097mL,1.20mmol,1.2eq)和碳酸钾(138mL,1.00mmol,1.0eq)，氩气保护，室温下搅拌过夜小时，加入氨水(10mL)，加水(20mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到7-乙酰基-6-甲基-2-[4-(1-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(180mg,收率43.5％)，类白色固体和7-乙酰基-6-甲基-2-[4-(2-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(210mg,收率51％)，类白色固体。7-Acetyl-2-[4-(4H-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuterylmethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (400 mg, 1.00 mmol, 1.0 eq) was dissolved in acetonitrile (10 mL), iodomethane (0.097 mL, 1.20 mmol, 1.2 eq) and potassium carbonate (138 mL, 1.00 mmol, 1.0 eq) were added, and the mixture was stirred at room temperature overnight under argon protection. Ammonia water (10 mL) was added, and the mixture was diluted with water (20 mL). The mixture was extracted with dichloromethane (20 mL) three times, and the organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-acetyl-6-methyl-2-[4-(1-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteromethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (180 mg, yield 43.5%) as an off-white solid and 7-acetyl-6-methyl-2-[4-(2-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteromethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (210 mg, yield 51%) as an off-white solid.

MS m/z:416.1[M+H]+ MS m/z:416.1[M+H] +

步骤3：6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸Step 3: 6-Chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以7-乙酰基-6-甲基-2-[4-(1-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，按照实施例67的方法制备得到6-氯-3-[(1-{6-甲基-2-[1-(1-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(18mg)，白色固体。Using 7-acetyl-6-methyl-2-[4-(1-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as starting material, 6-chloro-3-[(1-{6-methyl-2-[1-(1-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (18 mg) was prepared as a white solid according to the method of Example 67.

MS m/z:572.2[M+H]+ MS m/z:572.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),8.51(d,J＝8.1Hz,1H),7.42(d,J＝8.9Hz,1H),7.29(d,J＝9.1Hz,1H),5.16–5.05(m,1H),4.20(s,3H),2.63(s,3H),2.40–2.28(m,3H),2.24–2.08(m,9H),1.67(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),8.51(d,J＝8.1Hz,1H),7.42(d,J＝8.9Hz,1H),7.29(d,J＝9.1Hz,1H), 5.16–5.05(m,1H),4.20(s,3H),2.63(s,3H),2.40–2.28(m,3H),2.24–2.08(m,9H),1.67(d,J＝6.6Hz,3H).

实施例107 6-氯-3-[(1-{6-甲基-2-[1-(2-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 107 6-Chloro-3-[(1-{6-methyl-2-[1-(2-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]oct-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以7-乙酰基-6-甲基-2-[4-(2-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-1-基]-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，参照实施例67的方法制备得到6-氯-3-[(1-{6-甲基-2-[1-(2-甲基-1,2,3,4-四氮杂环戊熳-5-基)双环[2.2.2]辛-4-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(10mg)，白色固体。Using 7-acetyl-6-methyl-2-[4-(2-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-1-yl]-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as starting material, 6-chloro-3-[(1-{6-methyl-2-[1-(2-methyl-1,2,3,4-tetraazacyclopentan-5-yl)bicyclo[2.2.2]octan-4-yl]-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (10 mg) was prepared as a white solid by referring to the method of Example 67.

MS m/z：572.2[M+H]+ MS m/z：572.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.52(d,J＝8.2Hz,1H),7.42(d,J＝8.9Hz,1H),7.28(d,J＝9.0Hz,1H),5.11(p,J＝7.0Hz,1H),4.33(s,3H),2.63(s,3H),2.31(q,J＝8.1,7.3Hz,3H),2.23–2.11(m,3H),2.06(q,J＝8.0,7.3Hz,6H),1.67(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),8.52(d,J＝8.2Hz,1H),7.42(d,J＝8.9Hz,1H),7.28(d,J＝9.0Hz,1H),5.11(p,J＝7.0Hz,1 H),4.33(s,3H),2.63(s,3H),2.31(q,J＝8.1,7.3Hz,3H),2.23–2.11(m,3H),2.06(q,J＝8.0,7.3Hz,6H),1.67(d,J＝6.6Hz,3H).

实施例108 3-[(1-{2-[4-(5-氨基吡嗪-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸
Example 108 3-[(1-{2-[4-(5-aminopyrazin-2-yl)piperazin-1-yl]-6-methyl-4-oxydeoxy-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid

以氘代甲胺和{[5-(哌嗪-1-基)吡嗪-2-基]氨基}甲烷酸-2-甲基丙-2-基酯为原料，参照实施例63的方法制备得到3-[(1-{2-[4-(5-氨基吡嗪-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸(50mg)，黄色固体。Using deuterated methylamine and 2-methylpropan-2-yl {[5-(piperazin-1-yl)pyrazin-2-yl]amino}methane as raw materials, 3-[(1-{2-[4-(5-aminopyrazin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid (50 mg) was prepared as a yellow solid by referring to the method of Example 63.

MS m/z：559.2[M+H]+ MS m/z：559.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ7.75(d,J＝1.6Hz,1H),7.62(d,J＝1.5Hz,1H),7.23(d,J＝47.3Hz,2H),5.63(s,2H),5.03(s,1H),3.41(d,J＝13.5Hz,8H),2.59(d,J＝5.0Hz,3H),1.62(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ7.75(d,J＝1.6Hz,1H),7.62(d,J＝1.5Hz,1H),7.23(d,J＝47.3Hz,2H),5 .63(s,2H),5.03(s,1H),3.41(d,J＝13.5Hz,8H),2.59(d,J＝5.0Hz,3H),1.62(d,J＝6.7Hz,3H).

实施例109 3-[(1-{2-[1-(5-氨基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸
Example 109 3-[(1-{2-[1-(5-amino-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]oct-4-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid

步骤1：1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯
Step 1: 1-[7-acetyl-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester

以1-[7-溴-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯为原料，参照实施例16的方法制备得到1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯(712mg)，黄色固体。Using 1-[7-bromo-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester as raw material, referring to the method of Example 16 to prepare 1-[7-acetyl-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester (712 mg) as a yellow solid.

MS m/z：392.3[M+H]+MS m/z：392.3[M+H]+

步骤2：1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸
Step 2: 1-[7-acetyl-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid

1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸甲酯(712mg,1.82mmol,1.0eq)溶于四氢呋喃(10mL)、甲醇(2mL)和水(1mL)中，加入氢氧化锂(130mg,5.46mmol,3.0eq),50℃下搅拌2小时，冷却至室温，调节PH至3.0，加水(50mL)稀释，乙酸乙酯(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸(680mg,收率99％)，类白色固体。1-[7-Acetyl-6-methyl-4-oxyylidene-3-(trideuterylmethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid methyl ester (712 mg, 1.82 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), methanol (2 mL) and water (1 mL), and lithium hydroxide (130 mg, 5.46 mmol, 3.0 eq) was added, stirred at 50 ° C for 2 hours, cooled to room temperature, and adjusted to P H to 3.0, diluted with water (50 mL), extracted three times with ethyl acetate (20 mL), combined the organic phases, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 1-[7-acetyl-6-methyl-4-oxyylidene-3-(trideuteratedmethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid (680 mg, yield 99%) as an off-white solid.

MS m/z:378.1[M+H]+ MS m/z:378.1[M+H] +

步骤3：1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酰肼
Step 3: 1-[7-acetyl-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid hydrazide

1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酸(500mg,1.32mmol,1.0eq)溶于四氢呋喃(10mL)中，加入三吡咯烷基溴化鏻六氟磷酸盐(738mg,1.58mmol,1.2eq)、水合肼(0.096mL,1.98mmol,1.5eq)和二异丙基乙胺(426mg,3.3mmol,2.5eq)，氩气保护，室温下搅拌5小时，加水(50mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酰肼(471mg,收率91％)，白色固体。1-[7-Acetyl-6-methyl-4-oxyylidene-3-(trideuterylmethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid (500 mg, 1.32 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), and tripyrrolidinylphosphonium bromide hexafluorophosphate (738 mg, 1.58 mmol, 1.2 eq), hydrazine hydrate (0.096 mL, 1.98 mmol, 1.5 eq) and diisopropylethylamine (426 mg, 3.3 m mol, 2.5eq), protected by argon, stirred at room temperature for 5 hours, diluted with water (50 mL), extracted with dichloromethane (20 mL) three times, combined the organic phases, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1-[7-acetyl-6-methyl-4-oxyylidene-3-(trideuteratedmethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid hydrazide (471 mg, yield 91%) as a white solid.

MS m/z:392.1[M+H]+ MS m/z:392.1[M+H] +

步骤4：7-乙酰基-2-[4-(5-氨基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮
Step 4: 7-acetyl-2-[4-(5-amino-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one

1-[7-乙酰基-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-2-基]双环[2.2.2]辛烷-4-甲酰肼(471mg,1.2mmol,1.0eq)溶于乙醇(10mL)中，加入溴化氰(140mg,1.32mmol,1.2eq)和碳酸钾(249mg,1.8mmol,1.5eq)，氩气保护，60℃下搅拌4小时，冷却至室温，加水(50mL)稀释，二氯甲烷(20mL)萃取三次，合并有机相，饱和食盐水(20mL)洗涤,有机相无水硫酸钠干燥，过滤，减压浓缩，残留物柱层析纯化得到7-乙酰基-2-[4-(5-氨基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮(217mg,收率43％)，黄色固体。1-[7-Acetyl-6-methyl-4-oxyylidene-3-(trideuterylmethyl)thieno[3,2-d]pyrimidin-2-yl]bicyclo[2.2.2]octane-4-carboxylic acid hydrazide (471 mg, 1.2 mmol, 1.0 eq) was dissolved in ethanol (10 mL), and cyanogen bromide (140 mg, 1.32 mmol, 1.2 eq) and potassium carbonate (249 mg, 1.8 mmol, 1.5 eq) were added. The mixture was stirred at 60 ° C for 4 hours under argon protection, cooled to room temperature, and water (50 m L), extracted three times with dichloromethane (20 mL), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-acetyl-2-[4-(5-amino-1,3,4-oxadiazacyclopentane-2-yl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteratedmethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (217 mg, yield 43%) as a yellow solid.

MS m/z:417.1[M+H]+ MS m/z:417.1[M+H] +

步骤5：3-[(1-{2-[1-(5-氨基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸Step 5: 3-[(1-{2-[1-(5-amino-1,3,4-oxadiazacyclopentyl-2-yl)bicyclo[2.2.2]octan-4-yl]-6-methyl-4-oxoylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid

以7-乙酰基-2-[4-(5-氨基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-1-基]-6-甲基-3-(三氘基甲基)-3,4-二氢噻吩并[3,2-d]嘧啶-4-酮为原料，参照实施例63的方法制备得到3-[(1-{2-[1-(5-氨基-1,3,4-氧杂二氮杂环戊熳-2-基)双环[2.2.2]辛-4-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸(33mg)，白色固体。Using 7-acetyl-2-[4-(5-amino-1,3,4-oxadiazacyclopentyl)bicyclo[2.2.2]octan-1-yl]-6-methyl-3-(trideuteriomethyl)-3,4-dihydrothieno[3,2-d]pyrimidin-4-one as starting material, 3-[(1-{2-[1-(5-amino-1,3,4-oxadiazacyclopentyl)bicyclo[2.2.2]octan-4-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid (33 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：573.2[M+H]+ MS m/z：573.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ7.29(s,1H),7.11(s,1H),6.90(s,2H),5.06(s,1H),2.59(s,3H),2.35–2.23(m,3H),2.21–2.10(m,3H),1.95(t,J＝7.8Hz,6H),1.63(d,J＝6.7Hz,3H)。 1 H NMR(400MHz,DMSO-d6)δ7.29(s,1H),7.11(s,1H),6.90(s,2H),5.06(s,1H),2.59(s,3 H), 2.35–2.23 (m, 3H), 2.21–2.10 (m, 3H), 1.95 (t, J = 7.8Hz, 6H), 1.63 (d, J = 6.7Hz, 3H).

实施例110 3-[(1-{3-氨基-6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸
Example 110 3-[(1-{3-amino-6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxydithieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid

以乙氮基甲烷酸-2-甲基丙-2-基酯和5-甲基-2-(哌嗪-1-基)嘧啶为原料，参照实施例63的方法制备得到3-[(1-{3-氨基-6-甲基-2-[4-(5-甲基嘧啶-2-基)哌嗪-1-基]-4-氧亚基噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]-6-氯吡啶-2-甲酸(5mg)，白色固体。Using 2-methylpropanediol and 5-methyl-2-(piperazin-1-yl)pyrimidine as raw materials, 3-[(1-{3-amino-6-methyl-2-[4-(5-methylpyrimidin-2-yl)piperazin-1-yl]-4-oxyylidenethieno[3,2-d]pyrimidin-7-yl}ethyl)amino]-6-chloropyridine-2-carboxylic acid (5 mg) was prepared as a white solid by referring to the method of Example 63.

MS m/z：556.2[M+H]+ MS m/z：556.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.63(s,1H),8.28(s,2H),7.40(d,J＝8.9Hz,1H),7.24(d,J＝9.2Hz,1H),5.71(s,2H),5.08–4.99(m,1H),3.91–3.80(m,4H),3.62(t,J＝5.4Hz,4H),2.60(s,3H),2.11(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.65(s,1H),8.63(s,1H),8.28(s,2H),7.40(d,J＝8.9Hz,1H),7.24(d,J＝9.2Hz,1H),5.71( s,2H),5.08–4.99(m,1H),3.91–3.80(m,4H),3.62(t,J＝5.4Hz,4H),2.60(s,3H),2.11(s,3H),1.63(d,J＝6.7Hz,3H).

实施例111 6-氯-3-({1-[2-(4-{5-[(2-甲氧基乙基)氧基]嘧啶-2-基}哌嗪-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 111 6-Chloro-3-({1-[2-(4-{5-[(2-methoxyethyl)oxy]pyrimidin-2-yl}piperazin-1-yl)-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以氘代甲胺和5-[(2-甲氧基乙基)氧基]-2-(哌嗪-1-基)嘧啶为原料，参照实施例63的方法制备得到6-氯-3-({1-[2-(4-{5-[(2-甲氧基乙基)氧基]嘧啶-2-基}哌嗪-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(61mg)，白色固体。Using deuterated methylamine and 5-[(2-methoxyethyl)oxy]-2-(piperazin-1-yl)pyrimidine as raw materials, refer to the method of Example 63 to prepare 6-chloro-3-({1-[2-(4-{5-[(2-methoxyethyl)oxy]pyrimidin-2-yl}piperazin-1-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (61 mg) as a white solid.

MS m/z：618.2[M+H]+ MS m/z：618.2[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.60(d,J＝8.5Hz,1H),8.28(s,2H),7.41(d,J＝9.0Hz,1H),7.28(d,J＝9.1Hz,1H),5.06(s,1H),4.19-4.08(m,2H),3.82(p,J＝4.9,4.3Hz,4H),3.69-3.59(m,2H),3.34(s,4H),3.31(s,3H),2.61(s,3H),1.63(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),8.60(d,J＝8.5Hz,1H),8.28(s,2H),7.41(d,J＝9.0Hz,1H),7.28(d,J＝9.1Hz,1H),5.06(s,1H ),4.19-4.08(m,2H),3.82(p,J＝4.9,4.3Hz,4H),3.69-3.59(m,2H),3.34(s,4H),3.31(s,3H),2.61(s,3H),1.63(d,J＝6.7Hz,3H).

实施例112 6-氯-3-[(1-{2-[4-(5-甲氧基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 112 6-Chloro-3-[(1-{2-[4-(5-methoxypyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺和5-甲氧基-2-(哌嗪-1-基)嘧啶为原料，参照实施例63的方法制备得到6-氯-3-[(1-{2-[4-(5-甲氧基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(11mg)，白色固体。Using deuterated methylamine and 5-methoxy-2-(piperazin-1-yl)pyrimidine as raw materials, refer to the method of Example 63 to prepare 6-chloro-3-[(1-{2-[4-(5-methoxypyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (11 mg) as a white solid.

MS m/z：574.1[M+H]+ MS m/z：574.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.8(s,1H),8.60(s,1H),8.27(s,2H),7.41(d,1H),7.26(d,1H),5.05(m,1H),3.81(m,7H),3.35(m,4H),2.61(s,3H),1.63(d,3H)。 1 H NMR(400MHz,DMSO-d6)δ12.8(s,1H),8.60(s,1H),8.27(s,2H),7.41(d,1H),7 .26(d,1H),5.05(m,1H),3.81(m,7H),3.35(m,4H),2.61(s,3H),1.63(d,3H).

实施例113 6-氯-3-({1-[3-(氰基甲基)-2-[4-(5-氰基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸
Example 113 6-Chloro-3-({1-[3-(cyanomethyl)-2-[4-(5-cyanopyrimidin-2-yl)piperazin-1-yl]-6-methyl-4-oxothieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid

以氨基乙腈和2-(哌嗪-1-基)嘧啶-5-甲腈为原料，参照实施例63的方法制备得到6-氯-3-({1-[3-(氰基甲基)-2-[4-(5-氰基嘧啶-2-基)哌嗪-1-基]-6-甲基-4-氧亚基噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)吡啶-2-甲酸(5mg)，白色固体。Using aminoacetonitrile and 2-(piperazine-1-yl)pyrimidine-5-carbonitrile as raw materials, refer to the method of Example 63 to prepare 6-chloro-3-({1-[3-(cyanomethyl)-2-[4-(5-cyanopyrimidin-2-yl)piperazine-1-yl]-6-methyl-4-oxythieno[3,2-d]pyrimidin-7-yl]ethyl}amino)pyridine-2-carboxylic acid (5 mg) as a white solid.

MS m/z：591.1[M+H]+ MS m/z：591.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.63(s,1H),7.48(d,1H),7.28(d,1H),5.08(m,1H),4.12(m,4H),3.35(m,4H),3.02(s,1H),2.65(s,3H),1.62(d,3H)。 1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),8.63(s,1H),7.48(d,1H),7.28(d,1H),5 .08(m,1H),4.12(m,4H),3.35(m,4H),3.02(s,1H),2.65(s,3H),1.62(d,3H).

实施例114 6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[1.1.1]戊-3-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸
Example 114 6-Chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,3,4-thiadiazacyclopentyl-2-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid

以氘代甲胺和3-(甲氧基羰基)双环[1.1.1]戊烷-1-甲酸为原料，参照实施例99的方法制备得到6-氯-3-[(1-{6-甲基-2-[1-(5-甲基-1,3,4-硫杂二氮杂环戊熳-2-基)双环[1.1.1]戊-3-基]-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基}乙基)氨基]吡啶-2-甲酸(1mg)，白色固体。Using deuterated methylamine and 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid as raw materials, referring to the method of Example 99, 6-chloro-3-[(1-{6-methyl-2-[1-(5-methyl-1,3,4-thiadiazacyclopentane-2-yl)bicyclo[1.1.1]pentan-3-yl]-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl}ethyl)amino]pyridine-2-carboxylic acid (1 mg) was prepared as a white solid.

MS m/z：546.1[M+H]+ MS m/z：546.1[M+H] +

实施例115 3-({1-[2-(4-{5-[(1-甲酰胺基乙基)氧基]嘧啶-2-基}哌嗪-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-6-氯吡啶-2-甲酸
Example 115 3-({1-[2-(4-{5-[(1-formamidoethyl)oxy]pyrimidin-2-yl}piperazin-1-yl)-6-methyl-4-oxyylidene-3-(trideuterated methyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-6-chloropyridine-2-carboxylic acid

以氘代甲胺和2-{[2-(哌嗪-1-基)嘧啶-5-基]氧基}丙酰胺为原料，参照实施例63的方法制备得到3-({1-[2-(4-{5-[(1-甲酰胺基乙基)氧基]嘧啶-2-基}哌嗪-1-基)-6-甲基-4-氧亚基-3-(三氘基甲基)噻吩并[3,2-d]嘧啶-7-基]乙基}氨基)-6-氯吡啶-2-甲酸异构体A(16mg)和B(25mg)，白色固体。Using deuterated methylamine and 2-{[2-(piperazin-1-yl)pyrimidin-5-yl]oxy}propionamide as raw materials, refer to the method of Example 63 to prepare 3-({1-[2-(4-{5-[(1-formamidoethyl)oxy]pyrimidin-2-yl}piperazin-1-yl)-6-methyl-4-oxyylidene-3-(trideuteriomethyl)thieno[3,2-d]pyrimidin-7-yl]ethyl}amino)-6-chloropyridine-2-carboxylic acid isomers A (16 mg) and B (25 mg) as white solids.

MS m/z：631.1[M+H]+ MS m/z：631.1[M+H] +

1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),9.74(s,1H),8.69(s,2H),8.61(d,J＝8.4Hz,1H),7.41(d,J＝8.9Hz,1H),7.27(d,J＝9.1Hz,1H),5.84(d,J＝5.1Hz,1H),5.05(q,J＝7.3Hz,1H),4.15(dd,J＝6.7,4.5Hz,1H),3.95–3.80(m,4H),3.34(m,4H),2.61(s,3H),1.63(d,J＝6.7Hz,3H),1.32(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),9.74(s,1H),8.69(s,2H),8.61(d,J＝8.4Hz,1H),7.41(d,J＝8.9Hz,1H),7.27(d,J＝9.1Hz,1H),5.84(d,J＝5.1H z,1H),5.05(q,J＝7.3Hz,1H),4.15(dd,J＝6.7,4.5Hz,1H),3.95–3.80(m,4 H), 3.34 (m, 4H), 2.61 (s, 3H), 1.63 (d, J = 6.7Hz, 3H), 1.32 (d, J = 6.8Hz, 3H).

1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.59(d,J＝8.5Hz,1H),8.24(s,2H),7.64–7.53(m,1H),7.42(d,J＝9.0Hz,1H),7.34–7.17(m,2H),5.06(p,J＝6.8Hz,1H),4.62(q,J＝6.6Hz,1H),3.97–3.71(m,4H),3.31(d,J＝5.7Hz,4H),2.61(s,3H),1.63(d,J＝6.7Hz,3H),1.43(d,J＝6.6Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.59(d,J＝8.5Hz,1H),8.24(s,2H),7.64–7.53(m,1H),7.42(d,J＝9.0Hz,1H),7.34–7.17(m,2H),5.06 (p,J＝6.8Hz,1H),4.62(q,J＝6.6Hz,1H),3.97–3.71(m,4H),3.31(d,J＝5.7Hz,4H),2.61(s,3H),1.63(d,J＝6.7Hz,3H),1.43(d,J＝6.6Hz,3H).

参考化合物的合成Synthesis of reference compounds

化合物A参照专利WO2022/235574实施例21的方法制备。
Compound A was prepared according to the method of Example 21 of patent WO2022/235574.

测试实施例1：针对PI3K-Alpha酶(PI3K H1047R突变及PI3K WT)的抑制活性Test Example 1: Inhibitory activity against PI3K-Alpha enzyme (PI3K H1047R mutation and PI3K WT)

N末端GST标签融合全长PIK3CA蛋白/PIK3R1共表达蛋白(以下简写为PIK3CA/PIK3R1)、N末端BTN标签融合全长PIK3CA H1047R突变蛋白和PIK3R1共表达蛋白(以下简写为PIK3CA[H1047R]/PIK3R1)均来自于Carna，货号分别为11-101、11-415-20N)；PIP2:3PS脂激酶底物由1mg/mL磷酸肌醇-4,5-二磷酸(PIP2)与3mg/mL磷酸丝氨酸(PS)共同构成，是I型PI3Ks的选择性底物，来自于Promega，货号V1701。N-terminal GST tag fusion full-length PIK3CA protein/PIK3R1 co-expression protein (hereinafter abbreviated as PIK3CA/PIK3R1), N-terminal BTN tag fusion full-length PIK3CA H1047R mutant protein and PIK3R1 co-expression protein (hereinafter abbreviated as PIK3CA[H1047R]/PIK3R1) are all from Carna, with catalog numbers 11-101 and 11-415-20N respectively); PIP2:3PS lipid kinase substrate is composed of 1 mg/mL phosphoinositide-4,5-bisphosphate (PIP2) and 3 mg/mL phosphoserine (PS), which is a selective substrate for type I PI3Ks and is from Promega, with catalog number V1701.

将各待测化合物事先用二甲基亚砜(DMSO)配制成20mmol/L储存液，然后在384孔稀释板中加入60μL体积/孔，然后用DMSO以1:3连续稀释，共10个浓度，并将板加热至室温。Each test compound was prepared in advance with dimethyl sulfoxide (DMSO) into a 20 mmol/L stock solution, then added to a 384-well dilution plate at a volume of 60 μL/well, and then serially diluted with DMSO at a ratio of 1:3 for a total of 10 concentrations, and the plate was warmed to room temperature.

384孔检测板中加入稀释后的各浓度待测化合物0.1μL(DMSO对照组、无底物对照组加入0.1μL的DMSO)，每个化合物浓度设置两个复孔。然后每孔加入5μL的1ng/μL PIK3CA/PIK3R1、PIK3CA[H1047R]/PIK3R1酶缓冲液(该缓冲液中含50mmol/L 4-(2-羟乙基)-1-哌嗪乙磺酸(HEPES)、50mmol/LNaCl、3mmol/L MgCl2、0.025mg/mL牛血清白蛋白(BSA)，pH 7.5)，1500转/分短暂旋1分钟，25℃孵育10分钟。再在384孔检测板中加入5μL的0.1mg/mL底物分析缓冲液(该分析缓冲液中含50mmol/L HEPES，0.5mmol/L乙二醇双(2-氨基乙基醚)四乙酸(EGTA)，50μmol/L三磷酸腺苷(ATP)，pH7.5)启动反应(无底物对照组加入5μL的分析缓冲液)，25℃孵育180分钟。接着加入10μL ADP-Glo试剂(Promega，货号：V912C)终止二磷酸腺苷(ADP)生成并去除ATP，25℃孵育40分钟。最后加入10μL的ADP-Glo检测试剂(Promega，货号：V917A)将ADP转化为ATP，并引入萤光素酶和萤光素检测ATP，25℃孵育40分钟。在PHERAstar FSX(BMG)上读取384孔检测板的相对发光单位(RLU)。按以下公式计算各浓度化合物的抑制率。
0.1 μL of the diluted test compound of each concentration was added to the 384-well detection plate (DMSO control group and substrate-free control group were added with 0.1 μL of DMSO), and two replicate wells were set for each compound concentration. Then 5 μL of 1 ng/μL PIK3CA/PIK3R1, PIK3CA[H1047R]/PIK3R1 enzyme buffer (the buffer contained 50 mmol/L 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 50 mmol/L NaCl, 3 mmol/L MgCl 2 , 0.025 mg/mL bovine serum albumin (BSA), pH 7.5) was added to each well, and the plate was briefly rotated at 1500 rpm for 1 minute and incubated at 25°C for 10 minutes. Then, 5 μL of 0.1 mg/mL substrate assay buffer (the assay buffer contains 50 mmol/L HEPES, 0.5 mmol/L ethylene glycol bis(2-aminoethyl ether) tetraacetic acid (EGTA), 50 μmol/L adenosine triphosphate (ATP), pH 7.5) was added to the 384-well assay plate to start the reaction (5 μL of assay buffer was added to the substrate-free control group) and incubated at 25°C for 180 minutes. Then, 10 μL of ADP-Glo reagent (Promega, catalog number: V912C) was added to terminate the generation of adenosine diphosphate (ADP) and remove ATP, and incubated at 25°C for 40 minutes. Finally, 10 μL of ADP-Glo detection reagent (Promega, catalog number: V917A) was added to convert ADP into ATP, and luciferase and luciferin were introduced to detect ATP, and incubated at 25°C for 40 minutes. The relative luminescence units (RLU) of the 384-well assay plate were read on the PHERAstar FSX (BMG). The inhibition rate of each concentration of the compound was calculated according to the following formula.

使用XLfit 5.5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值，结果见表1。The data were analyzed using XLfit 5.5.0 software. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC50 value was calculated based on this. The results are shown in Table 1.

表1

Table 1

其中，ND表示IC50>30μMND means IC 50 >30μM

测试结果表明，本发明化合物对PI3Kα(H1047R)酶具有良好的抑制活性，同时对PI3Kα(WT)酶的抑制活性相对较弱，具有良好的选择性。The test results show that the compound of the present invention has good inhibitory activity against PI3Kα (H1047R) enzyme, while the inhibitory activity against PI3Kα (WT) enzyme is relatively weak, and has good selectivity.

测试实施例2：对人乳腺癌细胞SK-BR-3、T-47D的增殖抑制活性Test Example 2: Proliferation inhibition activity on human breast cancer cells SK-BR-3 and T-47D

通过PrestoBlue法测定化合物在体外对人乳腺癌细胞SK-BR-3、T-47D的增殖抑制活性。The PrestoBlue method was used to determine the proliferation inhibitory activity of the compounds on human breast cancer cells SK-BR-3 and T-47D in vitro.

T-47D(药明康德)细胞培养于添加了10μg/ml重组人胰岛素(recombinant human insulin)(碧云天生物，货号：P3376-400IU)的含10％胎牛血清的RPMI1640完全培养基中；SK-BR-3细胞(武汉普诺赛生命科技有限公司，货号：CL-0211)细胞培养于含10％胎牛血清的McCoy’s 5A完全培养基中。取处于对数生长期SK-BR-3、T-47D细胞，分别按1500细胞/135μl完全培养基/孔、1500细胞/135μl完全培养基/孔的细胞密度，接种在96孔板中，置于37℃含有5％ CO2的恒温培养箱中培养24小时。将各化合物事先溶解在二甲基亚砜(DMSO)中配制成10mM的储存液，再依次用DMSO、完全培养基稀释化合物。取出接种细胞的96孔板，取其中一块单独作为无生长对照组(0小时细胞无生长的培养基对照组)；其他96孔板则每孔加入15μl的不同浓度化合物，使其终浓度为10000、2500、625、156.3、39.1、9.8、2.4、0.6、0.15、0.04nM，每个化合物浓度设置三个复孔，并设阴性对照组(含细胞、未加 化合物的培养基对照组)，每个孔中DMSO的浓度均为0.5％。留出的无生长对照组即刻加入PrestoBlueTM HS细胞活力检测试剂(Thermo Fisher，InvitrogenTM货号：P50201)并进行后续检测，其他的96孔板继续于37℃含有5％ CO2的恒温培养箱中培养120小时再加入PrestoBlueTM HS细胞活力检测试剂并进行后续检测。T-47D (WuXi AppTec) cells were cultured in RPMI1640 complete medium containing 10% fetal bovine serum supplemented with 10 μg/ml recombinant human insulin (Biyuntian Biotechnology, Catalog No.: P3376-400IU); SK-BR-3 cells (Wuhan Pronosai Life Science Co., Ltd., Catalog No.: CL-0211) were cultured in McCoy's 5A complete medium containing 10% fetal bovine serum. SK-BR-3 and T-47D cells in logarithmic growth phase were seeded in 96-well plates at a cell density of 1500 cells/135μl complete medium/well and 1500 cells/135μl complete medium/well, respectively, and cultured in a constant temperature incubator at 37°C containing 5% CO 2 for 24 hours. Each compound was dissolved in dimethyl sulfoxide (DMSO) in advance to prepare a 10mM storage solution, and then the compound was diluted with DMSO and complete medium in turn. The 96-well plate inoculated with cells was taken out, and one of them was used as a no-growth control group (the medium control group with no cell growth at 0 h); 15 μl of different concentrations of compounds were added to each well of the other 96-well plates, so that the final concentrations were 10000, 2500, 625, 156.3, 39.1, 9.8, 2.4, 0.6, 0.15, and 0.04 nM, and three replicate wells were set for each compound concentration, and a negative control group (containing cells, no addition of culture medium) was set up. The concentration of DMSO in each well was 0.5%. The reserved non-growth control group was immediately added with PrestoBlue ™ HS cell viability detection reagent (Thermo Fisher, Invitrogen™ Catalog No.: P50201) and subjected to subsequent detection. The other 96-well plates were continued to be cultured in a constant temperature incubator containing 5% CO 2 at 37°C for 120 hours and then added with PrestoBlue ™ HS cell viability detection reagent and subjected to subsequent detection.

加入PrestoBlueTM HS细胞活力检测试剂及后续检测步骤如下：从CO2恒温培养箱中取出96孔细胞培养板，每孔加入PrestoBlueTM HS细胞活力检测试剂15μl，继续于37℃含有5％CO2的恒温培养箱中孵育3小时。取出96孔细胞培养板，在酶标仪560nm激发波长、590nm发射波长处测相对荧光强度(RFU)。按以下公式计算各浓度化合物的细胞抑制率。
Add PrestoBlue ™ HS cell viability detection reagent and the subsequent detection steps are as follows: Take out the 96-well cell culture plate from the CO2 constant temperature incubator, add 15μl of PrestoBlue ™ HS cell viability detection reagent to each well, and continue to incubate in a constant temperature incubator at 37°C containing 5% CO2 for 3 hours. Take out the 96-well cell culture plate and measure the relative fluorescence intensity (RFU) at 560nm excitation wavelength and 590nm emission wavelength on a microplate reader. Calculate the cell inhibition rate of each concentration of the compound according to the following formula.

使用GraphPad Prism 8.3软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值，本发明结果见下表2。The data were analyzed using GraphPad Prism 8.3 software, and the dose-effect curve was obtained by fitting the data using nonlinear S-curve regression, and the IC 50 value was calculated accordingly. The results of the present invention are shown in Table 2 below.

表2

Table 2

表中“/”表示未测试。“/” in the table means not tested.

其中，Alpelisib购买得到，其结构如下：
Among them, Alpelisib is purchased and has the following structure:

测试结果表明，本发明化合物对具有PI3KαH1047R突变的人乳腺癌细胞T-47D具有良好的增殖抑制活性，而对野生型PI3Kα人乳腺癌细胞SK-BR-3的增殖抑制活性相对较弱，具有良好的选择性。The test results show that the compound of the present invention has good proliferation inhibition activity against human breast cancer cells T-47D with PI3KαH1047R mutation, but relatively weak proliferation inhibition activity against wild-type PI3Kα human breast cancer cells SK-BR-3, and has good selectivity.

测试实施例3：大鼠在化合物给药后的药代动力学评价Test Example 3: Pharmacokinetic evaluation in rats after administration of compound

对各化合物在大鼠体内的药代动力学研究进行评估。各化合物以溶液(主要溶媒有二甲基亚砜、氮，氮-二甲基乙酰胺、聚乙二醇-15羟基硬脂酸酯、聚乙二醇400和生理盐水)形式进行给药。对于静脉注射给药，动物给予2mg/kg的剂量；对于灌胃口服给药，动物给予10mg/kg剂量。在时间点为0.083、0.25，0.5，1，2，5，7和24小时取血(约0.2mL)，并在12000rpm下离心2分钟。收集血浆样品，并于-20℃或-70℃下保存直到进行LC-MS/MS分析。The pharmacokinetic study of each compound in rats was evaluated. Each compound was administered in the form of a solution (the main solvents were dimethyl sulfoxide, nitrogen, nitrogen-dimethylacetamide, polyethylene glycol-15 hydroxystearate, polyethylene glycol 400 and normal saline). For intravenous administration, the animals were given a dose of 2 mg/kg; for oral administration by gavage, the animals were given a dose of 10 mg/kg. Blood (about 0.2 mL) was collected at time points of 0.083, 0.25, 0.5, 1, 2, 5, 7 and 24 hours and centrifuged at 12000 rpm for 2 minutes. Plasma samples were collected and stored at -20°C or -70°C until LC-MS/MS analysis.

各化合物在大鼠体内的药代动力学数据见表3。The pharmacokinetic data of each compound in rats are shown in Table 3.

表3
Table 3

结论：本发明化合物的药代动力学良好。 Conclusion: The pharmacokinetics of the compounds of the present invention are good.

Claims (19)

一种如式I所示的化合物或其药学上可接受的盐，
A compound as shown in formula I or a pharmaceutically acceptable salt thereof,
其中：in: R1为氢、羟基、-N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R1a取代；R 1 is hydrogen, hydroxyl, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 1a ; 每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6- 10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 2a ; 每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; Cy1为 Cy 1 is X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S; R7为氢、羟基、-N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 7a ; 每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl; R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个 R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more R 8a substitution; 每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl; R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、-C(O)N(R9)2、-C(O)R9、-C(O)OR9、-SO2R9、-SO2N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12- membered cycloalkenyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkenyl, C 6-10 aryl, and 5-10-membered heteroaryl are each independently optionally substituted with one or more R 4a ; 每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、-S(O)2R10、-S(O)2N(R11)2、-S(O)R10、-S(O)N(R11)2、-S(O)(NR11)OR11、-C(O)R10、-C(O)OR11、-C(O)N(R11)2、-C(O)N(R11)OR11、-OC(O)R10、-OC(O)N(R11)2、-N(R11)C(O)OR11、-N(R11)C(O)R10、-N(R11)C(O)N(R11)2、-N(R11)C(NR11)(R10)、-N(R11)C(NR11)N(R11)2、-N(R11)S(O)2N(R11)2、-N(R11)S(O)2R10、-P(O)(R10)2、-P(O)(R11)(OR11)、-B(OR11)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4-a取代；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(NR 11 )(R 10 ), -N(R 11 )C(NR 11 )N(R 11 ) 2 , -N(R 11 )S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 10 , -P(O)(R 10 ) 2 , -P(O)(R 11 )(OR 11 ), -B(OR 11 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C R 4- a; R 4- b; R 4 -c; R 4- d; R 4- d; R 4 - d; R 4-e; R 4 - f; R 4- g; R 4-h; R 4-i ... 每个R4-a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 4-a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; R4B为氢、羟基、-N(R9)2、-C(O)N(R9)2、-C(O)R9、-C(O)OR9、-SO2R9、-SO2N(R9)2、C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3- 12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , -C(O)R 9 , -C(O)OR 9 , -SO 2 R 9 , -SO 2 N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl , C 6-10- membered aryl and 5-10-membered heteroaryl are each independently optionally substituted with one or more R 4b ; 每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、-S(O)2R10、-S(O)2N(R11)2、-S(O)R10、-S(O)N(R11)2、-S(O)(NR11)OR11、-C(O)R10、-C(O)OR11、-C(O)N(R11)2、-C(O)N(R11)OR11、-OC(O)R10、-OC(O)N(R11)2、-N(R11)C(O)OR11、-N(R11)C(O)R10、-N(R11)C(O)N(R11)2、-N(R11)C(NR11)(R10)、-N(R11)C(NR11)N(R11)2、-N(R11)S(O)2N(R11)2、-N(R11)S(O)2R10、-P(O)(R10)2、-P(O)(R11)(OR11)、-B(OR11)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R4-b取代；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, -S(O) 2 R 10 , -S(O) 2 N(R 11 ) 2 , -S(O)R 10 , -S(O)N(R 11 ) 2 , -S(O)(NR 11 )OR 11 , -C(O)R 10 , -C(O)OR 11 , -C(O)N(R 11 ) 2 , -C(O)N(R 11 )OR 11 , -OC(O)R 10 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)OR 11 , -N(R 11 )C(O)R 10 , -N(R 11 )C(O)N(R 11 ) 2 , -N(R 11 )C(NR 11 )(R 10 ), -N(R 11 )C(NR 11 )N(R 11 ) 2 , -N(R 11 )S(O) 2 N(R 11 ) 2 , -N(R 11 )S(O) 2 R 10 , -P(O)(R 10 ) 2 , -P(O)(R 11 )(OR 11 ), -B(OR 11 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C R 4- b; R 4-b is substituted with one or more C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl and 5-10 membered heteroaryl; 每个R4-b独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 4-b is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R10独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地为任选被一个或多个R10a取代；each R 10 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 10a ; 每个R10a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 10a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R11独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂 环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地为任选被一个或多个R11a取代；Each R 11 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered hetero cycloalkenyl, C 6-10 aryl or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted by one or more R 11a ; 每个R11a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 11a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、-S(O)2R12、-S(O)2N(R13)2、-S(O)R12、-S(O)N(R13)2、-S(O)(NR13)OR13、-C(O)R12、-C(O)OR13、-C(O)N(R13)2、-C(O)N(R13)OR13、-OC(O)R12、-OC(O)N(R13)2、-N(R13)C(O)OR13、-N(R13)C(O)R12、-N(R13)C(O)N(R13)2、-N(R13)C(NR13)(R12)、-N(R13)C(NR13)N(R13)2、-N(R13)S(O)2N(R13)2、-N(R13)S(O)2R12、-P(O)(R12)2、-P(O)(R13)(OR13)、-B(OR13)2、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6烯基、被一个或多个R5-d取代的C2-6烯基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、C3-12环烷基、被一个或多个R5-f取代的C3-12环烷基、C3-12环烯基、被一个或多个R5-g取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)N(R 13 ) 2 , -N(R 13 )C(NR 13 )(R 12 ), -N(R 13 )C(NR 13 )N(R 13 ) 2 , -N(R 13 )S(O) 2 N(R 13 ) 2 , -N(R 13 )S(O) 2 R 12 , -P(O)(R 12 ) 2 , -P(O)(R 13 )(OR 13 ), -B(OR 13 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC substituted by one or more R 5-c , C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 5-d , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5 -e , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5-f , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5-g , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-a、R5-b、R5-c、R5-d、R5-e、R5-f、R5-g、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, —C(O)NH 2 , —O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or —OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; 每个R12独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R12a取代；each R 12 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a ; 每个R12a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 12a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R13独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R13a取代；Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a ; 每个R13a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、-O-C1-6烷基、-S-C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基和5-10元杂芳基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, and 5-10 membered heteroaryl are each independently optionally substituted with one or more R 6a ; 每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每一“杂环烷基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heterocycloalkyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; 每一“杂环烯基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heterocycloalkenyl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; 每一“杂芳基”中，杂原子种类各自独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个、4个或5个；In each "heteroaryl", the heteroatom species are independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5; 且所述如式I所示的化合物不为以下化合物：
And the compound shown in formula I is not the following compound:
如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述如式I所示的化合物满足如下任一方案：The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound as shown in Formula I satisfies any of the following schemes: 方案1：Scenario 1: R1为氢、羟基、-N(R9)2或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R1a取代；R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ; 每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基或-S-C1-6烷基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ; 每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; Cy1为 Cy 1 is X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S； X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S; R7为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ; 每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl; R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ; 每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl; R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ; 每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; R4B为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ; 每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; 每个R11独立地为氢或C1-6烷基；Each R 11 is independently hydrogen or C 1-6 alkyl; 每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5- k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5 -c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 2-6 alkynyl substituted by one or more R 5-j 6-10 membered aryl, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R 5- k ; 每个R5-a、R5-b、R5-c、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, —C(O)NH 2 , —O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or —OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; 每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ; 每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 方案2：Scenario 2: R1为氢或C1-6烷基； R1 is hydrogen or C1-6 alkyl; R2和R3各自独立地为氢、卤素、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基；R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl; Cy1为 Cy 1 is X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ; R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ; 每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl; R8为氢、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 8a ; 每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl; R4A为氢、氘、卤素、羟基、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4a取代；每个R4a独立地为氘、卤素、-NH2或羟基；R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl; R4B为氢、C1-6烷基或-N(R9)2，其中所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen, C 1-6 alkyl or -N(R 9 ) 2 , wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ; 每个R4b独立地为氘、卤素、氰基、-NH2或羟基；each R 4b is independently deuterium, halogen, cyano, -NH 2 or hydroxyl; 每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-a、R5-b、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或 多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；Each of R5 -a , R5 -b , R5 -e , R5 -h , R5 -i , R5 -j and R5 -k is independently -NH2 , hydroxy, C1-6 alkyl, -OC1-6 alkyl, cyano, -N( C1-6 alkyl) 2 , -C(O) -C1-6 alkyl, deuterated C1-6 alkyl, -C(O) NH2 , -O-(3-12 membered heterocycloalkyl), substituted by one or more C 1-6 alkyl substituted by multiple R 5a' or -OC 1-6 alkyl substituted by one or more R 5b' ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; 每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基；Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl; 方案3：Scenario 3: R1为氢或C1-6烷基； R1 is hydrogen or C1-6 alkyl; R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl; Cy1为 Cy 1 is X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ; R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；每个R7a独立地为卤素；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen; R8为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为氢、-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen, -NH 2 or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; 每个R4b为氘或氰基；each R 4b is deuterium or cyano; 每个R5分别独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2； Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、-NH2或羟基；Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy; 方案4：Solution 4: R1为氢； R1 is hydrogen; R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl; Cy1为 Cy 1 is X为S，Y为CR8；X is S, Y is CR 8 ; R8为C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为氢、-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen, -NH 2 or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; 每个R4b为氘或氰基；each R 4b is deuterium or cyano; 每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ; 每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; Cy2为 Cy 2 is 每个R6独立地为氢或卤素；Each R 6 is independently hydrogen or halogen; 方案5：Solution 5: R1为氢； R1 is hydrogen; R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl; Cy1为 Cy 1 is X为S，Y为CR8；X is S, Y is CR 8 ; R8为C1-6烷基； R8 is C1-6 alkyl; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘或氰基；R 4B is -NH 2 or C 1-6 alkyl; the C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium or cyano; 每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ; 每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; Cy2为 Cy 2 is 每个R6独立地为氢或卤素；Each R 6 is independently hydrogen or halogen; 方案6：Solution 6: R1为氢； R1 is hydrogen; R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl; Cy1为 Cy 1 is X为S，Y为CR8；X is S, Y is CR 8 ; R8为C1-6烷基； R8 is C1-6 alkyl; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘； R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium; 每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为氰基、卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ; 每个R5-k和R5-j各自独立地为C1-6烷基、氰基、氘代C1-6烷基、-O-C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；Each R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl, -OC 1-6 alkyl, or -OC 1-6 alkyl substituted with one or more R 5b' ; 每个R5b’独立地为-O-C1-6烷基；Each R 5b' is independently -OC 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢或卤素；Each R 6 is independently hydrogen or halogen; 优选地，Preferably, R1为氢； R1 is hydrogen; R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl; Cy1为 Cy 1 is X为S，Y为CR8；X is S, Y is CR 8 ; R8为C1-6烷基； R8 is C1-6 alkyl; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium; 每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ; 每个R5-k和R5-j各自独立地为C1-6烷基或-O-C1-6烷基；Each R 5-k and R 5-j is independently C 1-6 alkyl or -OC 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述如式I所示的化合物满足如下任一方案：The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound as shown in Formula I satisfies any of the following schemes: 方案1：Scenario 1: R1为氢、羟基、-N(R9)2或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R1a取代；R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ; 每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基或-S-C1-6烷基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ; 每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; Cy1为 Cy 1 is X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S; R7为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ; 每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl; R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ; 每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl; R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ; 每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; R4B为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ; 每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; 每个R11独立地为氢或C1-6烷基；Each R 11 is independently hydrogen or C 1-6 alkyl; 每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的 3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5- k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5 -c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, substituted by one or more R 5-i 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5- k ; 每个R5-a、R5-b、R5-c、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; 每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ; 每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 方案2：Scenario 2: R1为氢或C1-6烷基； R1 is hydrogen or C1-6 alkyl; R2和R3各自独立地为氢、卤素、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基；R 2 and R 3 are each independently hydrogen, halogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl; Cy1为 Cy 1 is X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ; R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ; 每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl; R8为氢、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 8a ; 每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl; R4A为氢、氘、卤素、羟基、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4a取代；每个R4a独立地为氘、卤素、-NH2或羟基；R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted with one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl; R4B为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ; 每个R4b独立地为氘、卤素、-NH2或羟基；Each R 4b is independently deuterium, halogen, -NH 2 or hydroxy; 每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、C3-12环烷基、被 一个或多个R5a取代的C3-12环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-a、R5-b、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; 每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基；Each R 6 is independently hydrogen, deuterium, halogen, hydroxy, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl; 方案3：Scenario 3: R1为氢或C1-6烷基； R1 is hydrogen or C1-6 alkyl; R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl; Cy1为 Cy 1 is X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ; R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；每个R7a独立地为卤素；R 7 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen; R8为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为氢或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; 每个R4b为氘；each R 4b is deuterium; 每个R5分别独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基； Each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、-NH2或羟基；Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy; 方案4：Solution 4: R1为氢； R1 is hydrogen; R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl; Cy1为 Cy 1 is X为S，Y为CR8；X is S, Y is CR 8 ; R8为C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为氢或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；R 4B is hydrogen or C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; 每个R4b为氘；each R 4b is deuterium; 每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ; 每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基； Each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢或卤素；Each R 6 is independently hydrogen or halogen; 方案5：Solution 5: R1为氢； R1 is hydrogen; R2和R3中，一个为氢，另一个为C1-6烷基；Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl; Cy1为 Cy 1 is X为S，Y为CR8；X is S, Y is CR 8 ; R8为C1-6烷基； R8 is C1-6 alkyl; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium; 每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ; 每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢或卤素；Each R 6 is independently hydrogen or halogen; 方案6：Solution 6: R1为氢； R1 is hydrogen; R2和R3中，一个为氢，另一个为C1-6烷基； Of R 2 and R 3 , one is hydrogen and the other is C 1-6 alkyl; Cy1为 Cy 1 is X为S，Y为CR8；X is S, Y is CR 8 ; R8为C1-6烷基； R8 is C1-6 alkyl; R4A为氢或C1-6烷基；R 4A is hydrogen or C 1-6 alkyl; R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium; 每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为氰基、卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ; 每个R5-k和R5-j各自独立地为C1-6烷基、氰基、氘代C1-6烷基或-O-C1-6烷基；Each of R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl or -OC 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述如式I所示的化合物满足如下任一方案：The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound as shown in Formula I satisfies any of the following schemes: 方案1：Scenario 1: R1为氢、羟基、-N(R9)2或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R1a取代；R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted with one or more R 1a ; 每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基或-S-C1-6烷基各自独立地任选被一个或多个R2a取代；R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ; 每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; Cy1为 Cy 1 is X和Y各自独立地为NR7、N、O、S或CR8；且，其中一个为CR8，另一个为NR7、N、O或S；X and Y are each independently NR 7 , N, O, S or CR 8 ; and one of them is CR 8 and the other is NR 7 , N, O or S; R7为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R7a取代；R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ; 每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基； Each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl; R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R8a取代；R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ; 每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl; R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R4a取代；R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ; 每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; R4B为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4b取代；R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ; 每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; 每个R11独立地为氢或C1-6烷基；Each R 11 is independently hydrogen or C 1-6 alkyl; 每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5-c , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or substituted by one or more R 5-k substituted 5-10 membered heteroaryl; 每个R5-a、R5-b、R5-c、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R6a取代；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ; 每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 方案2： Scenario 2: R1为氢或C1-6烷基； R1 is hydrogen or C1-6 alkyl; R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl; Cy1为 Cy 1 is X为NR7、N、O或S，Y为CR8；X is NR 7 , N, O or S, and Y is CR 8 ; R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；每个R7a独立地为卤素；R 7 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently halogen; R8为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen; R4A和R4B分别独立地为氢或C1-6烷基；R 4A and R 4B are each independently hydrogen or C 1-6 alkyl; 每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基或-O-C1-6烷基；Each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢、氘、卤素、-NH2或羟基；Each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxy; 方案3：Scenario 3: R1为氢； R1 is hydrogen; R2和R3各自独立地为氢或C1-6烷基； R2 and R3 are each independently hydrogen or C1-6 alkyl; Cy1为 Cy 1 is X为S，Y为CR8；X is S, Y is CR 8 ; R8为C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；R 8 is C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen; R4A和R4B分别独立地为氢或C1-6烷基； R 4A and R 4B are each independently hydrogen or C 1-6 alkyl; 每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；Each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基或被一个或多个R5-k取代的5-10元杂芳基；Each of R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-j和R5-k各自独立地为C1-6烷基或-O-C1-6烷基；Each R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl; Cy2为 Cy 2 is 每个R6独立地为氢或卤素。Each R 6 is independently hydrogen or halogen. 如权利要求1-4任一项所述的化合物或其药学上可接受的盐，其特征在于，其满足以下条件的一个或多个：The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that it satisfies one or more of the following conditions: (1)R1为氢、羟基、-N(R9)2或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R1a取代；每个R1a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；(1) R 1 is hydrogen, hydroxy, -N(R 9 ) 2 or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 1a ; each R 1a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl; 优选地，R1为氢或C1-6烷基；更优选地，R1为氢；Preferably, R 1 is hydrogen or C 1-6 alkyl; More preferably, R 1 is hydrogen; (2)R2和R3各自独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基或-S-C1-6烷基各自独立地任选被一个或多个R2a取代；每个R2a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；(2) R 2 and R 3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl are each independently optionally substituted by one or more R 2a ; each R 2a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 优选地，R2和R3各自独立地为氢、卤素、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基；Preferably, R 2 and R 3 are each independently hydrogen, halogen, hydroxyl, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl; 更优选地，R2和R3各自独立地为氢或C1-6烷基；More preferably, R 2 and R 3 are each independently hydrogen or C 1-6 alkyl; 还优选地，R2和R3中，一个为H，另一个为C1-6烷基；Also preferably, of R 2 and R 3 , one is H and the other is C 1-6 alkyl; (3)R7为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R7a取代；每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1- 6烷基；(3) R 7 is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein the C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 7a ; each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxy, C 1-6 alkyl or -OC 1-6 alkyl; 优选地，R7为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R7a取代；每个R7a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；较佳地，每个R7a独立地为卤素；Preferably, R 7 is hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is independently optionally substituted by one or more R 7a ; each R 7a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; preferably, each R 7a is independently halogen; (4)R8为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R8a取代；每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；(4) R 8 is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 8a ; each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 优选地，R8为氢、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R8a取代；每个R8a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Preferably, R 8 is hydrogen, halogen, hydroxyl, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 8a ; each R 8a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 更优选地，R8为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素； More preferably, R 8 is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 8a ; each R 8a is independently halogen; 还优选地，R8为C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R8a取代；每个R8a独立地为卤素；Also preferably, R 8 is C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 8a ; each R 8a is independently halogen; 例如，R8为C1-6烷基；For example, R 8 is C 1-6 alkyl; (5)R4A为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R4a取代；每个R4a独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；每个R11独立地为氢或C1-6烷基；(5) R 4A is hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted by one or more R 4a ; each R 4a is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl; each R 11 is independently hydrogen or C 1-6 alkyl; 优选地，R4A为氢、氘、卤素、羟基、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4a取代；每个R4a独立地为氘、卤素、-NH2或羟基；Preferably, R 4A is hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4a ; each R 4a is independently deuterium, halogen, -NH 2 or hydroxyl; 更优选地，R4A为氢或C1-6烷基；More preferably, R 4A is hydrogen or C 1-6 alkyl; (6)R4B为氢、羟基、-N(R9)2、C1-6烷基或-O-C1-6烷基，其中所述C1-6烷基和-O-C1-6烷基各自独立地任选被一个或多个R4b取代；每个R4b独立地为氘、卤素、氰基、硝基、-N(R11)2、羟基、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基；每个R11独立地为氢或C1-6烷基；(6) R 4B is hydrogen, hydroxy, -N(R 9 ) 2 , C 1-6 alkyl, or -OC 1-6 alkyl, wherein the C 1-6 alkyl and -OC 1-6 alkyl are each independently optionally substituted by one or more R 4b ; each R 4b is independently deuterium, halogen, cyano, nitro, -N(R 11 ) 2 , hydroxy, C 1-6 alkyl, -OC 1-6 alkyl, or -SC 1-6 alkyl; each R 11 is independently hydrogen or C 1-6 alkyl; 优选地，R4B为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b独立地为氘、卤素、-NH2或羟基；Preferably, R 4B is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is independently deuterium, halogen, -NH 2 or hydroxyl; 更优选地，R4B为氢或C1-6烷基，其中所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；More preferably, R 4B is hydrogen or C 1-6 alkyl, wherein said C 1-6 alkyl is independently optionally substituted with one or more R 4b ; each R 4b is deuterium; 例如，R4B为C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘；For example, R 4B is C 1-6 alkyl; said C 1-6 alkyl is independently optionally substituted with one or more R 4b ; each R 4b is deuterium; 最优选地，R4B为氢或C1-6烷基；例如，R4B为C1-6烷基；Most preferably, R 4B is hydrogen or C 1-6 alkyl; for example, R 4B is C 1-6 alkyl; (7)每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；每个R5-a、R5-b、R5-c、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；每个R13独立地为氢或C1-6烷基；(7) each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; each R 5a , R 5b , R 5c, R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC 1-6 alkyl, -SC 1-6 alkyl substituted by one or more R 5-c , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; each of R 5-a , R 5-b, R 5 -c , R 5-h, R 5-i , R 5- j and R 5 -k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5 -k; 1-6 alkyl or -OC 1-6 alkyl; each R 13 is independently hydrogen or C 1-6 alkyl; 优选地，每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；每个R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；每个R5-a、R5-b、R5-h、R5-i、R5- j和R5-k各自独立地为-NH2、羟基、C1-6烷基或-O-C1-6烷基；每个R13独立地为氢或C1-6烷基；较佳地，每个R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基或-O-C1-6烷基；Preferably, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; each R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5 -a, -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , 3-12 membered heterocycloalkyl, C 6-10 aryl substituted by one or more R 5e, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f. R 5-a, R 5-b, R 5-h, R 5-i , R 5-1, R 5-2, R 5-3, R 5-4, R 5-5, R 5-6 , R 5-7, R 5-8, R 5-9 , R 5-10 , R 5-11, R 5-12, R 5-13, R 5-14, R 5-15, R 5-16, R 5-17, R 5-18, R 5-19, R 5-20, R 5-21 , R 5-22, R 5-33, R 5-44 , R 5-55, R 5-65, R 5-76, R 5-8, R 5-9 , R 5-10 , R 5-11, R 5-12, R 5-13, R 5-14 , R 5-15 R 5- i and R 5-k are each independently -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; each R 13 is independently hydrogen or C 1-6 alkyl; preferably, each R 5c , R 5d , R 5e and R 5f are each independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl or 5-10 membered heteroaryl substituted by one or more R 5-k ; each R 5-h , R 5-i , R 5-j and R 5-k are each independently C 1-6 alkyl or -OC 1-6 alkyl; 更优选地，每个R5分别独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；每个R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基或被一个或多个R5-k取代的5-10元杂芳基；每个R5-j和R5- k各自独立地为C1-6烷基或-O-C1-6烷基；较佳地，每个R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C6-10芳基或被一个或多个R5-k取代的5-10元杂芳基；每个R5-k独立地为C1-6烷基；更佳地，每个R5c、R5e和R5f各自独立地为卤素、C1-6烷基、-O-C1-6烷基或被一个或多个R5-k取代的5-10元杂芳基；每个R5-k独立地为C1-6烷基；More preferably, each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl or 5-10 membered heteroaryl substituted by one or more R 5f ; each R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5- j or 5-10 membered heteroaryl substituted by one or more R 5 - k; each R 5-j and R 5-k is independently C 1-6 alkyl or -OC 1-6 alkyl; preferably, each R 5c, R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j or 5-10 membered heteroaryl substituted by one or more R 5 - k R 5f is each independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 6-10 aryl, or a 5-10 membered heteroaryl substituted by one or more R 5-k ; each R 5-k is independently C 1-6 alkyl; more preferably, each R 5c , R 5e and R 5f is each independently halogen, C 1-6 alkyl, -OC 1-6 alkyl, or a 5-10 membered heteroaryl substituted by one or more R 5-k ; each R 5-k is independently C 1-6 alkyl; (8)Cy2为 (8) Cy 2 每个R6独立地为氢、氘、卤素、羟基、氰基、硝基、-N(R9)2、C1-6烷基、-O-C1-6烷基或-S-C1-6烷基，其中所述C1-6烷基、-O-C1-6烷基和-S-C1-6烷基各自独立地任选被一个或多个R6a取代；每个R6a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, -N(R 9 ) 2 , C 1-6 alkyl, -OC 1-6 alkyl or -SC 1-6 alkyl, wherein said C 1-6 alkyl, -OC 1-6 alkyl and -SC 1-6 alkyl are each independently optionally substituted with one or more R 6a ; each R 6a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 优选地，Cy2为 Preferably, Cy 2 is 每个R6独立地为氢、氘、卤素、羟基、-NH2、C1-6烷基或-O-C1-6烷基；较佳地，每个R6独立地为氢、氘、卤素、-NH2或羟基； Each R 6 is independently hydrogen, deuterium, halogen, hydroxyl, -NH 2 , C 1-6 alkyl or -OC 1-6 alkyl; preferably, each R 6 is independently hydrogen, deuterium, halogen, -NH 2 or hydroxyl; 更优选地，Cy2为每个R6独立地为氢或卤素；More preferably, Cy 2 is Each R 6 is independently hydrogen or halogen; 和(9)X为NR7、N、O或S，Y为CR8；优选地，X为S，Y为CR8。and (9) X is NR 7 , N, O or S, and Y is CR 8 ; preferably, X is S, and Y is CR 8 . 如权利要求1-4任一项所述的化合物或其药学上可接受的盐，其特征在于，其满足以下任一条件：The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that it satisfies any of the following conditions: (1)每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(1) each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、-S(O)2R12、-S(O)2N(R13)2、-S(O)R12、-S(O)N(R13)2、-S(O)(NR13)OR13、-C(O)R12、-C(O)OR13、-C(O)N(R13)2、-C(O)N(R13)OR13、-OC(O)R12、-OC(O)N(R13)2、-N(R13)C(O)OR13、-N(R13)C(O)R12、-N(R13)C(O)N(R13)2、-N(R13)C(NR13)(R12)、-N(R13)C(NR13)N(R13)2、-N(R13)S(O)2N(R13)2、-N(R13)S(O)2R12、-P(O)(R12)2、-P(O)(R13)(OR13)、-B(OR13)2、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6烯基、被一个或多个R5-d取代的C2-6烯基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、C3-12环烷基、被一个或多个R5-f取代的C3-12环烷基、C3-12环烯基、被一个或多个R5-g取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)N(R 13 ) 2 , -N(R 13 )C(NR 13 )(R 12 ), -N(R 13 )C(NR 13 )N(R 13 ) 2 , -N(R 13 )S(O) 2 N(R 13 ) 2 , -N(R 13 )S(O) 2 R 12 , -P(O)(R 12 ) 2 , -P(O)(R 13 )(OR 13 ), -B(OR 13 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC substituted by one or more R 5-c , C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 5-d , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5 -e , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5-f , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5-g , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-a、R5-b、R5-c、R5-d、R5-e、R5-f、R5-g、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；each of R 5-a , R 5-b , R 5-c , R 5-d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; (2)每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(2) each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5- k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , —SC 1-6 alkyl, —SC 1-6 alkyl substituted by one or more R 5 -c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 2-6 alkynyl substituted by one or more R 5-j 6-10 membered aryl, 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted with one or more R 5- k ; 每个R5-a、R5-b、R5-c、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、 C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; (3)每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(3) each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-a、R5-b、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; (4)每个R5分别独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(4) each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; (5)每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(5) each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ; 每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; (6)每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(6) each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ; 每个R5-k和R5-j各自独立地为C1-6烷基或-O-C1-6烷基； Each R 5-k and R 5-j is independently C 1-6 alkyl or -OC 1-6 alkyl; (7)每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(7) each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为氰基、卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ; 每个R5-k和R5-j各自独立地为C1-6烷基、氰基、氘代C1-6烷基或-O-C1-6烷基；Each of R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl or -OC 1-6 alkyl; (8)每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(8) each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、-S(O)2R12、-S(O)2N(R13)2、-S(O)R12、-S(O)N(R13)2、-S(O)(NR13)OR13、-C(O)R12、-C(O)OR13、-C(O)N(R13)2、-C(O)N(R13)OR13、-OC(O)R12、-OC(O)N(R13)2、-N(R13)C(O)OR13、-N(R13)C(O)R12、-N(R13)C(O)N(R13)2、-N(R13)C(NR13)(R12)、-N(R13)C(NR13)N(R13)2、-N(R13)S(O)2N(R13)2、-N(R13)S(O)2R12、-P(O)(R12)2、-P(O)(R13)(OR13)、-B(OR13)2、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6烯基、被一个或多个R5-d取代的C2-6烯基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、C3-12环烷基、被一个或多个R5-f取代的C3-12环烷基、C3-12环烯基、被一个或多个R5-g取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5b , R 5c , R 5d , R 5e , and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxy, -S(O) 2 R 12 , -S(O) 2 N(R 13 ) 2 , -S(O)R 12 , -S(O)N(R 13 ) 2 , -S(O)(NR 13 )OR 13 , -C(O)R 12 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -C(O)N(R 13 )OR 13 , -OC(O)R 12 , -OC(O)N(R 13 ) 2 , -N(R 13 )C(O)OR 13 -N(R 13 )C(O)R 12 , -N(R 13 )C(O)N(R 13 ) 2 , -N(R 13 )C(NR 13 )(R 12 ), -N(R 13 )C(NR 13 )N(R 13 ) 2 , -N(R 13 )S(O) 2 N(R 13 ) 2 , -N(R 13 )S(O) 2 R 12 , -P(O)(R 12 ) 2 , -P(O)(R 13 )(OR 13 ), -B(OR 13 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC substituted by one or more R 5-c , C 2-6 alkenyl, C 2-6 alkenyl substituted by one or more R 5-d , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5 -e , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5-f , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5-g , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-a、R5-b、R5-c、R5-d、R5-e、R5-f、R5-g、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基或氘代C1-6烷基；Each of R 5-a , R 5-b , R 5-c , R 5 -d , R 5-e , R 5-f , R 5-g , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl or deuterated C 1-6 alkyl; 每个R12独立地为氢、卤素、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基，其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R12a取代；each R 12 is independently hydrogen, halogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 12a ; 每个R12a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 12a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; 每个R13独立地为氢、羟基、C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基或5-10元杂芳基；其中所述C1-6烷基、C3-12环烷基、C3-12环烯基、3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、5-10元杂芳基各自独立地任选被一个或多个R13a取代；Each R 13 is independently hydrogen, hydroxy, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, or 5-10 membered heteroaryl; wherein the C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl are each independently optionally substituted with one or more R 13a ; 每个R13a独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基或-O-C1-6烷基；Each R 13a is independently deuterium, halogen, cyano, -NH 2 , hydroxyl, C 1-6 alkyl or -OC 1-6 alkyl; (9)每个R5独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、C3-12环烯基、被一个或多个R5b取代的C3-12环烯基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(9) each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , C 3-12 cycloalkenyl, C 3-12 cycloalkenyl substituted by one or more R 5b , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5b、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6 烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、-S-C1-6烷基、被一个或多个R5-c取代的-S-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5- k取代的5-10元杂芳基；Each of R 5a , R 5b , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, -N(R 13 ) 2 , hydroxyl, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , -OC 1-6 alkyl, -OC 1-6 alkyl substituted by one or more R 5-b , -SC 1-6 alkyl, -SC 1-6 alkyl substituted by one or more R 5-c , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5- k ; 每个R5-a、R5-b、R5-c、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为氘、卤素、氰基、-NH2、羟基、C1-6烷基、-O-C1-6烷基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-c , R 5 -e , R 5-h , R 5-i , R 5-j and R 5-k is independently deuterium, halogen, cyano, —NH 2 , hydroxyl, C 1-6 alkyl, —OC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, —C(O)NH 2 , —O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or —OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; 每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl; (10)每个R5独立地为3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(10) each R 5 is independently 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5d、R5e和R5f各自独立地为氘、卤素、氰基、硝基、-N(R13)2、羟基、C1-6烷基、被一个或多个R5-a取代的C1-6烷基、-O-C1-6烷基、被一个或多个R5-b取代的-O-C1-6烷基、C2-6炔基、被一个或多个R5-e取代的C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6- 10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently deuterium, halogen, cyano, nitro, —N(R 13 ) 2 , hydroxy, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5-a , —OC 1-6 alkyl, —OC 1-6 alkyl substituted by one or more R 5-b , C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 5-e , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-a、R5-b、R5-e、R5-h、R5-i、R5-j和R5-k各自独立地为-NH2、羟基、C1-6烷基、-O-C1-6烷基、氰基、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-a , R 5-b , R 5-e , R 5-h , R 5-i , R 5-j and R 5-k is independently -NH 2 , hydroxyl, C 1-6 alkyl, -OC 1-6 alkyl, cyano, -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; 每个R13独立地为氢或C1-6烷基；Each R 13 is independently hydrogen or C 1-6 alkyl; (11)每个R5分别独立地为C3-12环烷基、被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5d取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(11) each R 5 is independently C 3-12 cycloalkyl, C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5d , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5d、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、3-12元杂环烷基、被一个或多个R5-h取代的3-12元杂环烷基、3-12元杂环烯基、被一个或多个R5-i取代的3-12元杂环烯基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基或被一个或多个R5-k取代的5-10元杂芳基；each of R 5a , R 5c , R 5d , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5-h , 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl substituted by one or more R 5-i , C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5-k ; 每个R5-h、R5-i、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-h , R 5-i , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2； Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; (12)每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(12) each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ; 每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、-O-(3-12元杂环烷基)、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each of R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , -O-(3-12 membered heterocycloalkyl), C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; (13)每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(13) each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为卤素、氰基、C1-6烷基、-O-C1-6烷基、C2-6炔基、C6-10芳基、被一个或多个R5-j取代的C6-10芳基、5-10元杂芳基、被一个或多个R5-k取代的5-10元杂芳基、3-12元杂环烷基或被一个或多个R5-h取代的3-12元杂环烷基；each of R 5a , R 5c , R 5e and R 5f is independently halogen, cyano, C 1-6 alkyl, -OC 1-6 alkyl, C 2-6 alkynyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5-j , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more R 5-k , 3-12 membered heterocycloalkyl, or 3-12 membered heterocycloalkyl substituted by one or more R 5-h ; 每个R5-h、R5-j和R5-k各自独立地为C1-6烷基、-O-C1-6烷基、氰基、-NH2、-N(C1-6烷基)2、-C(O)-C1-6烷基、氘代C1-6烷基、-C(O)NH2、被一个或多个R5a’取代的C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；each R 5-h , R 5-j and R 5-k is independently C 1-6 alkyl, -OC 1-6 alkyl, cyano, -NH 2 , -N(C 1-6 alkyl) 2 , -C(O)-C 1-6 alkyl, deuterated C 1-6 alkyl, -C(O)NH 2 , C 1-6 alkyl substituted by one or more R 5a′ , or -OC 1-6 alkyl substituted by one or more R 5b′ ; 每个R5a’和R5b’各自独立地为-NH2、-O-C1-6烷基或-C(O)NH2；Each of R 5a' and R 5b' is independently -NH 2 , -OC 1-6 alkyl or -C(O)NH 2 ; (14)每个R5分别独立地为被一个或多个R5a取代的C3-12环烷基、3-12元杂环烷基、被一个或多个R5c取代的3-12元杂环烷基、3-12元杂环烯基、C6-10芳基、被一个或多个R5e取代的C6-10芳基、5-10元杂芳基或被一个或多个R5f取代的5-10元杂芳基；(14) each R 5 is independently C 3-12 cycloalkyl substituted by one or more R 5a , 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl substituted by one or more R 5c , 3-12 membered heterocycloalkenyl, C 6-10 aryl, C 6-10 aryl substituted by one or more R 5e , 5-10 membered heteroaryl, or 5-10 membered heteroaryl substituted by one or more R 5f ; 每个R5a、R5c、R5e和R5f各自独立地为氰基、卤素、C1-6烷基、3-12元杂环烷基、-O-C1-6烷基、被一个或多个R5-k取代的5-10元杂芳基或被一个或多个R5-j取代的C6-10芳基；Each of R 5a , R 5c , R 5e and R 5f is independently cyano, halogen, C 1-6 alkyl, 3-12 membered heterocycloalkyl, -OC 1-6 alkyl, 5-10 membered heteroaryl substituted by one or more R 5-k , or C 6-10 aryl substituted by one or more R 5-j ; 每个R5-k和R5-j各自独立地为C1-6烷基、氰基、氘代C1-6烷基、-O-C1-6烷基或被一个或多个R5b’取代的-O-C1-6烷基；Each R 5-k and R 5-j is independently C 1-6 alkyl, cyano, deuterated C 1-6 alkyl, -OC 1-6 alkyl, or -OC 1-6 alkyl substituted with one or more R 5b' ; 每个R5b’独立地为-O-C1-6烷基；Each R 5b' is independently -OC 1-6 alkyl; (15)R4B为氢、C1-6烷基或-N(R9)2，其中所述C1-6烷基独立地任选被一个或多个R4b取代；(15) R 4B is hydrogen, C 1-6 alkyl or -N(R 9 ) 2 , wherein the C 1-6 alkyl is independently optionally substituted by one or more R 4b ; 每个R4b独立地为氘、卤素、氰基、-NH2或羟基；each R 4b is independently deuterium, halogen, cyano, -NH 2 or hydroxyl; 每个R9独立地为氢或C1-6烷基；Each R 9 is independently hydrogen or C 1-6 alkyl; (16)R4B为氢、-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；(16) R 4B is hydrogen, -NH 2 or C 1-6 alkyl; the C 1-6 alkyl is independently optionally substituted by one or more R 4b ; 每个R4b为氘或氰基；或each R 4b is deuterium or cyano; or (17)R4B为-NH2或C1-6烷基；所述C1-6烷基独立地任选被一个或多个R4b取代；每个R4b为氘或氰基。(17) R 4B is -NH 2 or C 1-6 alkyl; the C 1-6 alkyl is independently optionally substituted by one or more R 4b ; each R 4b is deuterium or cyano. 如权利要求1-6中任一项所述的化合物或其药学上可接受的盐，其特征在于，所述如式I所示 的化合物为如下式(I-A)～(I-D)任一所示化合物：
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that the compound is as shown in Formula I The compound is a compound represented by any one of the following formulas (IA) to (ID):
优选地，所述如式I所示的化合物为如下式(I-E)～(I-H)任一所示化合物：
Preferably, the compound as shown in formula I is a compound shown in any one of the following formulas (IE) to (IH):
如权利要求1-7中任一项所述的化合物或其药学上可接受的盐，其特征在于，其满足以下条件的一个或多个：The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that it satisfies one or more of the following conditions: (1)各所述“C1-6烷基”分别独立地为C1-4烷基；例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基；(1) Each of the "C 1-6 alkyl" is independently a C 1-4 alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl; (2)各所述“C2-6炔基”分别独立地为C2-4炔基；例如乙炔基、丙炔基或炔丙基，优选为乙炔基；(2) Each of the "C 2-6 alkynyl" is independently a C 2-4 alkynyl; for example, ethynyl, propynyl or propargyl, preferably ethynyl; (3)各所述“C2-6烯基”分别独立地为乙烯基、1-丙烯基、正烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基或戊-1,4-二烯基；(3) Each of the “C 2-6 alkenyl” groups is independently vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl or pent-1,4-dienyl; (4)各所述“C3-12环烷基”分别独立地为C3-6单环环烷基(例如环丙基、环丁基、环戊基或环己基)或C4-10桥环环烷基(例如又例如)；(4) Each of the "C 3-12 cycloalkyl" is independently a C 3-6 monocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or a C 4-10 bridged ring cycloalkyl (e.g., Another example ); (5)各所述“C3-12环烯基”分别独立地为C3-6环烯基；例如环丙烯基、环丁烯基、环戊烯基或环己烯基；(5) Each of the “C 3-12 cycloalkenyl” is independently a C 3-6 cycloalkenyl; for example, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; (6)各所述“3-12元杂环烷基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数独立地为1个、2个或3个的3-12元杂环烷基，优选为4-6元单环杂环烷基、7-10元螺环杂环烷基或7-10元桥环杂环烷基；所述4-6元单环杂环烷基优选为吗啉基、哌啶基、哌嗪基、四氢吡喃基、四氢吡咯基、氧杂环丁烷基或氮杂环丁烷基，例如 所述7-10元螺环杂环烷基优选为6-氮杂螺[2.5]辛烷基或2-氮杂螺[3.3]庚烷基，例如所述7-10元桥环杂环烷基优选为8-氮杂双环[3.2.1]辛烷基或2-氧杂双环[2.2.2]辛烷基，例如 (6) Each of the “3-12 membered heterocycloalkyl” is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl or a 7-10 membered bridged heterocycloalkyl; the 4-6 membered monocyclic heterocycloalkyl is preferably morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetidinyl, for example The 7-10 membered spirocyclic heterocycloalkyl is preferably 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example The 7-10 membered bridged heterocycloalkyl is preferably 8-azabicyclo[3.2.1]octyl or 2-oxabicyclo[2.2.2]octyl, for example 较佳地，各所述“3-12元杂环烷基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数独立地为1个、2个或3个的3-12元杂环烷基，优选为4-6元单环杂环烷基、7-10元螺环杂环烷基或7-10元桥环杂环烷基；所述4-6元单环杂环烷基优选为吗啉基、哌啶基、哌嗪基、四氢吡喃基、四氢吡咯基、氧杂环丁烷基或氮杂环丁烷基，例如 所述7-10元螺环杂环烷基优选为6-氮杂螺[2.5]辛烷基或2-氮杂螺[3.3]庚烷基，例如所述7-10元桥环杂环烷基优选为8-氮杂双环[3.2.1]辛烷基，例如 Preferably, each of the "3-12 membered heterocycloalkyl" is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2 or 3, preferably a 4-6 membered monocyclic heterocycloalkyl, a 7-10 membered spirocyclic heterocycloalkyl or a 7-10 membered bridged heterocycloalkyl; the 4-6 membered monocyclic heterocycloalkyl is preferably morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyrrolyl, oxetanyl or azetyl, for example The 7-10 membered spirocyclic heterocycloalkyl is preferably 6-azaspiro[2.5]octanyl or 2-azaspiro[3.3]heptyl, for example The 7-10 membered bridged heterocycloalkyl is preferably 8-azabicyclo[3.2.1]octanyl, for example (7)各所述“3-12元杂环烯基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个或3个的3-12元杂环烯基，优选为5-6元单环杂环烯基；所述5-6元单环杂环烯基优选为1,2,3,6-四氢吡啶基，例如 (7) Each of the “3- to 12-membered heterocycloalkenyl” is independently a 3- to 12-membered heterocycloalkenyl group having one, two or more heteroatoms independently selected from N, O and S, and the number of heteroatoms independently being 1, 2 or 3, preferably a 5- to 6-membered monocyclic heterocycloalkenyl group; the 5- to 6-membered monocyclic heterocycloalkenyl group is preferably a 1,2,3,6-tetrahydropyridyl group, for example (8)各所述“C6-10芳基”分别独立地为苯基或萘基；优选为苯基；(8) Each of the “C 6-10 aryl” groups is independently phenyl or naphthyl; preferably phenyl; (9)各所述“5-10元杂芳基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个或4个的5-10元杂芳基，优选为5-6元单环杂芳基或9-10元并环杂芳基；所述5-6元单环杂芳基优选为1H-四唑基、2H-四唑基、吡啶基、嘧啶基、吡唑基、噻吩基、1,2,4-恶二唑基、吡嗪基、哒嗪基、1,2,3-三唑基、1,3,4-噻二唑基、1,3,4-恶二唑基或 吡咯基，例如 所述9-10元并环杂芳基优选为喹啉基、喹唑啉基、吲哚基、1H-吡咯并[2,3-b]吡啶基、苯并[d][1,3]二氧杂环戊烯基、咪唑并[1,2-b]哒嗪基、吲唑基、1H-吡唑并[4,3-b]吡啶基、异吲哚啉基、[1,2,4]三唑并[4,3-b]哒嗪基或1,2,3,4-四氢异喹啉基，例如 (9) Each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group, wherein the heteroatom species is independently selected from one, two or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group or a 9-10 membered polycyclic heteroaryl group; the 5-6 membered monocyclic heteroaryl group is preferably a 1H-tetrazolyl group, a 2H-tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazolyl group, a thienyl group, a 1,2,4-oxadiazolyl group, a pyrazinyl group, a pyridazinyl group, a 1,2,3-triazolyl group, a 1,3,4-thiadiazolyl group, a 1,3,4-oxadiazolyl group or a Pyrrolyl, e.g. The 9-10 membered heteroaryl group is preferably quinolyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, [1,2,4]triazolo[4,3-b]pyridazinyl or 1,2,3,4-tetrahydroisoquinolyl, for example 较佳地，各所述“5-10元杂芳基”分别独立地为杂原子种类独立地选自N、O和S的一种、两种或多种，杂原子的个数各自独立地为1个、2个、3个或4个的5-10元杂芳基，优选为5-6元单环杂芳基或9-10元并环杂芳基；所述5-6元单环杂芳基优选为吡啶基、嘧啶基、吡唑基、噻吩基、1,2,4-恶二唑基、吡嗪基、哒嗪基、1,2,3-三唑基、1,3,4-噻二唑基、1,3,4-恶二唑基或吡咯基，例如 所述9-10元并环杂芳基优选为喹啉基、喹唑啉基、吲哚基、1H-吡咯并[2,3-b]吡啶基、苯并[d][1,3]二氧杂环戊烯基、咪唑并[1,2-b]哒嗪基、吲唑基、1H-吡唑并[4,3-b]吡啶基、异吲 哚啉基、[1,2,4]三唑并[4,3-b]哒嗪基或1,2,3,4-四氢异喹啉基，例如 Preferably, each of the “5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group whose heteroatom species is independently selected from one, two or more of N, O and S, and whose number of heteroatoms is independently 1, 2, 3 or 4, preferably a 5-6 membered monocyclic heteroaryl group or a 9-10 membered polycyclic heteroaryl group; the 5-6 membered monocyclic heteroaryl group is preferably a pyridyl, pyrimidyl, pyrazolyl, thienyl, 1,2,4-oxadiazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or pyrrolyl, for example The 9-10 membered heteroaryl ring is preferably quinolyl, quinazolinyl, indolyl, 1H-pyrrolo[2,3-b]pyridinyl, benzo[d][1,3]dioxolyl, imidazo[1,2-b]pyridazinyl, indazolyl, 1H-pyrazolo[4,3-b]pyridinyl, isoindolyl, Indolyl, [1,2,4]triazolo[4,3-b]pyridazinyl or 1,2,3,4-tetrahydroisoquinolinyl, for example (10)各所述“卤素”分别独立地为氟、氯、溴或碘，例如氟或氯；(10) Each of the above “halogen” is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; (11)各所述“氘代C1-6烷基”分别独立地为氘代甲烷或氘代乙烷，例如-CD3；(11) Each of the "deuterated C 1-6 alkyl" is independently deuterated methane or deuterated ethane, for example -CD 3 ; 和(12)各所述“-O-C1-6烷基”分别独立地为-O-C1-4烷基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，优选甲氧基或乙氧基，更优选甲氧基。and (12) each of the "-OC 1-6 alkyl" is independently -OC 1-4 alkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy or ethoxy, more preferably methoxy. 如权利要求1-8中任一项所述的化合物或其药学上可接受的盐，其特征在于，其满足以下条件的一个或多个：The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, characterized in that it satisfies one or more of the following conditions: (1)R2和R3中，一个为H，另一个为甲基；(1) Of R2 and R3 , one is H and the other is methyl; (2)X为S，Y为CCH3或CCF3；(2) X is S, and Y is CCH 3 or CCF 3 ; (3)R4A为氢或甲基；(3) R 4A is hydrogen or methyl; (4)R4B为甲基、氨基、-CH2CN或-CD3，优选甲基或-CD3，更优选甲基；(4) R 4B is methyl, amino, -CH 2 CN or -CD 3 , preferably methyl or -CD 3 , more preferably methyl; (5)每个R5独立地为苯基、 (5) each R 5 is independently phenyl, 和(6)Cy2为 and (6)Cy 2 is 优选地，Preferably, Cy1为 Cy 1 is 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述如式I所示的化合物为如下任一化合物：






The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound as shown in Formula I is any of the following compounds:






优选地，所述如式I所示的化合物含有手性中心，所述如式I所示的化合物为各立体异构体或其混合物。Preferably, the compound as shown in formula I contains a chiral center, and the compound as shown in formula I is each stereoisomer or a mixture thereof. 如权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述如式I所示的化合物 为如下任一化合物：


The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound as shown in Formula I Any of the following compounds:


优选地，所述如式I所示的化合物为如下任一化合物：Preferably, the compound as shown in formula I is any of the following compounds: 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm； The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝40/60；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /methanol=40/60; Flow rate: 100 mL/min; Detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝40/60；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /methanol=40/60; Flow rate: 100 mL/min; Detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[甲醇:乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm； The compound that eluted later under the following conditions was One stereoisomer in: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35°C; mobile phase: CO 2 /[methanol:acetonitrile=1:1]=50/50; flow rate: 100 mL/min; detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/[乙醇(0.1％甲酸):乙腈＝1:1]＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /[ethanol (0.1% formic acid): acetonitrile = 1:1] = 50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /methanol=50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝50/50；流速:100mL/min；检测波长:214nm；The compound that eluted later under the following conditions was One stereoisomer in: Instrument: SFC-150 (Waters); Chiral column: AD 25*250 mm, 10 μm (Daicel); Column temperature: 35°C; Mobile phase: CO 2 /methanol=50/50; Flow rate: 100 mL/min; Detection wavelength: 214 nm; 在以下条件下后出峰的化合物，其为中的一个立体异构体：仪器:SFC-150(Waters)；手性柱:AD 25*250mm,10μm(Daicel)；柱温:35℃；流动相:CO2/甲醇＝50/50；流速:100mL/min；检测波长:214nm。The compound that eluted later under the following conditions was The following table describes the method for detecting one stereoisomer in the chromatogram: instrument: SFC-150 (Waters); chiral column: AD 25*250 mm, 10 μm (Daicel); column temperature: 35° C.; mobile phase: CO 2 /methanol=50/50; flow rate: 100 mL/min; detection wavelength: 214 nm. 如下式(I-1)～(I-4)任一项所示的化合物：
A compound represented by any one of the following formulas (I-1) to (I-4):
其中，R4A、R4B、X、Y如权利要求1-11中任一项所定义；wherein R 4A , R 4B , X, and Y are as defined in any one of claims 1 to 11; 优选地，各R4A可独立地为H或甲基；R4B可为甲基；X可为S；Y可为CR8，例如CCH3； Preferably, each R 4A may be independently H or methyl; R 4B may be methyl; X may be S; Y may be CR 8 , such as CCH 3 ; 进一步优选地，如式I-1所示的化合物为如式I-2所示的化合物为 如式I-3所示的化合物为如式I-4所示的化合物为 Further preferably, the compound as shown in formula I-1 is The compound shown in formula I-2 is The compound shown in formula I-3 is The compound shown in formula I-4 is 一种药物组合物，其包含物质A和药用辅料(或药学上可接受的载体)；所述的物质A为如权利要求1-11中任一项所述的化合物或其药学上可接受的盐；所述的物质A可为治疗有效量的。A pharmaceutical composition comprising substance A and a pharmaceutical excipient (or a pharmaceutically acceptable carrier); the substance A is a compound as described in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; the substance A may be in a therapeutically effective amount. 一种物质A或如权利要求13所述的药物组合物在制备PI3Kα抑制剂中的应用，所述的物质A为如权利要求1-11中任一项所述的化合物或其药学上可接受的盐；在所述的应用中，所述的PI3Kα抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为抑制PI3Kα的效果提供快速检测。A use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a PI3Kα inhibitor, wherein the substance A is a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; in the use, the PI3Kα inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting PI3Kα. 一种物质A或如权利要求13所述的药物组合物在制备药物中的应用，所述的药物用于治疗和/或预防与PI3Kα调节相关的疾病或障碍；所述的物质A为如权利要求1-11中任一项所述的化合物或其药学上可接受的盐；所述的物质A为治疗有效量的；所述与PI3Kα调节相关的疾病或障碍优选为癌症，例如子宫内膜癌、胃癌、白血病、淋巴瘤、肉瘤、结肠直肠癌、肺癌、卵巢癌、皮肤癌、头颈癌、乳腺癌、脑癌或前列腺癌。A use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a drug, wherein the drug is used to treat and/or prevent a disease or disorder related to PI3Kα regulation; the substance A is a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11; the substance A is a therapeutically effective amount; the disease or disorder related to PI3Kα regulation is preferably cancer, such as endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer. 一种物质A或如权利要求13所述的药物组合物在制备药物中的应用，所述的药物用于治疗和/或预防与PI3Kα调节相关的疾病或障碍；所述的物质A为如权利要求1-11中任一项所述的化合物或其药学上可接受的盐；所述的物质A为治疗有效量的；所述与PI3Kα调节相关的疾病或障碍优选为CLOVES综合征或PI3Kα有关的过度生长综合征。A use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a drug, wherein the drug is used to treat and/or prevent a disease or disorder related to PI3Kα regulation; the substance A is a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 11; the substance A is a therapeutically effective amount; the disease or disorder related to PI3Kα regulation is preferably CLOVES syndrome or PI3Kα-related overgrowth syndrome. 一种物质A或如权利要求13所述的药物组合物在制备药物中的应用，所述的药物用于治疗和/或预防癌症；所述癌症优选为子宫内膜癌、胃癌、白血病、淋巴瘤、肉瘤、结肠直肠癌、肺癌、卵巢癌、皮肤癌、头颈癌、乳腺癌、脑癌或前列腺癌；所述的物质A为如权利要求1-11中任一项所述的化合物或其药学上可接受的盐；所述的物质A为治疗有效量的。A use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a drug, wherein the drug is used to treat and/or prevent cancer; the cancer is preferably endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer; the substance A is a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof; the substance A is a therapeutically effective amount. 一种物质A或如权利要求13所述的药物组合物在制备药物中的应用，所述的药物用于治疗和/或预防CLOVES综合征或PI3Kα有关的过度生长综合征；所述的物质A为如权利要求1-11中任一项所述的化合物或其药学上可接受的盐；所述的物质A为治疗有效量的。A use of a substance A or a pharmaceutical composition as claimed in claim 13 in the preparation of a drug, wherein the drug is used to treat and/or prevent CLOVES syndrome or PI3Kα-related overgrowth syndrome; the substance A is a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11; the substance A is a therapeutically effective amount. 如权利要求14-16、18中任一项所述的应用，其特征在于，所述的PI3Kα为PI3Kα突变，优选为PI3KαH1047R突变或PI3KαE545K突变，更优选为PI3KαH1047R突变。 The use according to any one of claims 14-16 and 18, characterized in that the PI3Kα is a PI3Kα mutation, preferably a PI3Kα H1047R mutation or a PI3Kα E545K mutation, and more preferably a PI3Kα H1047R mutation.
PCT/CN2024/114185 2023-08-24 2024-08-23 Phosphoinositide 3-kinase allosteric inhibitor for treating disease related to pi3k regulation Pending WO2025040167A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202311078076 2023-08-24
CN202311078076.1 2023-08-24
CN202410354541 2024-03-26
CN202410354541.8 2024-03-26
CN202410650650.4 2024-05-23
CN202410650650 2024-05-23

Publications (1)

Publication Number Publication Date
WO2025040167A1 true WO2025040167A1 (en) 2025-02-27

Family

ID=94731414

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/114185 Pending WO2025040167A1 (en) 2023-08-24 2024-08-23 Phosphoinositide 3-kinase allosteric inhibitor for treating disease related to pi3k regulation

Country Status (1)

Country Link
WO (1) WO2025040167A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100310466A1 (en) * 2008-01-24 2010-12-09 Morales Guillermo A Thienopyranones as kinase inhibitors
US20150344494A1 (en) * 2014-05-05 2015-12-03 Signalrx Pharmaceuticals, Inc. Thienopyranones as Kinase and Epigenetic Inhibitors
CN105308034A (en) * 2013-06-14 2016-02-03 吉联亚科学公司 Phosphatidylinositol 3-kinase inhibitors
WO2022235574A1 (en) * 2021-05-03 2022-11-10 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (pi3k) for the treatment of disease
WO2023060262A1 (en) * 2021-10-07 2023-04-13 Relay Therapeutics, Inc. Pi3k-alpha inhibitors and methods of use thereof
WO2023081209A1 (en) * 2021-11-03 2023-05-11 Zeno Management, Inc. Pi3k inhibitors and methods of treating cancer
WO2023159155A1 (en) * 2022-02-18 2023-08-24 Pivalent Therapeutics, Inc. Inhibitors of phosphoinositide 3-kinase (pi3k) and uses thereof
CN116715658A (en) * 2022-03-07 2023-09-08 上海翰森生物医药科技有限公司 Benzocyclic ketone derivative regulators, preparation methods and applications thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100310466A1 (en) * 2008-01-24 2010-12-09 Morales Guillermo A Thienopyranones as kinase inhibitors
CN105308034A (en) * 2013-06-14 2016-02-03 吉联亚科学公司 Phosphatidylinositol 3-kinase inhibitors
US20150344494A1 (en) * 2014-05-05 2015-12-03 Signalrx Pharmaceuticals, Inc. Thienopyranones as Kinase and Epigenetic Inhibitors
WO2022235574A1 (en) * 2021-05-03 2022-11-10 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (pi3k) for the treatment of disease
WO2023060262A1 (en) * 2021-10-07 2023-04-13 Relay Therapeutics, Inc. Pi3k-alpha inhibitors and methods of use thereof
WO2023081209A1 (en) * 2021-11-03 2023-05-11 Zeno Management, Inc. Pi3k inhibitors and methods of treating cancer
WO2023159155A1 (en) * 2022-02-18 2023-08-24 Pivalent Therapeutics, Inc. Inhibitors of phosphoinositide 3-kinase (pi3k) and uses thereof
CN116715658A (en) * 2022-03-07 2023-09-08 上海翰森生物医药科技有限公司 Benzocyclic ketone derivative regulators, preparation methods and applications thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 15 November 2018 (2018-11-15), " Ethanone, 1-(4-bromo-3-hydroxy-5-methyl-2-thienyl)- (CA INDEX NAME)", XP093283382, Database accession no. 1782841-00-2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (en) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Ras inhibitors

Similar Documents

Publication Publication Date Title
CN104781255B (en) N-pyrrolidinyl, N'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TRKA kinase inhibitors
CN103038233B (en) Pyridone and azapyridone compounds and methods of use
TWI880923B (en) Phosphatidylinositol 3-kinase inhibitors
CN116648250B (en) Novel quinazoline derivatives as SOS1 inhibitors and their use
CN110891953B (en) Pyrrolotriazine derivatives, preparation method and use thereof
CN115551868A (en) Macrocyclic compounds and uses thereof
RS64285B1 (en) NAPHTHYRIDINONE COMPOUNDS USEFUL AS T CELL ACTIVATORS
WO2021143680A1 (en) Heteroaryl derivative, preparation method therefor, and use thereof
CN115626919A (en) Pyridazinyl thiazole carboxamides
CN111285886B (en) Substituted pyrazolo [1,5-a ] pyridine compounds, compositions comprising the same and uses thereof
WO2023025320A1 (en) Nitrogen-containing heterocyclic derivative inhibitor, and preparation method therefor and use thereof
CN107531690A (en) The amines of 4,5,6,7 tetrahydrochysene 1H pyrazolos [4,3 c] pyridine 3 as CBP and/or EP300 inhibitor
CN113490670B (en) Nitrogen-containing polycyclic condensed ring compound, pharmaceutical composition, preparation method and application thereof
CN110520416B (en) Polysubstituted pyridone derivative, preparation method and medical application thereof
CN114401955A (en) Inhibitors of cyclin dependent kinases
CN106414443B (en) Pyridopyrimidine dione derivative
WO2025040167A1 (en) Phosphoinositide 3-kinase allosteric inhibitor for treating disease related to pi3k regulation
TW202204351A (en) Compounds having a macrocyclic structure and uses thereof
WO2020233645A1 (en) Macrolide derivatives, preparation method and application thereof
CN115873000A (en) Isoquinolone and quinazolinone compounds, and composition and application thereof
KR20230054696A (en) Aromatic ring lactam compound, manufacturing method and use thereof
CN118439991B (en) A class of RBJ small molecule inhibitors
JP7721167B2 (en) 1H-Imidazo[4,5-H]quinazoline compounds as novel selective FLT3 inhibitors
HK40050421B (en) Nitrogen-containing polycyclic fused ring compounds, and pharmaceutical composition thereof, preparation method therefor and application thereof
HK40050421A (en) Nitrogen-containing polycyclic fused ring compounds, and pharmaceutical composition thereof, preparation method therefor and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24855888

Country of ref document: EP

Kind code of ref document: A1