WO2023143135A1 - Quinazoline derivative and use thereof - Google Patents

Quinazoline derivative and use thereof Download PDF

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Publication number
WO2023143135A1
WO2023143135A1 PCT/CN2023/072121 CN2023072121W WO2023143135A1 WO 2023143135 A1 WO2023143135 A1 WO 2023143135A1 CN 2023072121 W CN2023072121 W CN 2023072121W WO 2023143135 A1 WO2023143135 A1 WO 2023143135A1
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membered
alkyl
cycloalkyl
halogen
alkoxy
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PCT/CN2023/072121
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French (fr)
Chinese (zh)
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王豪
易韬
孟江
贾志强
胡凯
张耀
胡东杰
张毅
张晓东
王静
唐元清
唐军
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赛诺哈勃药业（成都）有限公司
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Publication of WO2023143135A1 publication Critical patent/WO2023143135A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a quinazoline derivative or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, and its use as a CDK9 and/or TNIK-mediated disease.
  • Wnt signaling pathway Aberrant activation of the Wnt signaling pathway has been found in various human cancers such as colorectal cancer, pancreatic cancer, non-small cell lung cancer, and prostate cancer.
  • About 90% of colorectal cancers have mutations in at least one Wnt pathway regulator, such as adenomatous polyposis coli (APC) and ⁇ -catenin (CTNNB1) genes, which allow ⁇ -catenin to accumulate and translocate intracellularly
  • Wnt pathway regulator such as adenomatous polyposis coli (APC) and ⁇ -catenin (CTNNB1) genes, which allow ⁇ -catenin to accumulate and translocate intracellularly
  • APC adenomatous polyposis coli
  • CNNB1 ⁇ -catenin
  • TNIK Traf2- and NCK-interacting protein kinase (TRAF2 and NCK-interacting protein kinase, TNIK) was identified as an important component of the Wnt target gene transcriptional regulatory complex, which acts in a ⁇ -catenin-dependent manner Directly interacts with TCF4 and activates TCF4/LEF-driven transcription of Wnt target genes by phosphorylating TCF4, leading to Wnt signaling in tumor cells.
  • TNIK plays an important role in activating the Wnt signaling pathway and maintaining the growth of colorectal cancer cells. Inhibition of TNIK is expected to block the abnormal conduction of Wnt signaling in colorectal cancer cells. It is speculated that TNIK may be A potential drug target for the treatment of colorectal cancer with abnormal Wnt signaling pathway.
  • Cyclin-dependent kinase 9 is a kind of serine/threonine protein kinase, which usually forms a heterodimeric complex with the corresponding cycle protein Cyclin in the cell to regulate the transcription of the cell process. More and more studies have shown that CDK9 is highly expressed in a variety of malignant tumors and is associated with poor prognosis of cancer.
  • the CDK9/Cyclin T1 complex specifically phosphorylates the negative elongation factor NELF (negative elongation factor) and the DRB sensitivity inducing factor DSIF ( DRB sensitivity-inducing factor) and the Ser2 residue at the end of the CTD of RNA polymerase II (RNA polymerase II, Pol II), activate and regulate cell proliferation, development, stress and other genes such as MYC, nuclear factor- ⁇ B (nuclear factor- ⁇ B, NF- ⁇ B) and MCL1 transcription elongation, promote tumorigenesis and progression.
  • RNA polymerase II RNA polymerase II
  • Inhibiting CDK9 can block the phosphorylation and activation of RNA Pol II by P-TEFb, inhibit transcription elongation, reduce the mRNA level of oncogenes such as MYC in cells, and at the same time down-regulate the expression of anti-apoptotic genes, prevent tumor cell proliferation, and induce tumor cell apoptosis. Death. Therefore, the specific regulatory role of CDK9 in the transcription process makes it one of the most potential anti-tumor targets in the CDK family.
  • WO2007117607 reports a quinazoline compound, the structure of which is directed against PDK1 inhibitors, and has never been shown to have an activity inhibitory effect on CDK9.
  • CDK9 drug research is scarce, most of which are non-selective inhibitors.
  • Representative drugs of common non-selective inhibitors of CDK9 include P276-00, SCH727965 or AT7519, etc.
  • Non-selective inhibitors have obvious effects during use. Toxic side effects such as neutropenia, thrombocytopenia, etc.
  • CN201380026183.8 discloses the use of bicyclic thiazole compounds as TNIK inhibitors.
  • CN201980015875.X reports the use of heterocyclic fusion phenyl compounds for TNIK inhibition.
  • quinazoline derivatives as TNIK inhibitors especially those related to the selective inhibition of TNIK targets and/or CDK9 targets, are rarely reported.
  • the present invention provides a quinazoline derivative or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer.
  • This type of compound can selectively inhibit CDK9 and/or TNIK, and has good enzymatic and cellular activity.
  • the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I):
  • Q is selected from 5-6-membered aryl, 5-6-membered substituted aryl, 5-6-membered heteroaryl or 5-6-membered substituted heteroaryl;
  • the 5-6-membered substituted aryl or 5-6-membered substituted heteroaryl each optionally has one or more substituents
  • the substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy , C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a or SF 5
  • R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4- 7-membered heterocycloalkyl, aryl or heteroaryl
  • R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4 -7-membered heterocycloalkyl, ary
  • heteroaryl 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl or 4 to 6 membered heterocycloalkyl, which have one or more heteroatoms, so said heteroatom is arbitrarily selected from N, O or S;
  • n 0, 1, 2 or 3;
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl;
  • B represents O, NH, S or CH2 ;
  • W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from: halogen, amino, hydroxyl, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy are each optionally replaced by a substituent selected from: halogen, amino, cyano or hydroxyl replace.
  • the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I), which has formula (Ia)
  • X 1 represents O or NR 8
  • R 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkane radical, aryl or heteroaryl; C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl , is further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
  • X 2 , X 3 , X 4 or X 5 are each independently selected from N or CR 9 , and R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkane group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or SF 5 ;
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl;
  • R 5 or R 6 are each independently selected from C 1 -C 3 alkyl, halogen, or alternatively R 5 and R 6 together with the carbon atom to which they are attached optionally form a 3- to 5-membered cycloalkyl group or a 4- to 5-membered cycloalkyl group.
  • 6-membered heterocycloalkyl wherein 3-5 membered cycloalkyl or 4-6 membered heterocycloalkyl can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, further substituted by a substituent selected from: halogen, amino, cyano or hydroxy; 4-6 membered heterocycloalkyl, its heteroatom selected from N, O or S;
  • R 7 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: halogen, amino , cyano or hydroxyl substituents;
  • B represents O, NH, S or CH2 ;
  • Z represents halogen, amino, hydroxyl, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each arbitrarily selected Substituted from: halogen, amino, cyano or hydroxyl substituents;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2.
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is substituted or unsubstituted phenyl, substituted or Unsubstituted 6-membered heteroaryl; its substituted phenyl or substituted 6-membered heteroaryl, the substituents of which are each arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3 - C7 Cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a or SF 5 ; R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4- 7-membered heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is a 6-membered heteroaryl group having Substituted or non-substituted structures:
  • substituent is optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a or SF 5 ;
  • R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4- 7-membered heterocycloalkyl, aryl or heteroaryl;
  • R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4 -7-membered heterocycloalkyl, aryl or heteroaryl;
  • R5 or R6 is selected from C1 - C3 alkyl, halogen, or alternatively R5 and R
  • the present invention relates to a compound of general formula (Ia) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, each of X 2 , X 3 , X 4 or X 5 independently CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy group or SF 5 ; or one of X 2 , X 3 , X 4 , X 5 is N, and the rest are CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkane Oxygen, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy
  • the present invention relates to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I),
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I),
  • R is selected from H, F, Cl, Br , CF 3 , CN, CH 3 , OCH 3 or cyclopropyl.
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (Ia), Z is 4-hydroxy, and n is 1.
  • the present invention relates to compounds of general formula (I) or (Ia), or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, m is 1 .
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula (I) or (Ia) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, and pharmaceutically acceptable excipients.
  • the present invention relates to compounds of general formula (I) or (Ia) or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions, which are prepared in Use in CDK9 and/or TNIK mediated diseases.
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions of general formula (I) or (Ia), wherein CDK9 and /or the TNIK-mediated disease is a hyperproliferative disease.
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions of general formula (I) or (Ia), wherein CDK9 and /or TNIK-mediated diseases are cancers, further solid tumors and/or hematological tumors.
  • the present invention relates to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, or pharmaceutical composition of the general formula (I) or (Ia) , wherein the cancer mediated by CDK9 and/or TNIK can be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neuroblastoma.
  • the cancer mediated by CDK9 and/or TNIK can be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymph
  • the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I):
  • Q is selected from 5-6-membered aryl, 5-6-membered substituted aryl, 5-6-membered heteroaryl or 5-6-membered substituted heteroaryl;
  • the 5-6-membered substituted aryl or 5-6-membered substituted heteroaryl each optionally has one or more substituents
  • the substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy , C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl Cycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl , C 1 -C
  • heteroaryl 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl, 4 to 6 membered heterocycloalkyl, 3-7 membered heterocycloalkyl or 3 -7-membered substituted heterocycloalkyl having one or more heteroatoms arbitrarily selected from N, O or S;
  • n 0, 1, 2 or 3;
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl base, 4-7 membered heterocycloalkyl; wherein 5-6 membered substituted heteroaryl, the substituents are randomly selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; wherein C 1 -C 6 substituted alkyl A group whose substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl;
  • B represents O, NH, S or CH2 ;
  • W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from: halogen, amino, hydroxyl, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy are each optionally replaced by a substituent selected from: halogen, amino, cyano or hydroxyl replace.
  • the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I), which has formula (Ia)
  • X 1 represents O or NR 8
  • R 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkane radical, aryl or heteroaryl; C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl , is further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
  • X 2 , X 3 , X 4 or X 5 are each independently selected from N or CR 9 , and R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkane base, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; where 3-7 membered heterocycloalkyl, whose substituents are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl Cycloalkyl having one or more heteroatoms arbitrarily selected from N, O or S;
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered Substituted heteroaryl, C 1 -C 6 substituted alkyl or 4-7 membered heterocycloalkyl; wherein 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, It has one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O or S; wherein 5-6 membered substituted heteroaryls, whose substituents are arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6
  • R or R are each independently selected from H, C 1 -C 3 alkyl, halogen, or alternatively R and R together with the carbon atom to which they are attached optionally form a 3- to 5 -membered cycloalkyl or 4 3-membered to 6-membered heterocycloalkyl; among them, 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl, which can be further replaced by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen Substitution; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; 4-6 membered heterocycloalkyl, which The heteroatom is selected from N, O or S;
  • R 7 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: halogen, amino , cyano or hydroxyl substituents;
  • B represents O, NH, S or CH2 ;
  • Z represents halogen, amino, hydroxyl, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each arbitrarily selected Substituted from: halogen, amino, cyano or hydroxyl substituents;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2.
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is substituted or unsubstituted phenyl, substituted or Unsubstituted 6-membered heteroaryl; its substituted phenyl or substituted 6-membered heteroaryl, the substituents of which are each arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3 - C7 Cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl Cycloalkyl, whose substituent is selected from C 1 -C 6
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is a 6-membered heteroaryl group having Substituted or non-substituted structures:
  • substituent is optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; wherein the 3-7 membered heterocycloalkyl has one or more heterocycloalkyl Atom, wherein the heteroatom is arbitrarily selected from N, O or S; Ra is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 Member heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7
  • the present invention relates to a compound of general formula (Ia) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, each of X 2 , X 3 , X 4 or X 5 independently CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl, the substituents are selected from From C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein 3-7 membered heterocycloalkyl or 3-7 membered substituted substituted
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl or 4-7 membered heterocycloalkyl; where 5- 6-membered heteroaryl, 5-6-membered substituted heteroaryl or 4-7-membered heterocycloalkyl, which has one or more heteroatoms, and its heteroatoms are arbitrarily selected from N, O or S; wherein 5-6 Substituted heteroaryl, whose substitus, a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I),
  • R is selected from H, halogen, cyano , amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 6 substituted alkyl or 6-membered heteroaryl; wherein C 1 -C 6 substituted alkyl, whose substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl; Wherein the 6-membered heteroaryl group is selected from the following substituted or unsubstituted structures:
  • 6-membered heteroaryl substituent is arbitrarily selected from CH 3 , C 2 H 6 .
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I),
  • R is selected from H, F, Cl, Br , CF 3 , CN, CH 3 , OCH 3 , cyclopropyl, CH 2 CN or
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (Ia), Z is 4-hydroxy, and n is 1.
  • the present invention relates to compounds of general formula (I) or (Ia), or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, m is 1 .
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula (I) or (Ia) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, and pharmaceutically acceptable excipients.
  • the present invention relates to compounds of general formula (I) or (Ia) or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions, which are prepared in Use in CDK9 and/or TNIK mediated diseases.
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions of general formula (I) or (Ia), wherein CDK9 and /or the TNIK-mediated disease is a hyperproliferative disease.
  • the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions of general formula (I) or (Ia), wherein CDK9 and /or TNIK-mediated diseases are cancers, further solid tumors and/or hematological tumors.
  • the present invention relates to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, or pharmaceutical composition of the general formula (I) or (Ia) , wherein the cancer mediated by CDK9 and/or TNIK can be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neuroblastoma.
  • the cancer mediated by CDK9 and/or TNIK can be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymph
  • the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I):
  • Q is selected from 5-6-membered aryl, 5-6-membered substituted aryl, 5-6-membered heteroaryl or 5-6-membered substituted heteroaryl;
  • Each of the 5-6-membered substituted aryl or the 5-6-membered substituted heteroaryl optionally has one or more substituents, wherein the substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy , C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl Cycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkane radical,
  • heteroaryl 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl, 4 to 6 membered heterocycloalkyl or 3-7 membered heterocycloalkyl or 3 -7-membered substituted heterocycloalkyl having one or more heteroatoms arbitrarily selected from N, O or S;
  • n 0, 1, 2 or 3;
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl Base, 4-7 membered heterocycloalkyl; wherein 5-6 membered substituted heteroaryl, the substituents are arbitrarily selected from Halogen, amino, hydroxyl or C 1 -C 6 alkyl; C 1 -C 6 substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl;
  • B represents O, NH, S or CH2 ;
  • W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from: H, halogen, amino, hydroxyl, acetamido, haloalkane Base, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each arbitrarily selected from: halogen, amino, cyano Or substituted by a hydroxyl substituent.
  • the present invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I), which has formula (Ia)
  • X 1 represents O or NR 8
  • R 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkane base, aryl or heteroaryl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl The group is further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
  • X 2 , X 3 , X 4 or X 5 are each independently selected from N or CR 9 , and R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkane group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; 3 -7-membered substituted heterocycloalkyl, whose substituents are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; 3-7-membered heterocycloalkyl or 3-7-membered substituted heterocycloalkane A group having one or more heteroatoms arbitrarily selected from N, O or S;
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 substituted alkyl Base or 4-7 membered heterocycloalkyl; wherein 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, which has one or more heteroatoms, and its heteroatoms Arbitrarily selected from N, O or S; wherein 5-6 membered substituted heteroaryl, its substituents are arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; C 1
  • R or R are each independently selected from H, C 1 -C 3 alkyl, halogen, or alternatively R and R together with the carbon atom to which they are attached optionally form a 3- to 5 -membered cycloalkyl or 4 3-membered to 6-membered heterocycloalkyl; among them, 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl, which can be further replaced by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen Substitution; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; 4-6 membered heterocycloalkyl, which The heteroatom is selected from N, O or S;
  • R 7 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: halogen, amino, Substituted by cyano or hydroxyl substituents;
  • B represents O, NH, S or CH2 ;
  • Z represents H, halogen, amino, hydroxyl, acetamido, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy , each arbitrarily substituted by a substituent selected from: halogen, amino, cyano or hydroxyl;
  • r 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • n 0, 1 or 2.
  • the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or Tautomers, wherein Q is substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered heteroaryl; substituted phenyl or substituted 6-membered heteroaryl, each of which substituents are arbitrarily selected from halogen, cyano , amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl Cycloalkyl, whose substituent is selected from C
  • the present invention provides compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is a 6-membered heteroaryl group, which has the following substitutions or non-substituted constructs:
  • substituent is optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl has one or more heterocycloalkyl Atom, the heteroatom of which is arbitrarily selected from N, O or S; Ra is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 Member heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycl
  • the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer
  • X 2 , X 3 , X 4 or X 5 are each independently is CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, SF 5 , 3-7-membered cycloalkyl, 3-7-membered heterocycloalkyl or 3-7-membered substituted heterocycloalkyl; 3-7-membered substituted heterocycloalkyl, whose substituents are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; 3-7 membered heterocycloalkyl or 3-7 membered substituted hetero
  • the present invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I),
  • R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl , C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl or 4-7 membered heterocycloalkyl; 5-6 membered heteroaryl Base, 5-6-membered substituted heteroaryl or 4-7-membered heterocycloalkyl, which has one or more heteroatoms, and its heteroatoms are arbitrarily selected from N, O or S; 5-6-membered substituted heteroaryl , whose substituent
  • the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer
  • R is selected from H, halogen, cyano, amino, Hydroxy, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 - C 6 substituted alkyl or 6-membered heteroaryl; C 1 -C 6 substituted alkyl, whose substituents are optionally selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl; 6-membered heteroaryl
  • the group is selected from the following substituted or unsubstituted structures:
  • 6-membered heteroaryl substituent is arbitrarily selected from CH 3 , C 2 H 6 .
  • the present invention provides the compound of general formula (I) or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer, R is selected from H, F, Cl, Br, CF 3 , CN, CH 3 , OCH 3 , cyclopropyl, CH 2 CN or
  • the present invention provides the compound or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer of general formula (I), Z can be selected from H, acetamido, methyl or 4-hydroxy; n is 1; r is 0, 1 or 2.
  • the present invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer related to general formula (I), m is 1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, and a pharmaceutically acceptable Accepted excipients.
  • the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition, which is used in the preparation of CDK9 and/or or use in TNIK-mediated diseases.
  • the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition, wherein CDK9 and/or TNIK
  • the mediated disease is a hyperproliferative disease.
  • the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition, wherein CDK9 and/or TNIK
  • the mediated disease is cancer, further solid tumors and/or hematological tumors.
  • the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition, wherein CDK9 and/or TNIK
  • the mediated cancer may be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neuroblastoma.
  • Alkyl refers to an aliphatic hydrocarbon group and refers to a saturated hydrocarbon group.
  • the alkyl moiety may be straight-chain or branched-chain.
  • C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, such as an alkane having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms base.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-amyl, Hexyl, isohexyl, and groups are considered equivalents to any of the foregoing examples herein based on those skilled in the art and the teachings provided herein.
  • the alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, amino, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl group, amino group, halogen, sulfonyl group, sulfinyl group, phosphono group, etc.
  • ring refers to any covalently closed structure, including, for example, carbocycles (such as aryl or cycloalkyl), heterocycles (such as heteroaryl or heterocycloalkyl), aromatic groups (such as aryl or heterocycloalkyl), aryl), non-aromatic (such as cycloalkyl or heterocycloalkyl). Rings may be optionally substituted and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings.
  • the ring of the present application usually has 1-20 ring atoms, such as 1 ring atom, 2 ring atoms, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms ring atoms, 19 ring atoms or 20 ring atoms.
  • 1-20 ring atoms such as 1 ring atom, 2 ring atoms, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms ring atoms, 9 ring atoms, 10 ring atoms, 11
  • “Membrane” in the term means the number of skeleton atoms constituting the ring.
  • Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene;
  • typical 6-membered rings include, for example, cyclohexyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, etc. .
  • a ring containing a heteroatom in the skeleton atoms is a heterocyclic ring; an aromatic group containing a heteroatom is a heteroaryl group; a non-aromatic group containing a heteroatom is a heterocycloalkyl group.
  • heteroatom refers to an atom other than carbon or hydrogen.
  • One or more heteroatoms in the heterocycle of the present application may be independently selected from O, S, N, Si and P, but are not limited thereto.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • haloalkyl refers to an alkyl group in which at least one hydrogen is replaced by a halogen atom, such as CF 3 , (CH 2 )F, CHF 2 , CH 2 Br, CH 2 CF 3 and CH 2 CH 2 F.
  • haloalkoxy means that at least one hydrogen in an alkoxy group is replaced by a halogen atom, such as CH 3 OCH 2 F.
  • cycloalkyl refers to a saturated or partially unsaturated (containing one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system) cyclic hydrocarbon substituents containing 1-3 rings, It includes monocycloalkyl, bicycloalkyl and tricycloalkyl, which contain 3-20 carbon atoms that can form a ring, preferably 3-10 carbon atoms (ie 3-10 membered cycloalkyl, also known as C3-C10 cycloalkyl), such as 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms.
  • the cycloalkyl group is selected from monovalent cycloalkyl groups derived from the following rings:
  • cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
  • Heterocycloalkyl and “cycloheteroalkyl” are used interchangeably and refer to a saturated, nonaromatic, monocyclic ring containing one or more (eg, 1, 2, 3, or 4) heteroatoms , fused, bridged and spiro rings, wherein the heteroatoms can be N, O or S.
  • the heterocycloalkyl group can be 3-10-membered (for example, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, i.e. including 3, 4, 5, 6 , 7, 8, 9 or 10 ring atoms) monocyclic or bicyclic or tricyclic groups.
  • ring structure optional contain up to two oxo groups on carbon or sulfur ring members.
  • Typical heterocycloalkyl groups include, but are not limited to, monovalent radicals derived from the following rings:
  • heterocycloalkyl groups can also be represented by commonly understood structural formulas, for example
  • aryl refers to a monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having 6 to 14 carbon atoms (6 to 14 members) with a conjugated ⁇ -electron system
  • illustrative aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. Preferred is phenyl.
  • heteroaryl refers to a group containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms, 5 to 14 ring atoms (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14) heteroaromatic systems, wherein the heteroatom is selected from O, S or N.
  • ring atoms eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14
  • heteroaryl include the following entities in the form of appropriate bonding moieties:
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; preferably 5 or 6 membered, containing 1 to 3 heteroatoms; more preferably 6 membered heteroaryl, such as pyridyl, pyrimidinyl, pyridyl Azinyl, etc.
  • alkenyl refers to a straight chain, branched chain or cyclic hydrocarbon group containing 2 to 12 carbon atoms and having one or more double bonds.
  • C 2 -C 7 alkenyl refers to 2-7 carbon atoms, which can be vinyl with 2 carbon atoms, allyl with 3 carbon atoms, etc.
  • alkenyl groups can be terminal or non-terminal structures, and can be unsubstituted or substituted as described for alkyl or as described in the various examples provided herein. Included within this term are cis and trans isomers and mixtures thereof.
  • alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 12 carbon atoms in the chain and having one or more triple bonds. Alkynyl groups can be unsubstituted or substituted as described for alkyl groups or as described in the various examples provided herein.
  • substitution refers to one or more hydrogen atoms in the group, preferably up to 5 (such as 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms can be independently replaced by the corresponding number replaced by substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • each hydrogen atom in C1-C6 alkyl, 5-6 membered aryl, 5-6 membered heteroaryl is optionally independently substituted by C1-C6 alkyl
  • the alkyl may but It does not necessarily exist in any of the C1-C6 alkyl group, 5-6 membered aryl group, and 5-6 membered heteroaryl group by substituting the hydrogen atom of each alkyl group.
  • the "stereoisomer" mentioned in the present invention means that when the compound of the present invention contains one or more asymmetric centers, it can be used as racemate and racemic mixture, single enantiomer, diastereoisomer, etc. They exist as mixtures of enantiomers and as individual diastereoisomers.
  • the compounds of the present invention may have an asymmetric center and thus lead to the existence of two optical isomers.
  • the scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefinic double bonds, unless otherwise specified, the scope of the present invention includes cis-isomers and trans-isomers.
  • the compounds of the present invention may exist in the form of tautomers (one of functional group isomers) having different points of attachment of hydrogens by displacement of one or more double bonds, for example, the ketone and his enol forms are Keto-enol tautomers.
  • the individual tautomers and mixtures thereof are within the scope of the present invention.
  • Enantiomers of all compounds. Diastereoisomers, racemates, mesoisomers, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof, etc. are within the scope of the present invention .
  • compounds of the present invention is intended to cover compounds of general formula (I) as defined herein or any preferred or specific embodiment thereof (including compounds of formula (Ia) and example compounds), their stereoisomers , a pharmaceutically acceptable salt, tautomer or solvate.
  • pharmaceutically acceptable means approved or may be approved by the corresponding agency of each country, or listed in the generally accepted pharmacopoeia for use in animals, and more particularly in humans, or not when administered in appropriate amounts to animals, such as humans.
  • composition refers to the compound containing one or more formula (I), formula (Ia) or its stereoisomer, tautomer, pharmaceutically acceptable salt or solvate Compositions of substances, and carriers or excipients generally accepted in the art for delivering biologically active compounds to an organism, such as a human.
  • compositions of the present invention can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences 20th Edition.
  • the pharmaceutical composition of the present invention can be prepared by mixing the compound of the present invention or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients.
  • the preparation may further comprise the step of combining one or more other active ingredients with the compound of the present invention and one or more pharmaceutically acceptable excipients.
  • compositions provided depend on various factors, such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
  • Diluents such as glucose, lactose or mannitol
  • carriers pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents Floating agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, perfuming agents, flavoring agents, diluents, binders and other known additives.
  • compositions of the invention can be administered in standard manner.
  • suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ophthalmic, nasal, buccal or pulmonary (inhalation); wherein parenteral infusion includes intramuscular, intravenous, intraarterial , intraperitoneal or subcutaneous administration.
  • the compounds of the present invention can be formulated into tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments by methods known in the art , creams, drops, aerosols, dry powder injections and sterile injectable aqueous or oily solutions or suspensions.
  • the compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solutions, emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers according to conventional methods known in the art for preparing various dosage forms, Or be prepared together with pharmaceutically acceptable excipients into a commonly used pharmaceutically acceptable dosage form.
  • the size of the prophylactic or therapeutic dose of a compound of the invention will vary depending on a number of factors including the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 5000 mg per kg body weight per day, for example about 0.01 to about 1000 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 7000 mg/day, eg about 0.7 mg/day to about 1500 mg/day.
  • the content or dosage of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, Such as 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.; correspondingly, the pharmaceutical composition of the present invention will contain 0.05 to 99% w/w (percentage by weight), such as 0.05 to 80% w/w, such as 0.10 to 70% w/w, eg 0.10 to 50% w/w of the compound of the invention, all weight percentages being based on the total composition. It will be understood that it may be necessary to use dosages outside these limits in some cases.
  • the present invention also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but with one or more atoms replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, respectively. 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I and 36Cl, etc.
  • isotopically-labeled compounds of the disclosure are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3H) and carbon-14 (ie 14C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron emitting isotopes such as 15O, 13N, 11C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the disclosure can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (eg increased in vivo half-life or reduced dosage requirements), and thus in some cases It may be preferred, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • the present invention provides a class of compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers with the structural characteristics of the general formula (I). It is found through research that this type of structure can effectively inhibit CDK9-mediated and/or TNIK-mediated diseases, so as to prevent or treat CDK9- and/or TNIK-mediated related diseases.
  • Step 5 Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline
  • triphenylphosphine (10.4 g) was dissolved in tetrahydrofuran (150 mL), and diisopropyl azodicarboxylate (7.9 g) was added dropwise.
  • 2-chloro-8-hydroxyquinazoline (4.3g) and trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanol (6g) were dissolved in tetrahydrofuran solution (150 mL). Then the above two reaction solutions were mixed and reacted for half an hour. TLC and LCMS showed the reaction was complete. The reaction system was concentrated, and the obtained crude product was purified by column chromatography to obtain 4.0 g of the title compound.
  • Step 2 Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline
  • triphenylphosphine (10.2 g) was dissolved in anhydrous tetrahydrofuran (150 mL), and diisopropyl azodicarboxylate (7.9 g) was added slowly. Under nitrogen protection, 7-bromo-2-chloroquinazolin-8-ol (4.0g) and trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanol (6.0g) Soluble in tetrahydrofuran. Then the above two reaction solutions were mixed and reacted for 30 minutes Afterwards, TLC and LCMS showed that the reaction was complete. The reaction system was concentrated, and the obtained crude product was purified by column chromatography to obtain 5.0 g of the title compound.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 6.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • Step 1 Preparation of 8-fluoro-N-(3-((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazolin-2-amine
  • Step 2 8-(((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazoline - Preparation of 2-amine
  • Step 3 8-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)benzene base)-7-(trifluoromethyl)quinazolin-2-amine preparation
  • reaction solution was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.9 g of the title compound.
  • 2,7-dichloro-8-methoxyquinazoline (690mg) was dissolved in dry dichloromethane (20mL), and a solution of boron tribromide in dichloromethane (9mL, 1M) was added dropwise at 0°C, Move to room temperature overnight. TLC showed complete reaction of starting material. The reaction solution was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated brine (10 mL), respectively, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 600 mg of the title compound.
  • Step 5 Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline
  • reaction solution was quenched with water (20 mL), extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the crude product was purified by column chromatography to obtain 450 mg of the title compound.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • Step 3 Preparation of tert-butyl (2-((methylthio)methyl)pyridin-4-yl)carbamate
  • reaction solution was extracted four times with water and dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the obtained crude product was purified by column chromatography, and the obtained solid was washed with petroleum ether and dried to obtain 100 mg of the title compound.
  • Step 1 Preparation of 5-((tert-butoxycarbonyl)amino)nicotinic acid methyl ester
  • 5-aminonicotinic acid methyl ester (7.0g) was dissolved in dichloromethane (50mL), and triethylamine (13.0 mL), 4-dimethylaminopyridine (560 mg) and di-tert-butyl dicarbonate (12.0 g) to continue the reaction at room temperature. After stirring for 24 hours, the solvent was directly sucked dry, and the title compound (9.2 g) was obtained by silica gel column chromatography.
  • 2,5-difluorobenzoic acid (10.0 g) was placed in a round-bottomed flask, concentrated sulfuric acid (30 mL) was added in an ice-bath environment, and then a mixed liquid of concentrated sulfuric acid (9 mL) and concentrated nitric acid (9 mL) was added slowly and Stirring was continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, water was added, and then dichloromethane was extracted several times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of the title compound (10.0 g).
  • Methyl 3,6-difluoro-2-nitrobenzoate (8.5g) was dissolved in dry methanol (50mL) under nitrogen protection, and sodium methoxide (3.2g) was added slowly to continue the reaction at room temperature. After 12 hours, the reaction was monitored by TLC, and the reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and silica gel Separation by column chromatography gave the title compound (7.0 g).
  • Methyl 6-fluoro-3-methoxy-2-nitrobenzoate (6.0 g) was dissolved in tetrahydrofuran (50 mL), then sodium hydroxide (1.6 g) was added and the reaction was continued at room temperature. After 2 hours, the reaction was complete as monitored by TLC. Water was added, hydrochloric acid was added to adjust the pH ⁇ 3, and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (4.5 g).
  • Step 6 Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloro-5-fluoroquinazoline
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 2.
  • Step 5 Preparation of tert-butyl(3-((methylsulfinyl)methyl)phenyl)carbamate
  • tert-Butyl(3-((methylsulfinyl)methyl)phenyl)carbamate (100 mg) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (3.5 mL) was added at room temperature And continue to react at room temperature. After 2 hours, the reaction was monitored by LCMS to complete, and the solvent was directly dried to obtain the crude product. Dissolve the crude product in dichloromethane, add saturated aqueous sodium bicarbonate to adjust the aqueous layer to be alkaline, separate the organic phase, extract the aqueous phase with dichloromethane, combine, dry, filter and dry the solvent under reduced pressure, silica gel column chromatography The title compound (50 mg) was isolated.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 6.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • Step 1 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfinyl) ) methyl) phenyl) quinazoline-2-amine preparation
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • Step 2 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(1-methyl-1H-pyrazol-4-yl Preparation of )-N-(3-((methylsulfinyl)methyl)phenyl)quinazolin-2-amine
  • 6-bromo-8-methoxyquinazolin-2(1H)-one (2.0 g) was dissolved in phosphorus oxychloride (7.0 mL), and then heated to 120 ° C for 2 hours . Subsequently, the complete reaction of the raw materials was monitored by LCMS. The reaction solution was cooled to room temperature, concentrated to remove excess phosphorus oxychloride, and the residue was slowly added to an ice-water solution of saturated sodium bicarbonate, extracted four times with dichloromethane, and the organic phases were combined and anhydrous Dry over sodium sulfate, filter and concentrate, and the obtained crude product is purified by column chromatography to obtain the title compound (0.9 g).
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 14.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 21.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 41.
  • Step 1 Preparation of methyl 6-((tert-butoxycarbonyl)amino)picolinate
  • Step 3 Preparation of tert-butyl (6-(bromomethyl)pyridin-2-yl)carbamate
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 21.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 28.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 41.
  • Step 1 Preparation of 8-fluoro-N-(2-((methylthio)methyl)pyridin-4-yl)-7-(trifluoromethyl)quinazolin-2-amine
  • Step 2 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(2-((methylthio)methyl)pyridine- Preparation of 4-yl)-7-(trifluoromethyl)quinazolin-2-amine
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 53.
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 54.
  • Step 2 Preparation of 7-bromo-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine
  • Step 3 Preparation of 7-cyano-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine
  • the compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 25.
  • Step 1 (rac)-8-((cis-4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((S-methyl Preparation of sulfonylimido)methyl)phenyl)quinazolin-2-amine
  • Step 2 (rac)-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonimido)methyl)phenyl)quinone Preparation of oxazolin-2-amine
  • Step 1 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl) Preparation of methyl)phenyl)quinazolin-2-amine
  • Step 2 7-Bromo-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonyl)methyl)phenyl)quinazoline-2- Amine preparation
  • Step 1 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methylsulfonyl Preparation of amino)methyl)pyridin-4-yl)quinazolin-2-amine (isomers 13-1 and 13-2)
  • reaction solution was quenched by adding 5% aqueous sodium thiosulfate solution (10 mL), extracted with ethyl acetate (3*15 mL), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the crude product was purified by column chromatography to obtain 60 mg of the title compound.
  • the title compound was separated into the enantiomers by chiral preparative HPLC.
  • Step 1 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)benzene Base)-7-vinylquinazolin-2-amine preparation
  • Step 2 8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl)-7-vinylquinazolin-2-amine preparation of
  • Step 1 (rac)-7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-( Preparation of (S-methylsulfonylimido)methyl)phenyl)quinazolin-2-amine
  • Step 1 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-carbaldehyde-N-(3-((methylsulfonyl ) methyl) phenyl) quinazoline-2-amine preparation
  • reaction was quenched by adding water and aqueous sodium thiosulfate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography to obtain the title compound (150 mg).
  • Step 2 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-ethynyl-N-(3-((methylsulfonyl ) methyl) phenyl) quinazoline-2-amine preparation
  • Step 3 8-((cis-4-hydroxycyclohexyl)oxy)-7-ethynyl-N-(3-((methylsulfonyl)methyl)phenyl)quinazolin-2-amine preparation of
  • Step 1 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(isoxazol-4-yl)-N-(3 Preparation of -((methylsulfonyl)methyl)phenyl)quinazolin-2-amine
  • Step 2 2-(8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-((3-((methylsulfonyl) Preparation of methyl)phenyl)amino)quinazolin-7-yl)acetonitrile
  • Step 3 2-(8-((cis-4-hydroxycyclohexyl)oxy)-2-((3-((methylsulfonyl)methyl)phenyl)amino)quinazoline-7- base) the preparation of acetonitrile
  • Step 1 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(3-((methylsulfonyl) Preparation of methyl)phenyl)quinazolin-2-amine
  • Step 2 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(3-((methylsulfonyl)methyl)phenyl)quinazolin-2-amine preparation
  • Step 3 4-((7-Chloro-2-((3-((methylsulfonyl)methyl)phenyl)amino)quinazolin-8-yl)oxy)cyclohexane-1-one preparation of
  • Step 4 7-Chloro-8-((4-hydroxy-4-methylcyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl)quinazoline-2- Amine preparation
  • Test example 1 TNIK enzymatic activity test
  • the IC 50 value of the test compound against TNIK was detected by ADP-Glo Kinase Assay.
  • the initial concentration of the compound test is 1 ⁇ M
  • the 3-fold serial dilution is made into 10 concentration points.
  • the dose response-Variable slope of the analysis software GraphPad Prism 6 was used to fit the dose-effect curve, thereby obtaining the IC50 value of each compound on the enzyme activity.
  • Example number IC50(nM) Example number IC50(nM) 1 11.73 2 23.75 3 37.37 4 75.09 5 25.04 6 15.16 7 9.95 8 31.67 9 39.10 10 38.67 12 7.88 13 84.53 14 73.45 16 60.32 17 83.41 18 19.68 19 7.01 20 24.61
  • Test Example 2 CDK9/CycT1 enzymatic activity test
  • the IC 50 value of the test compound against CDK9/CycT1 was detected by Mobility shift assay.
  • the initial concentration of the compound test is 1 ⁇ M
  • the 3-fold serial dilution is made into 10 concentration points.
  • reaction mixture solution (containing 26.67 ⁇ M ATP, 16.67 mM MgCl 2 and 5 ⁇ M Peptide CTD3) with an enzyme buffer, add 15 ⁇ L of the reaction mixture solution to the test compound well and the negative control well respectively, start the reaction, and centrifuge at 1000 rpm for 30 seconds. Shake to mix and incubate at room temperature for 120 minutes. Then, 30 ⁇ L of stop reaction solution (BIOMOL Green TM Reagent, Enzo lifesciences, Cat. No. BML-AK111-1000) was added to stop the kinase reaction, centrifuged at 1000 rpm for 30 seconds, and vortexed to mix. The conversion rate was read with a microplate reader (Perkin Elmer, model Caliper EZ Reader II), and the data was processed.
  • stop reaction solution (BIOMOL Green TM Reagent, Enzo lifesciences, Cat. No. BML-AK111-1000) was added to stop the kinase reaction, centrifuged at 1000 r
  • the log (inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-effect curve to obtain the effect of each compound on the enzyme.
  • the IC50 value of the activity is used to fit the dose-effect curve to obtain the effect of each compound on the enzyme.
  • Example number IC50(nM) Example number IC50(nM) 1 68 2 1.3 3 17.9 4 12.5 5 1.8 6 1.3 7 1.63 8 1.12 9 1.1 10 1.21 11 5.39 12 1.07 13 1.10 14 1.23 16 1.12 17 1.39 18 0.84 19 1.45 20 1.46 twenty one 0.8 twenty two 2.0 twenty four 0.77 26 0.96 27 1.2 28 0.85 29 0.36 32 0.53 33 0.34 34 0.50 35 1.7 36 1.22 37 0.99 38 0.68 40 1.49 41 0.98 42 0.76 43 63.1 45 3.76 46 1.42 47 1.08 48 0.87 49 1.31(A)/1.46(B)
  • Test example 3 HCT116 cell (source: Nanjing Kebai Biotechnology Co., Ltd.) activity inhibition test
  • the IC50 value of the test compound on HCT116 cell proliferation inhibition was detected by CellTiter-Glo luminescent living cell detection system.
  • the specific steps are: on the first day, trypsinize the cells in the logarithmic growth phase, and resuspend the cells in McCoy's 5A medium (Sigma, product number M9309) containing 10% FBS (PAN, product number ST30-3302) to a suitable density, mixed Mix evenly, add 100 ⁇ L per well into a 96-well plate, the cell density is 3000-5000 cells per well, and grow overnight at 37°C in a 5% CO2 incubator to make it adhere to the wall.
  • McCoy's 5A medium Sigma, product number M9309
  • FBS PAN, product number ST30-3302
  • test compound was diluted to 2 mM from the 10 mM stock solution with DMSO, then 3.33 times and 3 times cross-gradient dilution to 8 concentration points (200 ⁇ ), and then the compound was diluted to 2 ⁇ with complete medium, adding Put 100 ⁇ L of complete medium containing 2 ⁇ compounds into a 96-well plate (making the test initial concentration 10 ⁇ M, DMSO content 0.5%), and incubate at 37° C. in a 5% CO 2 incubator for 3 days. On the 5th day, remove the compound-treated cells and equilibrate to room temperature, leave 50 ⁇ L of supernatant in each well, then add 50 ⁇ L of CellTiter-Glo (Promega, Cat. No. G7571) reagent, shake at room temperature for 5 minutes to fully lyse the cells, and then let stand 5 minutes, microplate reader (BMG, model FSX) detects Luminescence signal and processes data.
  • BMG model FSX
  • %cell viability Signal compound/Signal negative control ⁇ 100.
  • Example number IC50(nM) Example number IC50(nM) 1 148.4 2 15.15 3 262.4 4 273.8 5 31.24 6 20.8 7 14.2 8 16.09 9 16.5 10 21.7 11 643.7 12 73.5 13 41.3 14 32.97 16 39 17 10.2 18 1.9 19 40.8 20 22.8 twenty one 12.3 twenty two 174.2 twenty four 36 26 34.6 27 32.8 28 36.6 29 30.4 30 556.5 31 206.3 32 137.6 33 41.7 34 45.7 35 39.3 36 45.9 37 12.3 38 12.1 40 139.6 41 10.2 42 38.9 45 632.4 46 405.5 47 42.4 48 2.7 49 41.6(A)/45.5(B) the the

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Abstract

Provided are a quinazoline derivative represented by general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer. The compound can selectively inhibit CDK9 and/or TNIK.

Description

一种喹唑啉衍生物及其用途A kind of quinazoline derivative and its application 技术领域technical field
本发明涉及一种喹唑啉衍生物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，以及其作为CDK9和/或TNIK介导疾病中的用途。The present invention relates to a quinazoline derivative or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, and its use as a CDK9 and/or TNIK-mediated disease.
背景技术Background technique
Wnt信号通路的异常激活在结直肠癌、胰腺癌、非小细胞肺癌、前列腺癌等多种人类癌症中发现。约有90％的结直肠癌存在至少一个Wnt通路调节因子的突变，如腺瘤性大肠息肉病(APC)和β-catenin(CTNNB1)基因，这些突变使得β-catenin在胞内积累并易位到细胞核，刺激TCF4/LEF家族转录因子激活大量参与肠上皮细胞增殖、分化和死亡的基因，如MYC、CCND1、AXIN、JUN等，驱动肿瘤的发生和发展。因而抑制Wnt通路的异常激活是治疗结直肠癌的有效策略。在经典的Wnt通路中，Traf2-和NCK-相互作用激酶(TRAF2 and NCK-interacting protein kinase，TNIK)被鉴定为Wnt靶基因转录调控复合物的重要组成部分，其以依赖于β-catenin的方式与TCF4直接相互作用，通过磷酸化TCF4激活TCF4/LEF驱动的Wnt靶基因转录，导致Wnt信号在肿瘤细胞内传导。作为Wnt通路的最下游转录调控因子，TNIK对于激活Wnt信号通路和维持结直肠癌细胞生长都起着重要作用，抑制TNIK有望阻断Wnt信号在结直肠癌细胞中的异常传导，推测TNIK可能是治疗Wnt信号通路异常的结直肠癌的潜在药物靶点。Aberrant activation of the Wnt signaling pathway has been found in various human cancers such as colorectal cancer, pancreatic cancer, non-small cell lung cancer, and prostate cancer. About 90% of colorectal cancers have mutations in at least one Wnt pathway regulator, such as adenomatous polyposis coli (APC) and β-catenin (CTNNB1) genes, which allow β-catenin to accumulate and translocate intracellularly To the nucleus, stimulate TCF4/LEF family transcription factors to activate a large number of genes involved in the proliferation, differentiation and death of intestinal epithelial cells, such as MYC, CCND1, AXIN, JUN, etc., to drive the occurrence and development of tumors. Therefore, inhibiting the abnormal activation of Wnt pathway is an effective strategy for the treatment of colorectal cancer. In the canonical Wnt pathway, Traf2- and NCK-interacting protein kinase (TRAF2 and NCK-interacting protein kinase, TNIK) was identified as an important component of the Wnt target gene transcriptional regulatory complex, which acts in a β-catenin-dependent manner Directly interacts with TCF4 and activates TCF4/LEF-driven transcription of Wnt target genes by phosphorylating TCF4, leading to Wnt signaling in tumor cells. As the most downstream transcriptional regulator of the Wnt pathway, TNIK plays an important role in activating the Wnt signaling pathway and maintaining the growth of colorectal cancer cells. Inhibition of TNIK is expected to block the abnormal conduction of Wnt signaling in colorectal cancer cells. It is speculated that TNIK may be A potential drug target for the treatment of colorectal cancer with abnormal Wnt signaling pathway.
细胞周期蛋白依赖性激酶9(Cyclin-dependent kinase 9，CDK9)是一类丝氨酸/苏氨酸蛋白激酶，它通常与细胞内相应的周期蛋白Cyclin形成异源二聚体复合物，调控细胞的转录进程。越来越多的研究表明，CDK9在多种恶性肿瘤中高表达，并且与癌症的预后不良有关。作为正性转录延伸因子P-TEFb(Positive transcription elongation factor b)的重要组成部分，CDK9/Cyclin T1复合物通过特异性磷酸化负向延伸因子NELF(negative elongation factor)、DRB敏感性诱导因子DSIF(DRB sensitivity-inducing factor)及RNA聚合酶Ⅱ(RNA polymerase II，Pol II)CTD末端的Ser2残基，激活调控细胞增殖、发育、应激等基因如MYC、核因子-κB(nuclear factor-κB,NF-κB)和MCL1的转录延伸，促进肿瘤的发生和发展。抑制CDK9能够阻断P-TEFb对RNA Pol II的磷酸化激活，抑制转录延伸，降低细胞内MYC等癌基因的mRNA水平，同时能够下调抗凋亡基因表达，阻止肿瘤细胞增殖，诱导肿瘤细胞凋亡。因而CDK9在转录过程中的特异性调控作用使它成为CDK家族中极具潜力的抗肿瘤靶点之一。Cyclin-dependent kinase 9 (CDK9) is a kind of serine/threonine protein kinase, which usually forms a heterodimeric complex with the corresponding cycle protein Cyclin in the cell to regulate the transcription of the cell process. More and more studies have shown that CDK9 is highly expressed in a variety of malignant tumors and is associated with poor prognosis of cancer. As an important part of the positive transcription elongation factor P-TEFb (Positive transcription elongation factor b), the CDK9/Cyclin T1 complex specifically phosphorylates the negative elongation factor NELF (negative elongation factor) and the DRB sensitivity inducing factor DSIF ( DRB sensitivity-inducing factor) and the Ser2 residue at the end of the CTD of RNA polymerase II (RNA polymerase II, Pol II), activate and regulate cell proliferation, development, stress and other genes such as MYC, nuclear factor-κB (nuclear factor-κB, NF-κB) and MCL1 transcription elongation, promote tumorigenesis and progression. Inhibiting CDK9 can block the phosphorylation and activation of RNA Pol II by P-TEFb, inhibit transcription elongation, reduce the mRNA level of oncogenes such as MYC in cells, and at the same time down-regulate the expression of anti-apoptotic genes, prevent tumor cell proliferation, and induce tumor cell apoptosis. Death. Therefore, the specific regulatory role of CDK9 in the transcription process makes it one of the most potential anti-tumor targets in the CDK family.
WO2007117607报道了一种喹唑啉化合物，该化合物结构针对PDK1抑制剂，未曾表明对CDK9存在活性抑制的效果。此外CDK9的药物研究稀缺，绝大多数为非选择性抑制剂，常见的CDK9的非选择性抑制剂的代表药物包括P276-00、SCH727965或AT7519等，非选择性抑制剂在使用过程中具有明显的毒副作用如中性粒细胞减少症、血小板减少症等。WO2007117607 reports a quinazoline compound, the structure of which is directed against PDK1 inhibitors, and has never been shown to have an activity inhibitory effect on CDK9. In addition, CDK9 drug research is scarce, most of which are non-selective inhibitors. Representative drugs of common non-selective inhibitors of CDK9 include P276-00, SCH727965 or AT7519, etc. Non-selective inhibitors have obvious effects during use. Toxic side effects such as neutropenia, thrombocytopenia, etc.
目前关于Wnt传导途径也有研究报道，CN201380026183.8公开二环噻唑类化合物作为TNIK抑制剂的用途，CN201980015875.X报道杂环融合苯基化合物用于TNIK抑制的用途，然而对于喹唑啉衍生物作为TNIK抑制剂，尤其是涉及选择性抑制TNIK靶点和/或CDK9靶点相关的研究鲜有报道。At present, there are also research reports on the Wnt conduction pathway. CN201380026183.8 discloses the use of bicyclic thiazole compounds as TNIK inhibitors. CN201980015875.X reports the use of heterocyclic fusion phenyl compounds for TNIK inhibition. However, for quinazoline derivatives as TNIK inhibitors, especially those related to the selective inhibition of TNIK targets and/or CDK9 targets, are rarely reported.
因此，研究开发出一类具有高活性且具有选择性抑制CDK9和/或TNIK靶点的抑制剂，是急需解决的技术难题。Therefore, it is an urgent technical problem to research and develop a class of inhibitors with high activity and selective inhibition of CDK9 and/or TNIK targets.
发明内容Contents of the invention
本发明提供了一种喹唑啉衍生物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，该类化合物可选择性抑制CDK9和/或TNIK，具有好的酶学和细胞活性。The present invention provides a quinazoline derivative or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer. This type of compound can selectively inhibit CDK9 and/or TNIK, and has good enzymatic and cellular activity.
主要通过以下的技术方案来实现。 It is mainly realized through the following technical solutions.
一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体：
In one aspect, the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I):
其中，in,
Q选自5-6元芳基、5-6元取代芳基、5-6元杂芳基或5-6元取代杂芳基；Q is selected from 5-6-membered aryl, 5-6-membered substituted aryl, 5-6-membered heteroaryl or 5-6-membered substituted heteroaryl;
其中5-6元取代芳基或5-6元取代杂芳基各自任选地具有一个或多个取代基，取代基任意地选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra或SF5；Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；R5或R6选自C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；其中C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:烷基、卤素、氨基、氰基或羟基的取代基所取代；Wherein the 5-6-membered substituted aryl or 5-6-membered substituted heteroaryl each optionally has one or more substituents, the substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy , C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a or SF 5 ; R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4- 7-membered heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4 -7-membered heterocycloalkyl, aryl or heteroaryl; R5 or R6 is selected from C1 - C3 alkyl, halogen, or alternatively R5 and R6 are optionally together with the carbon atom to which they are attached Form 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl; wherein 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl can be further replaced by C 1 -C 6 alkyl , C 1 -C 6 alkoxy or halogen substitution; wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aromatic A group or a heteroaryl group is further substituted by a substituent selected from: an alkyl group, a halogen group, an amino group, a cyano group or a hydroxyl group;
5-6元杂芳基、5-6元取代杂芳基、4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl or 4 to 6 membered heterocycloalkyl, which have one or more heteroatoms, so said heteroatom is arbitrarily selected from N, O or S;
m是0、1、2或3；m is 0, 1, 2 or 3;
R1、R2、R3或R4各自独立地选自H、卤素、氨基、羟基、氰基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基或C2-C7炔基；R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl;
B表示O、NH、S或CH2；B represents O, NH, S or CH2 ;
W表示5-7元的饱和环烷基，其中5-7元的饱和环烷基任选具有一个或多个取代基，取代基选自：卤素、氨基、羟基、卤代烷基、C1-C6烷基或C1-C6烷氧基；其中C1-C6烷基或C1-C6烷氧基，各自任意地被选自:卤素、氨基、氰基或羟基的取代基所取代。W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from: halogen, amino, hydroxyl, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy are each optionally replaced by a substituent selected from: halogen, amino, cyano or hydroxyl replace.
在一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其具有式(Ia)
In one aspect, the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I), which has formula (Ia)
其中，in,
X1表示O或NR8，R8选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:烷基、卤素、氨基、氰基或羟基的取代基所取代； X 1 represents O or NR 8 , R 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkane radical, aryl or heteroaryl; C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl , is further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
X2、X3、X4或X5各自独立地选自N或CR9，R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基或SF5；X 2 , X 3 , X 4 or X 5 are each independently selected from N or CR 9 , and R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkane group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or SF 5 ;
R1、R2、R3或R4各自独立地选自H、卤素、氨基、羟基、氰基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基或C2-C7炔基；R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl;
R5或R6各自独立选自C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基或C1-C6烷氧基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；4元到6元杂环烷基，其杂原子选自N、O或S；R 5 or R 6 are each independently selected from C 1 -C 3 alkyl, halogen, or alternatively R 5 and R 6 together with the carbon atom to which they are attached optionally form a 3- to 5-membered cycloalkyl group or a 4- to 5-membered cycloalkyl group. 6-membered heterocycloalkyl; wherein 3-5 membered cycloalkyl or 4-6 membered heterocycloalkyl can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, further substituted by a substituent selected from: halogen, amino, cyano or hydroxy; 4-6 membered heterocycloalkyl, its heteroatom selected from N, O or S;
R7选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；其中C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；R 7 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: halogen, amino , cyano or hydroxyl substituents;
B表示O、NH、S或CH2；B represents O, NH, S or CH2 ;
Z表示卤素、氨基、羟基、卤代烷基、C1-C6烷基或C1-C6烷氧基；C1-C6烷基或C1-C6烷氧基，各自任意地被选自:卤素、氨基、氰基或羟基的取代基所取代；Z represents halogen, amino, hydroxyl, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each arbitrarily selected Substituted from: halogen, amino, cyano or hydroxyl substituents;
m是0、1、2或3；m is 0, 1, 2 or 3;
n是0、1或2。n is 0, 1 or 2.
在一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其中Q为取代或非取代苯基、取代或非取代的6元杂芳基；其取代苯基或取代的6元杂芳基，其取代基各自任意选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra或SF5；Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；R5或R6选自C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；其中取代或非取代的6元杂芳基、4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；m是0、1、2或3。In one aspect, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is substituted or unsubstituted phenyl, substituted or Unsubstituted 6-membered heteroaryl; its substituted phenyl or substituted 6-membered heteroaryl, the substituents of which are each arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3 - C7 Cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a or SF 5 ; R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4- 7-membered heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4 -7-membered heterocycloalkyl, aryl or heteroaryl; R5 or R6 is selected from C1 - C3 alkyl, halogen, or alternatively R5 and R6 are optionally together with the carbon atom to which they are attached Form 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl; wherein 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl can be further replaced by C 1 -C 6 alkyl , C 1 -C 6 alkoxy or halogen substitution; C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl Or heteroaryl, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; wherein substituted or unsubstituted 6-membered heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl or 4-membered to 6-membered heterocycloalkyl, which has one or more heteroatoms, the heteroatoms of which are arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.
在一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其中Q为6元杂芳基，其具有以下取代或非取代的结构：
In one aspect, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is a 6-membered heteroaryl group having Substituted or non-substituted structures:
其取代基任意地选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra或SF5；Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；R5或R6选自C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂 环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；m是0、1、2或3。Its substituent is optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a or SF 5 ; R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4- 7-membered heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4 -7-membered heterocycloalkyl, aryl or heteroaryl; R5 or R6 is selected from C1 - C3 alkyl, halogen, or alternatively R5 and R6 are optionally together with the carbon atom to which they are attached Form 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered hetero Cycloalkyl; where 3- to 5-membered cycloalkyl or 4- to 6-membered heterocycloalkyl can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; C 1 - C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: halogen, amino, cyano Substituents of radicals or hydroxyl groups; 4-7 membered heterocycloalkyl groups, heteroaryl groups, or 4-membered to 6-membered heterocycloalkyl groups, which have one or more heteroatoms, and their heteroatoms are arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.
在另一方面，本发明涉及通式(Ia)化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，X2、X3、X4或X5各自独立地为CR9，其中R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基或SF5；或者X2、X3、X4、X5其中一个为N，其余为CR9，其中R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基或SF5；作为优选R9选自H、F、Cl、Br、CH3或OCH3。 In another aspect, the present invention relates to a compound of general formula (Ia) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, each of X 2 , X 3 , X 4 or X 5 independently CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy group or SF 5 ; or one of X 2 , X 3 , X 4 , X 5 is N, and the rest are CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkane Oxygen, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or SF 5 ; as preferred R 9 is selected from H, F, Cl, Br, CH 3 or OCH 3.
在另一方面，本发明涉及的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1、R2、R3或R4各自独立地选自H、卤素、氰基、氨基、羟基、卤代烷基、C3-C7环烷基、C1-C6烷基或C1-C6烷氧基。In another aspect, the present invention relates to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I), R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
在另一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1选自H、F、Cl、Br、CF3、CN、CH3、OCH3或环丙基。In another aspect, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), R is selected from H, F, Cl, Br , CF 3 , CN, CH 3 , OCH 3 or cyclopropyl.
在另一方面，本发明涉及通式(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，Z为4-羟基，n是1。In another aspect, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (Ia), Z is 4-hydroxy, and n is 1.
在另一方面，本发明涉及通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，m是1。In another aspect, the present invention relates to compounds of general formula (I) or (Ia), or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, m is 1 .
在其他方面，本发明涉及一种药物组合物，其包含通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，以及药物可接受的辅料。In other aspects, the present invention relates to a pharmaceutical composition comprising a compound of general formula (I) or (Ia) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, and pharmaceutically acceptable excipients.
在其他面，本发明涉及通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，或药物组合物，其在制备CDK9和/或TNIK介导疾病中的用途。In other aspects, the present invention relates to compounds of general formula (I) or (Ia) or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions, which are prepared in Use in CDK9 and/or TNIK mediated diseases.
在其他方面，本发明涉及通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导疾病为过度增生性疾病。In other aspects, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions of general formula (I) or (Ia), wherein CDK9 and /or the TNIK-mediated disease is a hyperproliferative disease.
在其他方面，本发明涉及通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导疾病为癌症，进一步地为实体瘤和/或血液瘤。In other aspects, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions of general formula (I) or (Ia), wherein CDK9 and /or TNIK-mediated diseases are cancers, further solid tumors and/or hematological tumors.
在另一方面，本发明涉及所述的通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导的癌症可选自乳腺癌、卵巢癌、肺癌、胃癌、胰腺癌、结直肠癌、非小细胞肺癌、前列腺癌、甲状腺癌、肝癌、急性髓细胞白血病、多发性骨髓瘤、慢性淋巴细胞性白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或神经细胞瘤等。In another aspect, the present invention relates to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, or pharmaceutical composition of the general formula (I) or (Ia) , wherein the cancer mediated by CDK9 and/or TNIK can be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neuroblastoma.
此外，本发明还可以通过以下技术方案来实现：In addition, the present invention can also be realized through the following technical solutions:
一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体：
In one aspect, the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I):
其中，in,
Q选自5-6元芳基、5-6元取代芳基、5-6元杂芳基或5-6元取代杂芳基； Q is selected from 5-6-membered aryl, 5-6-membered substituted aryl, 5-6-membered heteroaryl or 5-6-membered substituted heteroaryl;
其中5-6元取代芳基或5-6元取代杂芳基各自任选地具有一个或多个取代基，取代基任意地选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；其中3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；R5或R6选自C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；其中C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:烷基、卤素、氨基、氰基或羟基的取代基所取代；Wherein the 5-6-membered substituted aryl or 5-6-membered substituted heteroaryl each optionally has one or more substituents, the substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy , C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl Cycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl , C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano radical, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; R 5 or R 6 is selected from C 1 -C 3 alkyl, halogen, or alternatively R 5 and R together with the carbon atom to which it is attached optionally forms a 3-membered to 5-membered cycloalkyl group or a 4-membered to 6-membered heterocycloalkyl group; can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy Base, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
5-6元杂芳基、5-6元取代杂芳基、4-7元杂环烷基、杂芳基、4元到6元杂环烷基、3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl, 4 to 6 membered heterocycloalkyl, 3-7 membered heterocycloalkyl or 3 -7-membered substituted heterocycloalkyl having one or more heteroatoms arbitrarily selected from N, O or S;
m是0、1、2或3；m is 0, 1, 2 or 3;
R1、R2、R3或R4各自独立地选自H、卤素、氨基、羟基、氰基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、5-6元杂芳基、5-6元取代杂芳基、C1-C6取代烷基、4-7元杂环烷基；其中5-6元取代杂芳基，其取代基任意地选自卤素、氨基、羟基或C1-C6烷基；其中C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl base, 4-7 membered heterocycloalkyl; wherein 5-6 membered substituted heteroaryl, the substituents are randomly selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; wherein C 1 -C 6 substituted alkyl A group whose substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl;
B表示O、NH、S或CH2；B represents O, NH, S or CH2 ;
W表示5-7元的饱和环烷基，其中5-7元的饱和环烷基任选具有一个或多个取代基，取代基选自：卤素、氨基、羟基、卤代烷基、C1-C6烷基或C1-C6烷氧基；其中C1-C6烷基或C1-C6烷氧基，各自任意地被选自:卤素、氨基、氰基或羟基的取代基所取代。W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from: halogen, amino, hydroxyl, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy are each optionally replaced by a substituent selected from: halogen, amino, cyano or hydroxyl replace.
在一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其具有式(Ia)
In one aspect, the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I), which has formula (Ia)
其中，in,
X1表示O或NR8，R8选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:烷基、卤素、氨基、氰基或羟基的取代基所取代；X 1 represents O or NR 8 , R 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkane radical, aryl or heteroaryl; C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl , is further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
X2、X3、X4或X5各自独立地选自N或CR9，R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；其中3-7元取代杂环烷基,其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；其中3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；X 2 , X 3 , X 4 or X 5 are each independently selected from N or CR 9 , and R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkane base, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; where 3-7 membered heterocycloalkyl, whose substituents are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl Cycloalkyl having one or more heteroatoms arbitrarily selected from N, O or S;
R1、R2、R3或R4各自独立地选自H、卤素、氨基、羟基、氰基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、5-6元杂芳基、5-6元取 代杂芳基、C1-C6取代烷基或4-7元杂环烷基；其中5-6元杂芳基、5-6元取代杂芳基、4-7元杂环烷基，其具有一个或多个杂原子，其中杂原子任意地选自N、O或S；其中5-6元取代杂芳基，其取代基任意地选自卤素、氨基、羟基或C1-C6烷基；其中C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered Substituted heteroaryl, C 1 -C 6 substituted alkyl or 4-7 membered heterocycloalkyl; wherein 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, It has one or more heteroatoms, wherein the heteroatoms are arbitrarily selected from N, O or S; wherein 5-6 membered substituted heteroaryls, whose substituents are arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6 Alkyl; wherein C 1 -C 6 substituted alkyl, the substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl;
R5或R6各自独立选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基或C1-C6烷氧基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；4元到6元杂环烷基，其杂原子选自N、O或S；R or R are each independently selected from H, C 1 -C 3 alkyl, halogen, or alternatively R and R together with the carbon atom to which they are attached optionally form a 3- to 5 -membered cycloalkyl or 4 3-membered to 6-membered heterocycloalkyl; among them, 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl, which can be further replaced by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen Substitution; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; 4-6 membered heterocycloalkyl, which The heteroatom is selected from N, O or S;
R7选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；其中C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；R 7 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: halogen, amino , cyano or hydroxyl substituents;
B表示O、NH、S或CH2；B represents O, NH, S or CH2 ;
Z表示卤素、氨基、羟基、卤代烷基、C1-C6烷基或C1-C6烷氧基；C1-C6烷基或C1-C6烷氧基，各自任意地被选自:卤素、氨基、氰基或羟基的取代基所取代；Z represents halogen, amino, hydroxyl, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each arbitrarily selected Substituted from: halogen, amino, cyano or hydroxyl substituents;
m是0、1、2或3；m is 0, 1, 2 or 3;
n是0、1或2。n is 0, 1 or 2.
在一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其中Q为取代或非取代苯基、取代或非取代的6元杂芳基；其取代苯基或取代的6元杂芳基，其取代基各自任意选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；其中3-7元取代杂环烷基,其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；R5或R6选自C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；其中取代或非取代的6元杂芳基、3-7元杂环烷基、3-7元取代杂环烷基或4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；m是0、1、2或3。In one aspect, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is substituted or unsubstituted phenyl, substituted or Unsubstituted 6-membered heteroaryl; its substituted phenyl or substituted 6-membered heteroaryl, the substituents of which are each arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C3 - C7 Cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl Cycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl , C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano radical, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; R 5 or R 6 is selected from C 1 -C 3 alkyl, halogen, or alternatively R 5 and R together with the carbon atom to which it is attached optionally forms a 3-membered to 5-membered cycloalkyl group or a 4-membered to 6-membered heterocycloalkyl group; C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy , 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted by substituents selected from: halogen, amino, cyano or hydroxyl; wherein substituted or unsubstituted 6 membered heteroaryl, 3 -7-membered heterocycloalkyl, 3-7-membered substituted heterocycloalkyl or 4-7-membered heterocycloalkyl, heteroaryl or 4-6 membered heterocycloalkyl, which has one or more heteroatoms, Its heteroatoms are arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.
在一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其中Q为6元杂芳基，其具有以下取代或非取代的结构：
In one aspect, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is a 6-membered heteroaryl group having Substituted or non-substituted structures:
其取代基任意地选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基或3-7元杂环烷基；其中3-7元杂环烷基，其具有一个或多个杂原子，其中杂原子任意地选自N、O或S；Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；R5 或R6选自C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；m是0、1、2或3。Its substituent is optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; wherein the 3-7 membered heterocycloalkyl has one or more heterocycloalkyl Atom, wherein the heteroatom is arbitrarily selected from N, O or S; Ra is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 Member heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4- 7-membered heterocycloalkyl, aryl or heteroaryl; R 5 or R6 is selected from C1 - C3 alkyl, halogen, or alternatively R5 and R6 together with the carbon atom to which they are attached optionally form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocyclic ring Alkyl; where 3-5 membered cycloalkyl or 4-6 membered heterocycloalkyl can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: halogen, amino, cyano Or substituted by a substituent of hydroxyl group; 4-7 membered heterocycloalkyl, heteroaryl or 4-6 membered heterocycloalkyl, which has one or more heteroatoms, and its heteroatoms are arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.
在另一方面，本发明涉及通式(Ia)化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，X2、X3、X4或X5各自独立地为CR9，其中R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；其中3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；其中3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；或者X2、X3、X4、X5其中一个为N，其余为CR9，其中R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；其中3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；其中3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；作为优选R9选自H、F、Cl、Br、CH3、OCH3、 In another aspect, the present invention relates to a compound of general formula (Ia) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, each of X 2 , X 3 , X 4 or X 5 independently CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl, the substituents are selected from From C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl has one or more heteroatoms, which Heteroatoms are arbitrarily selected from N, O or S; or one of X 2 , X 3 , X 4 , and X 5 is N, and the rest are CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, Haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycle Alkyl or 3-7 membered substituted heterocycloalkyl; wherein 3-7 membered substituted heterocycloalkyl, whose substituents are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein 3 -7-membered heterocycloalkyl or 3-7-membered substituted heterocycloalkyl, which has one or more heteroatoms, whose heteroatoms are arbitrarily selected from N, O or S; as preferred R9 is selected from H, F, Cl, Br, CH 3 , OCH 3 ,
在另一方面，本发明涉及的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1、R2、R3或R4各自独立地选自H、卤素、氰基、氨基、羟基、卤代烷基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、5-6元杂芳基、5-6元取代杂芳基、C1-C6取代烷基或4-7元杂环烷基；其中5-6元杂芳基、5-6元取代杂芳基或4-7元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；其中5-6元取代杂芳基，其取代基任意地选自卤素、氨基、羟基或C1-C6烷基；其中C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基。In another aspect, the present invention relates to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I), R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl or 4-7 membered heterocycloalkyl; where 5- 6-membered heteroaryl, 5-6-membered substituted heteroaryl or 4-7-membered heterocycloalkyl, which has one or more heteroatoms, and its heteroatoms are arbitrarily selected from N, O or S; wherein 5-6 Substituted heteroaryl, whose substituents are arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; wherein C 1 -C 6 substituted alkyl, whose substituents are arbitrarily selected from halogen, amino, cyano , hydroxyl or C 3 -C 7 cycloalkyl.
在另一方面，本发明涉及的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1选自H、卤素、氰基、氨基、羟基、卤代烷基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、C1-C6取代烷基或6元杂芳基；其中C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；其中6元杂芳基，选自以下取代或非取代的结构：
In another aspect, the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I) that the present invention relates to, R is selected from H, halogen, cyano , amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 6 substituted alkyl or 6-membered heteroaryl; wherein C 1 -C 6 substituted alkyl, whose substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl; Wherein the 6-membered heteroaryl group is selected from the following substituted or unsubstituted structures:
其中6元杂芳基取代基任意的选自CH3、C2H6。Wherein the 6-membered heteroaryl substituent is arbitrarily selected from CH 3 , C 2 H 6 .
在另一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1选自H、F、Cl、Br、CF3、CN、CH3、OCH3、环丙基、CH2CN或 In another aspect, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), R is selected from H, F, Cl, Br , CF 3 , CN, CH 3 , OCH 3 , cyclopropyl, CH 2 CN or
在另一方面，本发明涉及通式(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，Z为4-羟基，n是1。In another aspect, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (Ia), Z is 4-hydroxy, and n is 1.
在另一方面，本发明涉及通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，m是1。In another aspect, the present invention relates to compounds of general formula (I) or (Ia), or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, m is 1 .
在其他方面，本发明涉及一种药物组合物，其包含通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，以及药物可接受的辅料。 In other aspects, the present invention relates to a pharmaceutical composition comprising a compound of general formula (I) or (Ia) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, and pharmaceutically acceptable excipients.
在其他面，本发明涉及通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，或药物组合物，其在制备CDK9和/或TNIK介导疾病中的用途。In other aspects, the present invention relates to compounds of general formula (I) or (Ia) or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions, which are prepared in Use in CDK9 and/or TNIK mediated diseases.
在其他方面，本发明涉及通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导疾病为过度增生性疾病。In other aspects, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions of general formula (I) or (Ia), wherein CDK9 and /or the TNIK-mediated disease is a hyperproliferative disease.
在其他方面，本发明涉及通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导疾病为癌症，进一步地为实体瘤和/或血液瘤。In other aspects, the present invention relates to compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers, or pharmaceutical compositions of general formula (I) or (Ia), wherein CDK9 and /or TNIK-mediated diseases are cancers, further solid tumors and/or hematological tumors.
在另一方面，本发明涉及所述的通式(I)或(Ia)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导的癌症可选自乳腺癌、卵巢癌、肺癌、胃癌、胰腺癌、结直肠癌、非小细胞肺癌、前列腺癌、甲状腺癌、肝癌、急性髓细胞白血病、多发性骨髓瘤、慢性淋巴细胞性白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或神经细胞瘤等。In another aspect, the present invention relates to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, or pharmaceutical composition of the general formula (I) or (Ia) , wherein the cancer mediated by CDK9 and/or TNIK can be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neuroblastoma.
此外，本发明也可以通过以下技术方案来实现：In addition, the present invention can also be realized through the following technical solutions:
一方面，本发明涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体：
In one aspect, the present invention relates to a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I):
其中，in,
Q选自5-6元芳基、5-6元取代芳基、5-6元杂芳基或5-6元取代杂芳基；Q is selected from 5-6-membered aryl, 5-6-membered substituted aryl, 5-6-membered heteroaryl or 5-6-membered substituted heteroaryl;
5-6元取代芳基或5-6元取代杂芳基各自任选地具有一个或多个取代基，其中取代基任意地选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；其中3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；其中Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；其中Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；其中R5或R6选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基、4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；其中C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:烷基、卤素、氨基、氰基或羟基的取代基所取代；Each of the 5-6-membered substituted aryl or the 5-6-membered substituted heteroaryl optionally has one or more substituents, wherein the substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy , C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl Cycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkane radical, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy , cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; wherein R 5 or R 6 is selected from H, C 1 -C 3 alkyl, halogen, or As an option, R5 and R6 together with the carbon atoms to which they are attached optionally form a 3-membered to 5-membered cycloalkyl group or a 4-membered to 6-membered heterocycloalkyl group; 6-membered heterocycloalkyl, which can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; wherein C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
5-6元杂芳基、5-6元取代杂芳基、4-7元杂环烷基、杂芳基、4元到6元杂环烷基或3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl, 4 to 6 membered heterocycloalkyl or 3-7 membered heterocycloalkyl or 3 -7-membered substituted heterocycloalkyl having one or more heteroatoms arbitrarily selected from N, O or S;
m是0、1、2或3；m is 0, 1, 2 or 3;
R1、R2、R3或R4各自独立地选自H、卤素、氨基、羟基、氰基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、5-6元杂芳基、5-6元取代杂芳基、C1-C6取代烷基、4-7元杂环烷基；其中5-6元取代杂芳基，其取代基任意地选自 卤素、氨基、羟基或C1-C6烷基；C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl Base, 4-7 membered heterocycloalkyl; wherein 5-6 membered substituted heteroaryl, the substituents are arbitrarily selected from Halogen, amino, hydroxyl or C 1 -C 6 alkyl; C 1 -C 6 substituted alkyl, the substituents of which are optionally selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl;
B表示O、NH、S或CH2；B represents O, NH, S or CH2 ;
W表示5-7元的饱和环烷基，其中5-7元的饱和环烷基任选具有一个或多个取代基，其取代基选自：H、卤素、氨基、羟基、乙酰氨基、卤代烷基、C1-C6烷基或C1-C6烷氧基；其中C1-C6烷基或C1-C6烷氧基，各自任意地被选自:卤素、氨基、氰基或羟基的取代基所取代。W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from: H, halogen, amino, hydroxyl, acetamido, haloalkane Base, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy, each arbitrarily selected from: halogen, amino, cyano Or substituted by a hydroxyl substituent.
一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其具有式(Ia)
In one aspect, the present invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I), which has formula (Ia)
其中，in,
X1表示O或NR8，R8选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；其中C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:烷基、卤素、氨基、氰基或羟基的取代基所取代；X 1 represents O or NR 8 , R 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkane base, aryl or heteroaryl; wherein C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl The group is further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
X2、X3、X4或X5各自独立地选自N或CR9，R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；3-7元取代杂环烷基,其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；X 2 , X 3 , X 4 or X 5 are each independently selected from N or CR 9 , and R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkane group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; 3 -7-membered substituted heterocycloalkyl, whose substituents are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; 3-7-membered heterocycloalkyl or 3-7-membered substituted heterocycloalkane A group having one or more heteroatoms arbitrarily selected from N, O or S;
R1、R2、R3或R4各自独立地选自H、卤素、氨基、羟基、氰基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基或C2-C7炔基、5-6元杂芳基、5-6元取代杂芳基、C1-C6取代烷基或4-7元杂环烷基；其中5-6元杂芳基、5-6元取代杂芳基、4-7元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；其中5-6元取代杂芳基，其取代基任意地选自卤素、氨基、羟基或C1-C6烷基；C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 substituted alkyl Base or 4-7 membered heterocycloalkyl; wherein 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, 4-7 membered heterocycloalkyl, which has one or more heteroatoms, and its heteroatoms Arbitrarily selected from N, O or S; wherein 5-6 membered substituted heteroaryl, its substituents are arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; C 1 -C 6 substituted alkyl, Its substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl;
R5或R6各自独立选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基或C1-C6烷氧基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；4元到6元杂环烷基，其杂原子选自N、O或S；R or R are each independently selected from H, C 1 -C 3 alkyl, halogen, or alternatively R and R together with the carbon atom to which they are attached optionally form a 3- to 5 -membered cycloalkyl or 4 3-membered to 6-membered heterocycloalkyl; among them, 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl, which can be further replaced by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen Substitution; C 1 -C 6 alkyl or C 1 -C 6 alkoxy, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; 4-6 membered heterocycloalkyl, which The heteroatom is selected from N, O or S;
R7选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；R 7 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: halogen, amino, Substituted by cyano or hydroxyl substituents;
B表示O、NH、S或CH2；B represents O, NH, S or CH2 ;
Z表示H、卤素、氨基、羟基、乙酰氨基、卤代烷基、C1-C6烷基或C1-C6烷氧基；其中C1-C6烷基或C1-C6烷氧基，各自任意地被选自:卤素、氨基、氰基或羟基的取代基所取代；Z represents H, halogen, amino, hydroxyl, acetamido, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; wherein C 1 -C 6 alkyl or C 1 -C 6 alkoxy , each arbitrarily substituted by a substituent selected from: halogen, amino, cyano or hydroxyl;
r是0、1、2或3；r is 0, 1, 2 or 3;
m是0、1、2或3；m is 0, 1, 2 or 3;
n是0、1或2。n is 0, 1 or 2.
一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或 互变异构体，其中Q为取代或非取代苯基、取代或非取代的6元杂芳基；取代苯基或取代的6元杂芳基，其取代基各自任意选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；其中3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；R5或R6选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；其中取代或非取代的6元杂芳基、3-7元杂环烷基、3-7元取代杂环烷基或4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；其中m是0、1、2或3。In one aspect, the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or Tautomers, wherein Q is substituted or unsubstituted phenyl, substituted or unsubstituted 6-membered heteroaryl; substituted phenyl or substituted 6-membered heteroaryl, each of which substituents are arbitrarily selected from halogen, cyano , amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl Cycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl , C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano radical, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; R 5 or R 6 is selected from H, C 1 -C 3 alkyl, halogen, or as an option R 5 and R together with the carbon atom to which they are attached optionally form a 3- to 5-membered cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; a 3- to 5-membered cycloalkyl group or a 4- to 6-membered heterocycle Alkyl, which can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy Base, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted by substituents selected from: halogen, amino, cyano or hydroxyl; wherein substituted or unsubstituted 6 membered heteroaryl, 3-7 membered heterocycloalkyl, 3-7 membered substituted heterocycloalkyl or 4-7 membered heterocycloalkyl, heteroaryl or 4- to 6-membered heterocycloalkyl having one or more heteroatoms , whose heteroatoms are arbitrarily selected from N, O or S; wherein m is 0, 1, 2 or 3.
一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其中Q为6元杂芳基，其具有以下取代或非取代的结构：
In one aspect, the present invention provides compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers of general formula (I), wherein Q is a 6-membered heteroaryl group, which has the following substitutions or non-substituted constructs:
其取代基任意地选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基、3-7元杂环烷基；其中3-7元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；R5或R6选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；其中3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；m是0、1、2或3。Its substituent is optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; wherein 3-7 membered heterocycloalkyl has one or more heterocycloalkyl Atom, the heteroatom of which is arbitrarily selected from N, O or S; Ra is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 Member heterocycloalkyl, aryl or heteroaryl; R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4- 7-membered heterocycloalkyl, aryl or heteroaryl; R5 or R6 is selected from H, C1 - C3 alkyl, halogen, or as an option R5 and R6 are optionally together with the carbon atom to which they are attached Form 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl; wherein 3-membered to 5-membered cycloalkyl or 4-membered to 6-membered heterocycloalkyl can be further replaced by C 1 -C 6 alkane C 1 -C 6 alkoxy or halogen substitution; C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl Base or heteroaryl, further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; 4-7 membered heterocycloalkyl, heteroaryl or 4 to 6 membered heterocycloalkyl, which Has one or more heteroatoms, the heteroatoms are arbitrarily selected from N, O or S; m is 0, 1, 2 or 3.
一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，X2、X3、X4或X5各自独立地为CR9，其中R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，杂原子任意地选自N、O或S；或者X2、X3、X4、X5其中一个为N，其余为CR9，其中R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，杂原子任意地选自N、O或S；作为优选R9选自H、F、Cl、Br、CH3、OCH3、 In one aspect, the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, X 2 , X 3 , X 4 or X 5 are each independently is CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, SF 5 , 3-7-membered cycloalkyl, 3-7-membered heterocycloalkyl or 3-7-membered substituted heterocycloalkyl; 3-7-membered substituted heterocycloalkyl, whose substituents are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl, which has one or more heteroatoms, the heteroatoms are optionally Selected from N, O or S; or one of X 2 , X 3 , X 4 , X 5 is N, and the rest are CR 9 , wherein R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkane Oxygen, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3 -7-membered substituted heterocycloalkyl; 3-7-membered substituted heterocycloalkyl, whose substituents are selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; 3-7-membered heterocycloalkane A group or a 3-7 membered substituted heterocycloalkyl group, which has one or more heteroatoms, and the heteroatoms are arbitrarily selected from N, O or S; as preferred R 9 is selected from H, F, Cl, Br, CH 3 , OCH 3 ,
一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1、R2、R3或R4各自独立地选自H、卤素、氰基、氨基、羟基、卤代烷基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、5-6元杂芳基、5-6元取代杂芳基、C1-C6取代烷基或4-7元杂环烷基；5-6元杂芳基、5-6元取代杂芳基或4-7元杂环烷基，其具有一个或多个杂原子，其杂原子任意地选自N、O或S；5-6元取代杂芳基，其取代基任意地选自卤素、氨基、羟基或C1-C6烷基；C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基。In one aspect, the present invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of general formula (I), R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl , C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl or 4-7 membered heterocycloalkyl; 5-6 membered heteroaryl Base, 5-6-membered substituted heteroaryl or 4-7-membered heterocycloalkyl, which has one or more heteroatoms, and its heteroatoms are arbitrarily selected from N, O or S; 5-6-membered substituted heteroaryl , whose substituents are arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; C 1 -C 6 substituted alkyl, whose substituents are arbitrarily selected from halogen, amino, cyano, hydroxy or C 3 - C 7 cycloalkyl.
一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1选自H、卤素、氰基、氨基、羟基、卤代烷基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、C1-C6取代烷基或6元杂芳基；C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；6元杂芳基，选自以下取代或非取代的结构：
In one aspect, the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, R is selected from H, halogen, cyano, amino, Hydroxy, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 - C 6 substituted alkyl or 6-membered heteroaryl; C 1 -C 6 substituted alkyl, whose substituents are optionally selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl; 6-membered heteroaryl The group is selected from the following substituted or unsubstituted structures:
其中6元杂芳基取代基任意的选自CH3、C2H6。Wherein the 6-membered heteroaryl substituent is arbitrarily selected from CH 3 , C 2 H 6 .
一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1选自H、F、Cl、Br、CF3、CN、CH3、OCH3、环丙基、CH2CN或 On the one hand, the present invention provides the compound of general formula (I) or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer, R is selected from H, F, Cl, Br, CF 3 , CN, CH 3 , OCH 3 , cyclopropyl, CH 2 CN or
一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，Z可任意选自H、乙酰氨基、甲基或4-羟基；n是1；r是0、1或2。On the one hand, the present invention provides the compound or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer of general formula (I), Z can be selected from H, acetamido, methyl or 4-hydroxy; n is 1; r is 0, 1 or 2.
一方面，本发明提供涉及通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，m是1。In one aspect, the present invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer related to general formula (I), m is 1.
在另一方面，本发明提供一种药物组合物，其包含通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，以及药物可接受的辅料。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, and a pharmaceutically acceptable Accepted excipients.
在另一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，或药物组合物，其在制备CDK9和/或TNIK介导疾病中的用途。In another aspect, the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition, which is used in the preparation of CDK9 and/or or use in TNIK-mediated diseases.
在另一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导疾病为过度增生性疾病。In another aspect, the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition, wherein CDK9 and/or TNIK The mediated disease is a hyperproliferative disease.
在另一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导疾病为癌症，进一步地为实体瘤和/或血液瘤。In another aspect, the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition, wherein CDK9 and/or TNIK The mediated disease is cancer, further solid tumors and/or hematological tumors.
在另一方面，本发明提供通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，其中CDK9和/或TNIK介导的癌症可选自乳腺癌、卵巢癌、肺癌、胃癌、胰腺癌、结直肠癌、非小细胞肺癌、前列腺癌、甲状腺癌、肝癌、急性髓细胞白血病、多发性骨髓瘤、慢性淋巴细胞性白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或神经细胞瘤。In another aspect, the present invention provides a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a tautomer, or a pharmaceutical composition, wherein CDK9 and/or TNIK The mediated cancer may be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neuroblastoma.
具体实施方式Detailed ways
在进一步描述本发明之前，应了解本发明并不限于所述的具体实施例，本文所使用的术语仅出于描述具体实施例的目的，并非对其加以限制，此外本发明的范围仅受限于所附权利要求书和说明书。除非另外定义，否则本文所用的所有技术和科学术语具有与本公开所属领域的所属领域的一般技术人员通常所理解相同的含义。Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described, the terms used herein are only for the purpose of describing specific embodiments, and are not intended to limit it, and the scope of the present invention is only limited in the appended claims and description. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
化学定义chemical definition
“烷基”是指脂肪族烃基团，指饱和烃基。烷基部分可以是直链烷基，亦可以是支链烷基。例如，C1-C6烷基、C1-C4烷基或C1-C3烷基。C1-C6烷基指具有1至6个碳原子的烷基，例如具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子的烷基。烷基的实例包括(但不限于)甲基、乙基、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、叔戊基、己基、异己基，以及和本文根据熟悉此项技术者和本文提供的教示将视为与前述实例中的任一者等效的基团。所述烷基可以是非取代的或被一个或多个取代基所取代，所述取代基包括但不限于烷基、烷氧基、氰基、氨基、羟基、羰基、羧基、芳基、杂芳基、胺基、卤素、磺酰基、亚磺酰基、膦酰基等。"Alkyl" refers to an aliphatic hydrocarbon group and refers to a saturated hydrocarbon group. The alkyl moiety may be straight-chain or branched-chain. For example, C1-C6 alkyl, C1-C4 alkyl or C1-C3 alkyl. C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms, such as an alkane having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms base. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-amyl, Hexyl, isohexyl, and groups are considered equivalents to any of the foregoing examples herein based on those skilled in the art and the teachings provided herein. The alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, amino, hydroxyl, carbonyl, carboxyl, aryl, heteroaryl group, amino group, halogen, sulfonyl group, sulfinyl group, phosphono group, etc.
术语中“环”是指任意的共价封闭结构，包括例如碳环(例如芳基或环烷基)、杂环(例如杂芳基或杂环烷基)、芳香基(如芳基或杂芳基)、非芳香基(如环烷基或杂环烷基)。环可以是任选取代的，可以是单环或多环。典型的多环一般包括二环、三环。本申请的环通常具有1-20个环原子，例如1个环原子、2个环原子、3个环原子、4个环原子、5个环原子、6个环原子、7个环原子、8个环原子、9个环原子、10个环原子、11个环原子、12个环原子、13个环原子、14个环原子、15个环原子、16个环原子、17个环原子、18个环原子、19个环原子或20个环原子。The term "ring" refers to any covalently closed structure, including, for example, carbocycles (such as aryl or cycloalkyl), heterocycles (such as heteroaryl or heterocycloalkyl), aromatic groups (such as aryl or heterocycloalkyl), aryl), non-aromatic (such as cycloalkyl or heterocycloalkyl). Rings may be optionally substituted and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings. The ring of the present application usually has 1-20 ring atoms, such as 1 ring atom, 2 ring atoms, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms ring atoms, 19 ring atoms or 20 ring atoms.
术语中“元”是表示构成环的骨架原子的个数。典型的5元环包括例如环戊基、吡咯、咪唑、噻唑、呋喃和噻吩等；典型的6元环包括例如环己基、吡啶、吡喃、吡嗪、噻喃、哒嗪、嘧啶、苯等。其中，骨架原子中含有杂原子的环，即为杂环；含有杂原子的芳香基为杂芳基；含有杂原子的非芳香性基团为杂环烷基。"Membrane" in the term means the number of skeleton atoms constituting the ring. Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, for example, cyclohexyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, etc. . Among them, a ring containing a heteroatom in the skeleton atoms is a heterocyclic ring; an aromatic group containing a heteroatom is a heteroaryl group; a non-aromatic group containing a heteroatom is a heterocycloalkyl group.
术语中“杂原子”是指除了碳或氢以外的原子。本申请的杂环中的一个或多个杂原子可独立地选自O、S、N、Si和P，但不限于此。The term "heteroatom" refers to an atom other than carbon or hydrogen. One or more heteroatoms in the heterocycle of the present application may be independently selected from O, S, N, Si and P, but are not limited thereto.
“4-羟基”表示羟基处于该基团的4号位置或对位位置。"4-Hydroxy" means that the hydroxyl group is at the 4th or para position of the group.
术语中“卤素”是指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语中“氰基”是指-CN。"Cyano" in the term refers to -CN.
术语中“羟基”是指-OH。"Hydroxy" in the term refers to -OH.
术语中“氨基”是指-NH2。The term "amino" refers to -NH2 .
术语中“卤代烷基”是指烷基中至少一个氢被卤素原子置换，例如CF3、(CH2)F、CHF2、CH2Br、CH2CF3和CH2CH2F。The term "haloalkyl" refers to an alkyl group in which at least one hydrogen is replaced by a halogen atom, such as CF 3 , (CH 2 )F, CHF 2 , CH 2 Br, CH 2 CF 3 and CH 2 CH 2 F.
术语中“卤代烷氧基”是指烷氧基中至少一个氢被卤素原子置换，例如CH3OCH2F。The term "haloalkoxy" means that at least one hydrogen in an alkoxy group is replaced by a halogen atom, such as CH 3 OCH 2 F.
术语中“环烷基”是指饱和或部分不饱和(包含一个或多个双键，但没有一个环具有完全共轭的π电子体系)的包含1-3个环的环状烃取代基，其包括单环烷基、双环烷基以及三环烷基，其包含3-20个可形成环的碳原子，优选3-10个碳原子(即3-10元环烷基，也可称为C3-C10环烷基)，例如3至8个，3至7个，3至6个，5至6个碳原子。优选地，环烷基选自由以下环得到的单价环烷基：
The term "cycloalkyl" refers to a saturated or partially unsaturated (containing one or more double bonds, but none of the rings have a fully conjugated π-electron system) cyclic hydrocarbon substituents containing 1-3 rings, It includes monocycloalkyl, bicycloalkyl and tricycloalkyl, which contain 3-20 carbon atoms that can form a ring, preferably 3-10 carbon atoms (ie 3-10 membered cycloalkyl, also known as C3-C10 cycloalkyl), such as 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Preferably, the cycloalkyl group is selected from monovalent cycloalkyl groups derived from the following rings:
更优选，环烷基选自环丙基、环丁基、环戊基、环己基、环庚基、环辛基。More preferably, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
“杂环烷基”和“环杂烷基”可互换使用，指饱和的非芳香性的含一个或多个(例如，1个、2个、3个或4个)杂原子的单环、稠合、桥环和螺环，其中所述杂原子可为N、O或S。杂环烷基可为3元至10元(例如，3元、4元、5元、6元、7元、8元、9元、10元，即包含3个、4个、5个、6个、7个、8个、9个或10个环原子)的单环或双环或三环基团。环结构可任选 地在碳或硫环成员上含有至多两个氧代基。"Heterocycloalkyl" and "cycloheteroalkyl" are used interchangeably and refer to a saturated, nonaromatic, monocyclic ring containing one or more (eg, 1, 2, 3, or 4) heteroatoms , fused, bridged and spiro rings, wherein the heteroatoms can be N, O or S. The heterocycloalkyl group can be 3-10-membered (for example, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, i.e. including 3, 4, 5, 6 , 7, 8, 9 or 10 ring atoms) monocyclic or bicyclic or tricyclic groups. ring structure optional contain up to two oxo groups on carbon or sulfur ring members.
典型的杂环烷基包括但不限于由以下环得到的单价基团：
Typical heterocycloalkyl groups include, but are not limited to, monovalent radicals derived from the following rings:
这些杂环烷基也可用通常理解的结构式方式表示，例如
These heterocycloalkyl groups can also be represented by commonly understood structural formulas, for example
优选饱和的非芳香性的含一个或多个杂原子的单环结构。Preference is given to saturated non-aromatic monocyclic structures containing one or more heteroatoms.
术语中的“芳基”指具有共轭的π电子体系的具有6至14个碳原子(6至14元)的单环或稠合多环(也就是共享毗邻碳原子对的环)基团，说明性芳基包括但不限于苯基、萘基和蒽基等。优选为苯基。The term "aryl" refers to a monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having 6 to 14 carbon atoms (6 to 14 members) with a conjugated π-electron system , illustrative aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like. Preferred is phenyl.
术语“杂芳基”指包含1至4个(例如1、2、3或4个)杂原子、5至14个环原子(例如5、6、7、8、9、10、11、12、13、14个)的杂芳族体系，其中杂原子选自O、S或N。杂芳基的说明性实例包含以下呈适当键结部分形式的实体：
The term "heteroaryl" refers to a group containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms, 5 to 14 ring atoms (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14) heteroaromatic systems, wherein the heteroatom is selected from O, S or N. Illustrative examples of heteroaryl include the following entities in the form of appropriate bonding moieties:
杂芳基优选为5至10元，含1至3个杂原子；优选为5元或6元，含1至3个杂原子；更优选6元杂芳基，例如吡啶基、嘧啶基、吡嗪基等。Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; preferably 5 or 6 membered, containing 1 to 3 heteroatoms; more preferably 6 membered heteroaryl, such as pyridyl, pyrimidinyl, pyridyl Azinyl, etc.
术语“烯基”是指含有2到12个碳原子且具有一或多个双键的直链、具支链或环状烃基。如C2-C7烯基，是指含有2-7个碳原子，可以是2个碳原子的乙烯基，三个碳原子的烯丙基等。其中烯基可以是端烯或非端烯结构，可以未经取代，或如烷基所述或如本文提供的各种实施例中所述经取代。此术语中包括顺式和反式异构体和其混合物。 The term "alkenyl" refers to a straight chain, branched chain or cyclic hydrocarbon group containing 2 to 12 carbon atoms and having one or more double bonds. For example, C 2 -C 7 alkenyl refers to 2-7 carbon atoms, which can be vinyl with 2 carbon atoms, allyl with 3 carbon atoms, etc. Wherein alkenyl groups can be terminal or non-terminal structures, and can be unsubstituted or substituted as described for alkyl or as described in the various examples provided herein. Included within this term are cis and trans isomers and mixtures thereof.
术语“炔基”指在链中具有2到12个碳原子且具有一或多个三键的直链或具支链烃基。炔基可未经取代，或如针对烷基所述或如本文提供的各种实施例中所述经取代。The term "alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 12 carbon atoms in the chain and having one or more triple bonds. Alkynyl groups can be unsubstituted or substituted as described for alkyl groups or as described in the various examples provided herein.
化合物结构中“*”表示该处原子具有手性中心；化合物结构中如结构表示含有该结构的化合物可以以R或S的任一构型存在。"*" in the compound structure indicates that the atom has a chiral center; in the compound structure such as structure It means that the compound containing this structure can exist in any configuration of R or S.
“取代”指基团中的一个或多个氢原子，优选为最多5个(例如1、2、3、4、5个)，更优选为1～3个氢原子可彼此独立地被相应数目的取代基所取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。"Substitution" refers to one or more hydrogen atoms in the group, preferably up to 5 (such as 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms can be independently replaced by the corresponding number replaced by substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
“任意地”意味着随后描述的事件或情况可能但未必发生，且所述描述包含事件或情况发生的情况及其未发生的情况。举例来说，“其中C1-C6烷基、5-6元芳基、5-6元杂芳基中的各氢原子任选地独立地经C1-C6烷基取代”意味着烷基可能但未必通过置换各烷基的氢原子而存在于C1-C6烷基、5-6元芳基、5-6元杂芳基中的任一者上。"Arbitrarily" means that the subsequently described event or circumstance could but did not have to occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "wherein each hydrogen atom in C1-C6 alkyl, 5-6 membered aryl, 5-6 membered heteroaryl is optionally independently substituted by C1-C6 alkyl" means that the alkyl may but It does not necessarily exist in any of the C1-C6 alkyl group, 5-6 membered aryl group, and 5-6 membered heteroaryl group by substituting the hydrogen atom of each alkyl group.
“独立地”意味着随后描述的事件或情况应相对于其它类似事件或环境就其自身进行理解。举例来说，“各自独立地”意味着基团上氢原子的各情况可经另一基团取代，其中置换各氢原子的基团可相同或不同。或举例来说，如果存在多个基团，其均可选自可能性组，那么使用“独立地”意味着各基团可独立于任何其它基团而选自可能性组，且所述情况中所选的基团可相同或不同。"Independently" means that the subsequently described event or circumstance is to be understood in its own right relative to other similar events or circumstances. For example, "each independently" means that each instance of a hydrogen atom on a group may be replaced by another group, wherein the groups replacing each hydrogen atom may be the same or different. Or for example, if there are multiple groups, all of which can be selected from the group of possibilities, then the use of "independently" means that each group can be selected from the group of possibilities independently of any other group, and the situation The groups selected in may be the same or different.
本发明所述的“立体异构体”是指当本发明的化合物含有一个或者多个不对称中心时，其可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体的形式存在。本发明的化合物可具有不对称中心，并由此导致存在两个光学异构体。本发明的范围包括所有可能的光学异构体和他们的混合物。本发明的化合物若含有烯烃双键，则除非特别说明，本发明的范围包括顺式异构体和反式异构体。本发明的化合物可以以互变异构体(官能团异构体的一种)形式存在，其通过一个或多个双键位移具有不同的氢的连接点，例如，酮和他的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都在本发明的范围内。所有化合物的对映异构体。非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等均在本发明的范围内。The "stereoisomer" mentioned in the present invention means that when the compound of the present invention contains one or more asymmetric centers, it can be used as racemate and racemic mixture, single enantiomer, diastereoisomer, etc. They exist as mixtures of enantiomers and as individual diastereoisomers. The compounds of the present invention may have an asymmetric center and thus lead to the existence of two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefinic double bonds, unless otherwise specified, the scope of the present invention includes cis-isomers and trans-isomers. The compounds of the present invention may exist in the form of tautomers (one of functional group isomers) having different points of attachment of hydrogens by displacement of one or more double bonds, for example, the ketone and his enol forms are Keto-enol tautomers. The individual tautomers and mixtures thereof are within the scope of the present invention. Enantiomers of all compounds. Diastereoisomers, racemates, mesoisomers, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof, etc. are within the scope of the present invention .
术语“本发明的化合物”意欲涵盖如本文所定义的通式(I)的化合物或其任一优选或具体的实施方案(包括式(Ia)化合物及实施例化合物)、它们的立体异构体、药学上可接受的盐、互变异构体或溶剂合物。The term "compounds of the present invention" is intended to cover compounds of general formula (I) as defined herein or any preferred or specific embodiment thereof (including compounds of formula (Ia) and example compounds), their stereoisomers , a pharmaceutically acceptable salt, tautomer or solvate.
术语“药学上可接受的”意指由各个国家的相应机构批准的或可由其批准，或列于用于动物且更具体地人类的一般公认药典中，或当向动物例如人类适量施用时不会产生不利、过敏或其它不良反应的分子实体和组合物。具体地，此类盐无毒，可为无机酸加成盐或有机酸加成盐及碱加成盐。The term "pharmaceutically acceptable" means approved or may be approved by the corresponding agency of each country, or listed in the generally accepted pharmacopoeia for use in animals, and more particularly in humans, or not when administered in appropriate amounts to animals, such as humans. Molecular entities and compositions that produce adverse, allergic or other adverse reactions. Specifically, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts.
本发明所述的“药物组合物”，指包含一种或多种式(I)、式(Ia)化合物或者其立体异构体、互变异构体、药学上可接受的盐或溶剂合物，以及在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体或赋形剂的组合物。The "pharmaceutical composition" of the present invention refers to the compound containing one or more formula (I), formula (Ia) or its stereoisomer, tautomer, pharmaceutically acceptable salt or solvate Compositions of substances, and carriers or excipients generally accepted in the art for delivering biologically active compounds to an organism, such as a human.
本发明的药物组合物可以通过本领域技术人员已知的技术来配制，如在Remington’s Pharmaceutical Sciences第20版中公开的技术。本发明的药物组合物，可以通过将本发明化合物或其药学上可接受的盐与一种或多种药学可接受的赋形剂混合来制备。制备可进一步包括将一种或多种其它活性成分与本发明化合物和一种或多种药学可接受的辅料的步骤。The pharmaceutical compositions of the present invention can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences 20th Edition. The pharmaceutical composition of the present invention can be prepared by mixing the compound of the present invention or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients. The preparation may further comprise the step of combining one or more other active ingredients with the compound of the present invention and one or more pharmaceutically acceptable excipients.
本发明中药学上可接受的辅料的选择取决于多种因素，例如给药方式和所提供的组合物形式。合适的药学上可接受的赋形剂是本领域技术人员熟知且描述于例如Ansel,Howard C.,等，Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia Lippincott,Williams&Wikins，2004中，其实例如佐剂、稀释剂(例如葡萄糖、乳糖或甘露醇)、载体、pH调节剂、缓冲剂、甜味剂、填充剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬 浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、加香剂、调味剂、稀释剂、粘合剂以及其它已知添加剂。The choice of pharmaceutically acceptable excipients in the present invention depends on various factors, such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia Lippincott, Williams & Wikins, 2004, for example adjuvants, Diluents (such as glucose, lactose or mannitol), carriers, pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents Floating agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, perfuming agents, flavoring agents, diluents, binders and other known additives.
本发明的药物组合物可以以标准方式施用。例如，合适的施用方式包括口服、静脉内、直肠、胃肠外、局部、经皮、眼、鼻、颊或肺(吸入)给药；其中胃肠外输注包括肌肉、静脉内、动脉内、腹膜内或皮下施用。为了这些目的，本发明的化合物可以通过本领域已知的方法配置成片剂、胶囊、糖浆、粉末、颗粒、水性或油性溶液或悬浮液，(脂质)乳剂、可分散粉末、栓剂、软膏、乳膏、滴剂、气溶胶、干粉针剂和无菌可注射水性或油性溶液或悬浮液形式。本发明的化合物或其药学上可接受的盐，可根据本领域中已知用于制备各种剂型的常规方法调配成于适合医药溶剂或载剂中的溶液、乳液、悬浮液或分散液，或与药学上可接受地赋性剂一起调配成医药上可接受的常用剂型。The pharmaceutical compositions of the invention can be administered in standard manner. For example, suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ophthalmic, nasal, buccal or pulmonary (inhalation); wherein parenteral infusion includes intramuscular, intravenous, intraarterial , intraperitoneal or subcutaneous administration. For these purposes, the compounds of the present invention can be formulated into tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments by methods known in the art , creams, drops, aerosols, dry powder injections and sterile injectable aqueous or oily solutions or suspensions. The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solutions, emulsions, suspensions or dispersions in suitable pharmaceutical solvents or carriers according to conventional methods known in the art for preparing various dosage forms, Or be prepared together with pharmaceutically acceptable excipients into a commonly used pharmaceutically acceptable dosage form.
本发明化合物的预防或治疗剂量的大小将根据一系列因素而变化，包括所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约5000mg，例如约0.01至约1000mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约7000mg/日，例如约0.7mg/日至约1500mg/日。根据给药模式，本发明化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等；相应地，本发明的药物组合物将包含0.05至99％w/w(重量百分比)，例如0.05至80％w/w，例如0.10至70％w/w，例如0.10至50％w/w的本发明化合物，所有重量百分比均基于总组合物。应当理解，可能有必要在某些情况下使用超出这些限制的剂量。The size of the prophylactic or therapeutic dose of a compound of the invention will vary depending on a number of factors including the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. Generally, the effective dose is about 0.0001 to about 5000 mg per kg body weight per day, for example about 0.01 to about 1000 mg/kg/day (single or divided administration). For a 70 kg human this would amount to about 0.007 mg/day to about 7000 mg/day, eg about 0.7 mg/day to about 1500 mg/day. According to the mode of administration, the content or dosage of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, Such as 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.; correspondingly, the pharmaceutical composition of the present invention will contain 0.05 to 99% w/w (percentage by weight), such as 0.05 to 80% w/w, such as 0.10 to 70% w/w, eg 0.10 to 50% w/w of the compound of the invention, all weight percentages being based on the total composition. It will be understood that it may be necessary to use dosages outside these limits in some cases.
应当理解，本发明的化合物结构、基团等符合化学价键规则。某些基团或结构在书写时，省略了其连接键。例如，有些情况下，记载了式(Ia)中X2/X3/X4/X5选自N，基于通式结构可知X2/X3/X4/X5为＝N-。另外，本发明中取代基如＝NRb，基于通式结构可知NRb为＝N-Rb。其它基团也可类似地理解和解释。It should be understood that the structures, groups, etc. of the compounds of the present invention conform to the rules of chemical valence bonds. Certain groups or structures are written without their linkages. For example, in some cases, it is stated that X 2 /X 3 /X 4 /X 5 is selected from N in formula (Ia), and based on the structure of the general formula, it can be known that X 2 /X 3 /X 4 /X 5 is =N-. In addition, in the present invention, substituents such as =NR b , based on the general structure, it can be seen that NR b is =NR b . Other groups can be understood and interpreted similarly.
本发明还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。The present invention also includes isotopically labeled compounds of the disclosure that are identical to those described herein, but with one or more atoms replaced by an atom of an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, respectively. 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I and 36Cl, etc.
某些同位素标记的本公开化合物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。Certain isotopically-labeled compounds of the disclosure (eg, those labeled with3H and14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3H) and carbon-14 (ie 14C) isotopes are especially preferred for their ease of preparation and detectability. Positron emitting isotopes such as 15O, 13N, 11C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。Furthermore, substitution with heavier isotopes such as deuterium (i.e. 2H) may confer certain therapeutic advantages resulting from greater metabolic stability (eg increased in vivo half-life or reduced dosage requirements), and thus in some cases It may be preferred, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
显然，根据本发明的上述内容，按照本领域的普通技术知识和手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。Apparently, according to the above content of the present invention, according to the common technical knowledge and means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.
发明的有益效果Beneficial Effects of the Invention
本发明提供了一类具有通式(I)结构特征的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，经研究发现，该类结构可有效抑制CDK9介导和/或TNIK介导的疾病,从而预防或治疗CDK9和/或TNIK介导的相关疾病。The present invention provides a class of compounds or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers with the structural characteristics of the general formula (I). It is found through research that this type of structure can effectively inhibit CDK9-mediated and/or TNIK-mediated diseases, so as to prevent or treat CDK9- and/or TNIK-mediated related diseases.
具体实施方式Detailed ways
下面通过举例说明本发明的化合物和中间体的合成方法，下述举例仅作为本发明的示例，而不应作为对本发明范围的限制。除特殊说明外，本发明中所涉及的原料和试剂均可通过商 业化渠道获得，具体渠道来源并不影响本发明技术方案的实施。下列描述中使用的缩写和符号的含义如下：

The synthesis method of the compounds and intermediates of the present invention is illustrated below by way of example, and the following examples are only used as examples of the present invention, and should not be used as limitations to the scope of the present invention. Unless otherwise specified, the raw materials and reagents involved in the present invention can be obtained through commercial The specific channel source does not affect the implementation of the technical solution of the present invention. The abbreviations and symbols used in the following descriptions have the following meanings:

制备例1：3-((甲硫基)甲基)苯胺的制备
Preparation Example 1: Preparation of 3-((methylthio)methyl)aniline
步骤1：1-(氯甲基)-3-硝基苯的制备
Step 1: Preparation of 1-(chloromethyl)-3-nitrobenzene
将3-硝基苯甲醇(2.0g)溶于无水二甲基亚砜(50mL)中，缓慢加入三聚氯氰(2.0g)，室温反应1小时。TLC检测反应完全，加入水搅拌5分钟，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物1.8g。3-Nitrobenzyl alcohol (2.0 g) was dissolved in anhydrous dimethyl sulfoxide (50 mL), and cyanuric chloride (2.0 g) was added slowly, and reacted at room temperature for 1 hour. The reaction was complete as detected by TLC, added water and stirred for 5 minutes, extracted with dichloromethane, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 1.8 g of the title compound.
步骤2：(3-硝基苄基)硫醇的制备
Step 2: Preparation of (3-nitrobenzyl)thiol
将1-(氯甲基)-3-硝基苯(1.5g)溶于乙醇(10mL)，在0℃下缓慢滴加甲硫醇钠的水溶液(20％in H2O，3.5mL)，反应20分钟。TLC检测反应完全，加入水，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物1.2g。1-(Chloromethyl)-3-nitrobenzene (1.5g) was dissolved in ethanol (10mL), and an aqueous solution of sodium methylthiolate (20% in H 2 O, 3.5mL) was slowly added dropwise at 0°C, React for 20 minutes. TLC detected that the reaction was complete, water was added, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 1.2 g of the title compound.
步骤3：3-((甲硫基)甲基)苯胺的制备
Step 3: Preparation of 3-((methylthio)methyl)aniline
将(3-硝基苄基)硫醇(1.0g)溶于乙醇(4mL)，依次加入水(1mL)，铁粉(3.5g)和几滴盐酸，回流反应3小时。TLC检测反应完全，过滤除掉固体，滤液加入饱和碳酸氢钠水溶液调节pH为弱碱性，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物0.75g。Dissolve (3-nitrobenzyl)thiol (1.0g) in ethanol (4mL), add water (1mL), iron powder (3.5g) and a few drops of hydrochloric acid in sequence, and reflux for 3 hours. The reaction was complete as detected by TLC, the solid was removed by filtration, the filtrate was added with saturated aqueous sodium bicarbonate solution to adjust the pH to be weakly alkaline, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 0.75 g of the title compound.
MS(ESI)m/z(M+H)+＝154.1.MS (ESI) m/z (M+H) + = 154.1.
制备例2：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯喹唑啉的制备
Preparation Example 2: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline
步骤1：8-甲氧基喹唑啉-2,4(1H,3H)-二酮的制备
Step 1: Preparation of 8-methoxyquinazoline-2,4(1H,3H)-dione
将2-氨基-3-甲氧基苯甲酸(20.0g)溶于N-甲基吡咯烷酮(100mL)，缓慢加入尿素(30.0g)，160℃下加热反应6小时。TLC和LCMS显示反应完全。趁热加入水(100mL)析出固体，过滤，收集固体，石油醚洗涤，干燥，得标题化合物20.0g。2-Amino-3-methoxybenzoic acid (20.0 g) was dissolved in N-methylpyrrolidone (100 mL), urea (30.0 g) was added slowly, and the reaction was heated at 160° C. for 6 hours. TLC and LCMS showed the reaction was complete. Water (100 mL) was added while hot to precipitate a solid, which was collected by filtration, washed with petroleum ether, and dried to obtain 20.0 g of the title compound.
MS(ESI)m/z(M+H)+＝193.1。MS (ESI) m/z (M+H) + = 193.1.
步骤2：2,4-二氯-8-甲氧基喹唑啉的制备
Step 2: Preparation of 2,4-dichloro-8-methoxyquinazoline
将8-甲氧基喹唑啉-2,4(1H,3H)-二酮(20.0g)溶于三氯氧磷(100mL)，逐滴加入N,N-二甲基苯胺(30.0g)，130℃下回流反应3小时。TLC和LCMS显示反应完全。将反应液浓缩除去多余三氯氧磷，残留物缓慢加入到饱和碳酸氢钠的冰水溶液中，二氯甲烷萃取四次，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物15.0g。Dissolve 8-methoxyquinazoline-2,4(1H,3H)-dione (20.0g) in phosphorus oxychloride (100mL), add N,N-dimethylaniline (30.0g) dropwise , reflux reaction at 130°C for 3 hours. TLC and LCMS showed the reaction was complete. Concentrate the reaction solution to remove excess phosphorus oxychloride, slowly add the residue into saturated ice solution of sodium bicarbonate, extract four times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the obtained crude product is passed through the column Purified by chromatography to obtain 15.0 g of the title compound.
MS(ESI)m/z(M+H)+＝229.0。MS (ESI) m/z (M+H) + = 229.0.
步骤3：2-氯-8-甲氧基喹唑啉的制备
Step 3: Preparation of 2-chloro-8-methoxyquinazoline
将2,4-二氯-8-甲氧基喹唑啉(15.0g)溶于乙酸乙酯(200mL)，逐滴加入N，N-二异丙基乙胺(16.5mL)，加入钯炭(1.5g)，氢气置换3次，室温反应1小时。TLC和LCMS显示反应完全。将反应液过滤除去多余钯炭，收集滤液，浓缩，粗品经柱层析纯化得标题化合物8.0g。Dissolve 2,4-dichloro-8-methoxyquinazoline (15.0g) in ethyl acetate (200mL), add N,N-diisopropylethylamine (16.5mL) dropwise, add palladium carbon (1.5 g), replaced with hydrogen 3 times, and reacted at room temperature for 1 hour. TLC and LCMS showed the reaction was complete. The reaction solution was filtered to remove excess palladium carbon, the filtrate was collected, concentrated, and the crude product was purified by column chromatography to obtain 8.0 g of the title compound.
MS(ESI)m/z(M+H)+＝195.0。MS (ESI) m/z (M+H) + = 195.0.
步骤4：2-氯-8-羟基喹唑啉的制备
Step 4: Preparation of 2-chloro-8-hydroxyquinazoline
在冰水浴条件下，氮气氛围中，将2-氯-8-甲氧基喹唑啉(8.0g)溶于二氯甲烷(80mL)，缓慢加入三溴化硼(40mL)，移至室温反应过夜。TLC和LCMS显示反应完全。将反应液加水淬灭，二氯甲烷萃取四次，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物4.3g。Under ice-water bath conditions, in a nitrogen atmosphere, 2-chloro-8-methoxyquinazoline (8.0g) was dissolved in dichloromethane (80mL), slowly added boron tribromide (40mL), and moved to room temperature for reaction overnight. TLC and LCMS showed the reaction was complete. The reaction solution was quenched with water, extracted four times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was purified by column chromatography to obtain 4.3 g of the title compound.
MS(ESI)m/z(M+H)+＝181.0。MS (ESI) m/z (M+H) + = 181.0.
步骤5：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯喹唑啉的制备
Step 5: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline
氮气氛围中，将三苯基膦(10.4g)溶于四氢呋喃(150mL)，逐滴加入偶氮二甲酸二异丙酯(7.9g)。在氮气保护下，将2-氯-8-羟基喹唑啉(4.3g)和反式-4-((叔丁基二甲基甲硅烷基)氧基)环己醇(6g)溶于四氢呋喃溶液(150mL)中。随后将上述两种反应液混合，反应半小时。TLC和LCMS显示反应完全。将反应体系浓缩，所得粗品经柱层析纯化得标题化合物4.0g。Under nitrogen atmosphere, triphenylphosphine (10.4 g) was dissolved in tetrahydrofuran (150 mL), and diisopropyl azodicarboxylate (7.9 g) was added dropwise. Under nitrogen protection, 2-chloro-8-hydroxyquinazoline (4.3g) and trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanol (6g) were dissolved in tetrahydrofuran solution (150 mL). Then the above two reaction solutions were mixed and reacted for half an hour. TLC and LCMS showed the reaction was complete. The reaction system was concentrated, and the obtained crude product was purified by column chromatography to obtain 4.0 g of the title compound.
MS(ESI)m/z(M+H)+＝393.2。MS (ESI) m/z (M+H) + = 393.2.
制备例3：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 3: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)benzene Base) the preparation of quinazoline-2-amine
将3-((甲硫基)甲基)苯胺(0.5g)，8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯喹唑啉(1.3g)和碳酸铯(1.1g)溶于异丙醇(10mL)中，微波90℃条件下反应30分钟。TLC检测反应完全，过滤除掉固体，滤饼用乙酸乙酯洗涤，合并有机相，浓缩，粗品经柱层析纯化得到标题化合物0.9g。3-((methylthio)methyl)aniline (0.5g), 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2 - Chloroquinazoline (1.3 g) and cesium carbonate (1.1 g) were dissolved in isopropanol (10 mL), and reacted under microwave conditions at 90° C. for 30 minutes. TLC detected that the reaction was complete, and the solid was removed by filtration. The filter cake was washed with ethyl acetate, and the organic phases were combined and concentrated. The crude product was purified by column chromatography to obtain 0.9 g of the title compound.
MS(ESI)m/z(M+H)+＝510.3.MS (ESI) m/z (M+H) + = 510.3.
制备例4：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯喹唑啉的制备
Preparation Example 4: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline
步骤1：7-溴-2-氯喹唑啉-8-醇的制备
Step 1: Preparation of 7-bromo-2-chloroquinazolin-8-ol
将2-氯喹唑啉-8-醇(3.0g)溶于氯仿(150mL)，在冰浴条件下，缓慢加入二异丙胺(6mL)和N-溴代琥珀酰亚胺(3.1g)，反应2小时。TLC和LCMS显示反应完全。将反应液浓缩除去多余氯仿，加水(50mL)，二氯甲烷萃取四次，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化，得到的固体再用石油醚洗涤，干燥后得标题化合物3.5g。2-Chloroquinazolin-8-ol (3.0g) was dissolved in chloroform (150mL), under ice-bath conditions, slowly added diisopropylamine (6mL) and N-bromosuccinimide (3.1g), reacted 2 hours. TLC and LCMS showed the reaction was complete. Concentrate the reaction solution to remove excess chloroform, add water (50 mL), extract four times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The obtained crude product is purified by column chromatography, and the obtained solid is washed with petroleum ether , and dried to obtain 3.5 g of the title compound.
MS(ESI)m/z(M+H)+＝258.9，260.9。MS (ESI) m/z (M+H) + = 258.9, 260.9.
步骤2：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯喹唑啉的制备
Step 2: Preparation of 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline
在惰性气体保护条件下，将三苯基膦(10.2g)溶于无水四氢呋喃(150mL)，缓慢加入偶氮二甲酸二异丙酯(7.9g)。氮气保护下，将7-溴-2-氯喹唑啉-8-醇(4.0g)和反式-4-((叔丁基二甲基甲硅烷基)氧基)环己醇(6.0g)溶于四氢呋喃中。随后将上述两种反应液混合，反应30分钟 后，TLC和LCMS显示反应完全。将反应体系浓缩，所得粗品经柱层析纯化得标题化合物5.0g。Under the protection of an inert gas, triphenylphosphine (10.2 g) was dissolved in anhydrous tetrahydrofuran (150 mL), and diisopropyl azodicarboxylate (7.9 g) was added slowly. Under nitrogen protection, 7-bromo-2-chloroquinazolin-8-ol (4.0g) and trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanol (6.0g) Soluble in tetrahydrofuran. Then the above two reaction solutions were mixed and reacted for 30 minutes Afterwards, TLC and LCMS showed that the reaction was complete. The reaction system was concentrated, and the obtained crude product was purified by column chromatography to obtain 5.0 g of the title compound.
MS(ESI)m/z(M+H)+＝471.1，473.1。MS (ESI) m/z (M+H) + = 471.1, 473.1.
制备例5：7-溴-8-(顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 5: 7-bromo-8-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl Base) phenyl) quinazoline-2-amine preparation
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝588.2，590.2.MS (ESI) m/z (M+H) + = 588.2, 590.2.
制备例6：4-氯-3-((甲硫基)甲基)苯胺的制备
Preparation Example 6: Preparation of 4-chloro-3-((methylthio)methyl)aniline
步骤1：2-(溴甲基)-1-氯-4-硝基苯的制备
Step 1: Preparation of 2-(bromomethyl)-1-chloro-4-nitrobenzene
将(2-氯-5-硝基苯基)甲醇(1.20g)溶于二氯甲烷(15mL)，0℃下分别加入三苯基膦(2.17g)和N-溴代丁二酰亚胺(1.48g)，移至室温反应1小时。反应液加水淬灭(30mL)，二氯甲烷萃取(2*30mL)，合并有机相，无水硫酸钠干燥，过滤，浓缩，得标题化合物1.2g，粗品无需纯化直接用于下一步反应。Dissolve (2-chloro-5-nitrophenyl)methanol (1.20g) in dichloromethane (15mL), and add triphenylphosphine (2.17g) and N-bromosuccinimide respectively at 0°C (1.48g), moved to room temperature for 1 hour. The reaction solution was quenched with water (30 mL), extracted with dichloromethane (2*30 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.2 g of the title compound, which was directly used in the next reaction without purification.
步骤2：(2-氯-5-硝基苄基)(甲基)硫烷的制备
Step 2: Preparation of (2-chloro-5-nitrobenzyl)(methyl)sulfane
将2-(溴甲基)-1-氯-4-硝基苯(1.20g)溶于四氢呋喃(20mL)，-20℃下滴加20％甲硫醇钠水溶液(5mL)，反应过夜。乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱色谱纯化得标题化合物935mg。2-(Bromomethyl)-1-chloro-4-nitrobenzene (1.20 g) was dissolved in tetrahydrofuran (20 mL), and 20% aqueous solution of sodium methyl mercaptide (5 mL) was added dropwise at -20°C to react overnight. Extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and the crude product is purified by column chromatography to obtain 935 mg of the title compound.
步骤3：4-氯-3-((甲硫基)甲基)苯胺的制备
Step 3: Preparation of 4-chloro-3-((methylthio)methyl)aniline
将(2-氯-5-硝基苄基)(甲基)硫烷(930mg)溶于乙醇/水(16mL,3:1)，加入铁粉(721mg)和氯化铵(708mg)，50℃加热反应1小时。TLC显示反应完毕。过滤除去不溶物，收集滤液，浓缩除去溶剂，粗品经柱色谱纯化得标题化合物590mg。Dissolve (2-chloro-5-nitrobenzyl)(methyl)sulfane (930mg) in ethanol/water (16mL, 3:1), add iron powder (721mg) and ammonium chloride (708mg), 50 The reaction was heated at °C for 1 hour. TLC showed the reaction was complete. The insoluble matter was removed by filtration, the filtrate was collected, concentrated to remove the solvent, and the crude product was purified by column chromatography to obtain 590 mg of the title compound.
MS(ESI)m/z(M+H)+＝188.2。MS (ESI) m/z (M+H) + = 188.2.
制备例7：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(4-氯-3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 7: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(4-chloro-3-((methylthio) Preparation of methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝544.2.MS (ESI) m/z (M+H) + = 544.2.
制备例8：3-氟-5-((甲硫基)甲基)苯胺的制备
Preparation Example 8: Preparation of 3-fluoro-5-((methylthio)methyl)aniline
参考前述制备例6中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 6.
MS(ESI)m/z(M+H)+＝172.1.MS (ESI) m/z (M+H) + = 172.1.
制备例9：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-氟-5-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 9: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-fluoro-5-((methylthio) Preparation of methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝528.2.MS (ESI) m/z (M+H) + = 528.2.
制备例10：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-氟-5-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 10: 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-fluoro-5-(( Preparation of methylthio)methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝606.2,608.2.MS (ESI) m/z (M+H) + = 606.2, 608.2.
制备例11：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(4-氯-3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 11: 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(4-chloro-3-(( Preparation of methylthio)methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝622.1,624.1.MS (ESI) m/z (M+H) + = 622.1, 624.1.
制备例12：2-氯-8-氟-7-(三氟甲基)喹唑啉的制备
Preparation 12: Preparation of 2-chloro-8-fluoro-7-(trifluoromethyl)quinazoline
步骤1：2-(2,3-二氟苯基)-1,3-二氧戊环的制备
Step 1: Preparation of 2-(2,3-difluorophenyl)-1,3-dioxolane
将2,3-二氟苯甲醛(14.2g)溶于甲苯(100ml)，加入乙二醇(9.3g)和对甲苯磺酸(1.90g)，体系回流三小时。TLC显示原料反应完毕。反应液降至室温，加饱和碳酸氢铵水溶液(100mL)，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤，浓缩，粗品经柱色谱纯化得标题化合物17.2g。2,3-Difluorobenzaldehyde (14.2g) was dissolved in toluene (100ml), ethylene glycol (9.3g) and p-toluenesulfonic acid (1.90g) were added, and the system was refluxed for three hours. TLC showed complete reaction of starting material. The reaction solution was lowered to room temperature, added saturated aqueous ammonium bicarbonate (100 mL), extracted with ethyl acetate, combined organic phases, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the title Compound 17.2g.
步骤2：2-(2,3-二氟-4-碘苯基)-1,3-二氧戊环的制备
Step 2: Preparation of 2-(2,3-difluoro-4-iodophenyl)-1,3-dioxolane
将2-(2,3-二氟苯基)-1,3-二氧戊环(5.6g)溶于无水四氢呋喃(50mL)，体系于无水无氧氮气保护下，-78℃搅拌，缓慢滴加二异丙基氨基锂(25mL,2M)，加毕，体系升温至-50℃搅拌1小时后，加入碘单质(11.4g)。体系移至室温反应过夜。LCMS显示原料反应完毕，加适量饱和硫代硫酸钠溶液淬灭反应，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物7.7g。Dissolve 2-(2,3-difluorophenyl)-1,3-dioxolane (5.6g) in anhydrous tetrahydrofuran (50mL), and stir the system at -78°C under the protection of anhydrous and oxygen-free nitrogen. Lithium diisopropylamide (25mL, 2M) was slowly added dropwise. After the addition was complete, the system was warmed up to -50°C and stirred for 1 hour, then iodine (11.4g) was added. The system was moved to room temperature to react overnight. LCMS showed that the reaction of the raw material was complete, adding an appropriate amount of saturated sodium thiosulfate solution to quench the reaction, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, filtering, and concentrating, the crude product was purified by column chromatography to obtain 7.7 g of the title compound.
步骤3：2,3-二氟-4-碘苯甲醛的制备
Step 3: Preparation of 2,3-difluoro-4-iodobenzaldehyde
将2-(2,3-二氟-4-碘苯基)-1,3-二氧戊环(3.1g)溶于盐酸(10mL,2N)和四氢呋喃(10mL)的混合溶液，室温反应2小时。TLC检测无原料剩余，浓缩除去部分反应液，乙酸乙酯稀释，饱和碳酸氢钠溶液和饱和食盐水洗涤，收集有机相，无水硫酸钠干燥，过滤，浓缩，得到粗品2.5g，未经纯化直接用于下一步反应。Dissolve 2-(2,3-difluoro-4-iodophenyl)-1,3-dioxolane (3.1g) in a mixed solution of hydrochloric acid (10mL, 2N) and tetrahydrofuran (10mL), and react at room temperature for 2 Hour. TLC detected that there was no remaining raw material, concentrated to remove part of the reaction solution, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated brine, collected the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.5 g of crude product without purification used directly in the next reaction.
步骤4：8-氟-7-碘喹唑啉-2-胺的制备
Step 4: Preparation of 8-fluoro-7-iodoquinazolin-2-amine
将2,3-二氟-4-碘苯甲醛(2.5g)、碳酸胍(2.0g)和N,N-二异丙基乙胺(2.4g)溶于N-甲基吡咯烷酮(20mL)，140℃下反应2小时。LCMS检测无原料剩余，待反应液冷却后，缓慢加入冰水，直至无新的固体生成，过滤反应液，收集固体，干燥，得到粗品1.9g，未经纯化直接用于下一步反应。2,3-difluoro-4-iodobenzaldehyde (2.5 g), guanidine carbonate (2.0 g) and N,N-diisopropylethylamine (2.4 g) were dissolved in N-methylpyrrolidone (20 mL), The reaction was carried out at 140° C. for 2 hours. LCMS detected that there was no remaining raw material. After the reaction solution was cooled, ice water was slowly added until no new solid was formed. The reaction solution was filtered, the solid was collected, and dried to obtain 1.9 g of crude product, which was directly used in the next reaction without purification.
MS(ESI)m/z(M+H)+＝289.9。MS (ESI) m/z (M+H) + = 289.9.
步骤5：2-氯-8-氟-7-碘喹唑啉的制备
Step 5: Preparation of 2-chloro-8-fluoro-7-iodoquinazoline
将8-氟-7-碘喹唑啉-2-胺(3.1g)和四丁基氯化铵(2.2g)溶于二氯甲烷(15mL)和N,N-二甲基甲酰胺(1.5mL)的混合溶液，室温下搅拌均匀，缓慢加入三甲基氯硅烷(2.9g)，继续搅拌20分钟后，加入亚硝酸叔丁酯(2.1g)，继续反应3小时。TLC检测无原料剩余，反应液中加入饱和碳酸氢钠溶液调节pH约至10，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物1.0g。8-Fluoro-7-iodoquinazolin-2-amine (3.1 g) and tetrabutylammonium chloride (2.2 g) were dissolved in dichloromethane (15 mL) and N,N-dimethylformamide (1.5 mL) was stirred evenly at room temperature, and trimethylchlorosilane (2.9 g) was slowly added, and after stirring for 20 minutes, tert-butyl nitrite (2.1 g) was added, and the reaction was continued for 3 hours. TLC detects that there is no remaining raw material. Add saturated sodium bicarbonate solution to the reaction solution to adjust the pH to about 10, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The crude product is purified by column chromatography to obtain the title compound 1.0 g.
MS(ESI)m/z(M+H)+＝308.9。MS (ESI) m/z (M+H) + = 308.9.
步骤6：2-氯-8-氟-7-(三氟甲基)喹唑啉的制备
Step 6: Preparation of 2-chloro-8-fluoro-7-(trifluoromethyl)quinazoline
将2-氯-8-氟-7-碘喹唑啉(1.0g)，氟磺酰基二氟乙酸甲酯(1.3g)和碘化亚铜(0.74g)溶于N,N-二甲基甲酰胺(15mL)，体系于无水无氧氮气保护下80℃反应3小时。LCMS检测无原料剩余，过滤反应液，收集滤液，乙酸乙酯稀释，饱和食盐水洗涤，收集有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物0.35g。2-Chloro-8-fluoro-7-iodoquinazoline (1.0g), methyl fluorosulfonyl difluoroacetate (1.3g) and cuprous iodide (0.74g) were dissolved in N,N-dimethyl Formamide (15 mL), the system was reacted at 80° C. for 3 hours under the protection of anhydrous and oxygen-free nitrogen. LCMS detected that there was no remaining raw material. The reaction solution was filtered, and the filtrate was collected, diluted with ethyl acetate, washed with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 0.35 g of the title compound.
MS(ESI)m/z(M+H)+＝251.0。 MS (ESI) m/z (M+H) + = 251.0.
制备例13：8-(((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)-7-(三氟甲基)喹唑啉-2-胺的制备
Preparation 13: 8-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl) Preparation of phenyl)-7-(trifluoromethyl)quinazolin-2-amine
步骤1：8-氟-N-(3-((甲硫基)甲基)苯基)-7-(三氟甲基)喹唑啉-2-胺的制备
Step 1: Preparation of 8-fluoro-N-(3-((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazolin-2-amine
将2-氯-8-氟-7-(三氟甲基)喹唑啉(330mg)，3-((甲硫基)甲基)苯胺(200mg)，醋酸钯(30mg)，2-二环己基膦-2',4',6'-三异丙基联苯(130mg)和碳酸铯(860mg)溶于1,4-二氧六环(15mL)，体系于无水无氧氮气保护条件下，80℃加热反应2小时。LCMS检测无原料剩余，过滤，收集滤液，浓缩，粗品经柱层析纯化得标题化合物300mg。2-Chloro-8-fluoro-7-(trifluoromethyl)quinazoline (330mg), 3-((methylthio)methyl)aniline (200mg), palladium acetate (30mg), 2-bicyclic Hexylphosphine-2',4',6'-triisopropylbiphenyl (130mg) and cesium carbonate (860mg) were dissolved in 1,4-dioxane (15mL), and the system was kept under anhydrous and oxygen-free nitrogen protection conditions The reaction was heated at 80°C for 2 hours. LCMS detected that there was no remaining raw material. After filtration, the filtrate was collected and concentrated. The crude product was purified by column chromatography to obtain 300 mg of the title compound.
MS(ESI)m/z(M+H)+＝368.0。MS (ESI) m/z (M+H) + = 368.0.
步骤2：8-(((顺式-4-羟基环己基)氧基)-N-(3-((甲硫基)甲基)苯基)-7-(三氟甲基)喹唑啉-2-胺的制备
Step 2: 8-(((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazoline - Preparation of 2-amine
将8-氟-N-(3-((甲硫基)甲基)苯基)-7-(三氟甲基)喹唑啉-2-胺(100mg)，顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己-1-醇(62mg)和叔丁醇钠(52mg)溶于N,N-二甲基甲酰胺(15mL)，120℃加热反应2小时。LCMS检测无原料剩余，加水淬灭反应，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，得粗品120mg，未经纯化直接用于下一步反应。8-fluoro-N-(3-((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazolin-2-amine (100mg), cis-4-((tert Butyldimethylsilyl)oxy)cyclohexan-1-ol (62mg) and sodium tert-butoxide (52mg) were dissolved in N,N-dimethylformamide (15mL), heated at 120°C for 2 hours . LCMS detected that there was no remaining raw material, the reaction was quenched by adding water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 120 mg of crude product, which was directly used in the next reaction without purification.
MS(ESI)m/z(M+H)+＝464.1。MS (ESI) m/z (M+H) + = 464.1.
步骤3：8-(((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)-7-(三氟甲基)喹唑啉-2-胺的制备
Step 3: 8-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)benzene base)-7-(trifluoromethyl)quinazolin-2-amine preparation
将8-(((顺式-4-羟基环己基)氧基)-N-(3-((甲硫基)甲基)苯基)-7-(三氟甲基)喹唑啉-2-胺(120mg)，1-甲基-1H-咪唑(64mg)和叔丁基二甲基氯硅烷(120mg)溶于二氯甲烷(5mL)，40℃加热反应3小时。LCMS检测无原料剩余，加水淬灭反应，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经制备TLC纯化得标题化合物60mg。8-(((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)-7-(trifluoromethyl)quinazoline-2 -Amine (120mg), 1-methyl-1H-imidazole (64mg) and tert-butyldimethylsilyl chloride (120mg) were dissolved in dichloromethane (5mL) and heated at 40°C for 3 hours. No raw material was detected by LCMS , quenched the reaction with water, extracted with dichloromethane, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative TLC to obtain 60 mg of the title compound.
MS(ESI)m/z(M+H)+＝578.3。MS (ESI) m/z (M+H) + = 578.3.
制备例14：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2,7-二氯喹唑啉的制备
Preparation Example 14: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline
步骤1：4-氯-2-氟-3-甲氧基苯甲醛制备
Step 1: Preparation of 4-chloro-2-fluoro-3-methoxybenzaldehyde
将1-氯-3-氟-2-甲氧基苯(4.8g)溶于无水四氢呋喃(50mL)，置换氩气3次，于-78℃条件下滴加正丁基锂的正己烷溶液(15.6mL,2.5M)，搅拌30分钟。加入无水N,N-二甲基甲酰胺(10mL)，移至室温反应1小时。TLC监测显示无原料剩余。反应液加入饱和氯化铵水溶液淬灭，乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得标题化合物5.9g。Dissolve 1-chloro-3-fluoro-2-methoxybenzene (4.8g) in anhydrous tetrahydrofuran (50mL), replace argon 3 times, and add n-butyllithium in n-hexane dropwise at -78°C (15.6 mL, 2.5M), stirred for 30 minutes. Anhydrous N,N-dimethylformamide (10 mL) was added, and the reaction was carried out at room temperature for 1 hour. TLC monitoring showed no starting material remaining. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 5.9 g of the title compound.
步骤2：7-氯-8-甲氧基喹唑啉-2-胺制备
Step 2: Preparation of 7-chloro-8-methoxyquinazolin-2-amine
将4-氯-2-氟-3-甲氧基苯甲醛(5.9g)和碳酸胍(6.78g)溶于N,N-二甲基乙酰胺(15mL)，体 系于140℃加热反应2小时。TLC显示无原料剩余，反应液冷却至室温后加入水(100mL)并持续搅拌30分钟。收集析出的固体，用水洗涤，干燥后得标题化合物3.2g，粗品无需纯化直接用于下一步反应。4-Chloro-2-fluoro-3-methoxybenzaldehyde (5.9g) and guanidine carbonate (6.78g) were dissolved in N,N-dimethylacetamide (15mL). The reaction was heated at 140°C for 2 hours. TLC showed that there was no remaining raw material. After the reaction solution was cooled to room temperature, water (100 mL) was added and stirring was continued for 30 minutes. The precipitated solid was collected, washed with water, and dried to obtain 3.2 g of the title compound, which was directly used in the next reaction without further purification.
MS(ESI)m/z(M+H)+＝210.0。MS (ESI) m/z (M+H) + = 210.0.
步骤3：2,7-二氯-8-甲氧基喹唑啉制备
Step 3: Preparation of 2,7-dichloro-8-methoxyquinazoline
将7-氯-8-甲氧基喹唑啉-2-胺(1.0g)溶于N,N-二甲基甲酰胺/二氯甲烷(12mL,1:5)的混合溶剂，加入四丁基氯化铵(1.3g)，三甲基氯硅烷(2.1g)和亚硝酸叔丁酯(1.5g)，体系于50℃加热反应1小时。TLC显示无原料剩余。反应液用饱和碳酸氢钠水溶液淬灭，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱色谱纯化得标题化合物254mg。Dissolve 7-chloro-8-methoxyquinazolin-2-amine (1.0g) in a mixed solvent of N,N-dimethylformamide/dichloromethane (12mL, 1:5), add tetrabutyl ammonium chloride (1.3g), trimethylchlorosilane (2.1g) and tert-butyl nitrite (1.5g), and the system was heated at 50°C for 1 hour. TLC showed no starting material remaining. The reaction solution was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 254 mg of the title compound.
MS(ESI)m/z(M+H)+＝229.1。MS (ESI) m/z (M+H) + = 229.1.
步骤4：2,7-二氯喹唑啉-8-醇的制备
Step 4: Preparation of 2,7-dichloroquinazolin-8-ol
将2,7-二氯-8-甲氧基喹唑啉(690mg)溶于干燥二氯甲烷(20mL)，0℃条件下滴加三溴化硼的二氯甲烷溶液(9mL,1M)，移至室温反应过夜。TLC显示原料反应完毕。反应液分别加饱和碳酸氢钠水溶液(10mL)和饱和食盐水(10mL)洗涤，收集有机相，无水硫酸钠干燥，过滤，浓缩得标题化合物600mg。2,7-dichloro-8-methoxyquinazoline (690mg) was dissolved in dry dichloromethane (20mL), and a solution of boron tribromide in dichloromethane (9mL, 1M) was added dropwise at 0°C, Move to room temperature overnight. TLC showed complete reaction of starting material. The reaction solution was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated brine (10 mL), respectively, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 600 mg of the title compound.
MS(ESI)m/z(M+H)+＝215.1。MS (ESI) m/z (M+H) + = 215.1.
步骤5：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2,7-二氯喹唑啉的制备
Step 5: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline
将三苯基膦(732mg)溶于无水四氢呋喃(15mL)，0℃下滴加偶氮二甲酸二异丙酯(564mg)，加毕搅拌15分钟，随后分别加入反式-4-((叔丁基二甲基甲硅烷基)氧基)环己-1-醇(643mg)和2,7-二氯喹唑啉-8-醇(400mg)，反应体系移至室温反应1小时。TLC显示原料反应完毕。反应液加水(20mL)淬灭，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱色谱纯化得标题化合物450mg。 Dissolve triphenylphosphine (732 mg) in anhydrous tetrahydrofuran (15 mL), add diisopropyl azodicarboxylate (564 mg) dropwise at 0° C., stir for 15 minutes after addition, and then add trans-4-(( tert-butyldimethylsilyl)oxy)cyclohex-1-ol (643 mg) and 2,7-dichloroquinazolin-8-ol (400 mg), and the reaction system was moved to room temperature for 1 hour. TLC showed complete reaction of starting material. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 450 mg of the title compound.
MS(ESI)m/z(M+H)+＝427.1。MS (ESI) m/z (M+H) + = 427.1.
制备例15：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 15: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(3-((methylthio) Preparation of methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝544.1.MS (ESI) m/z (M+H) + = 544.1.
制备例16：2-((甲硫基)甲基)吡啶-4-胺的制备
Preparation Example 16: Preparation of 2-((methylthio)methyl)pyridin-4-amine
步骤1：2-(溴甲基)-4-氯吡啶的制备
Step 1: Preparation of 2-(bromomethyl)-4-chloropyridine
将(4-氯吡啶-2-基)甲醇(1.4g)溶于二氯甲烷(20mL)，0℃下分别加入三苯基膦(3.9g)和N-溴代丁二酰亚胺(2.7g)，室温反应1小时。反应液加水淬灭，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得粗品2.01g，无需纯化直接用于下一步反应。(4-Chloropyridin-2-yl)methanol (1.4g) was dissolved in dichloromethane (20mL), and triphenylphosphine (3.9g) and N-bromosuccinimide (2.7 g), react at room temperature for 1 hour. The reaction solution was quenched with water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.01 g of a crude product, which was directly used in the next reaction without purification.
MS(ESI)m/z(M+H)+＝206.1MS (ESI) m/z (M+H) + = 206.1
步骤2：4-氯-2-((甲硫基)甲基)吡啶制备
Step 2: Preparation of 4-chloro-2-((methylthio)methyl)pyridine
将2-(溴甲基)-4-氯吡啶(2.0g)溶于四氢呋喃(20mL)，-20℃下滴加20％甲硫醇钠水溶液(5mL)，反应过夜。乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱色谱纯化得标题化合物0.95g。2-(Bromomethyl)-4-chloropyridine (2.0 g) was dissolved in tetrahydrofuran (20 mL), and 20% aqueous solution of sodium methylthiolate (5 mL) was added dropwise at -20°C to react overnight. Extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and the crude product is purified by column chromatography to obtain 0.95 g of the title compound.
MS(ESI)m/z(M+H)+＝174.1。MS (ESI) m/z (M+H) + = 174.1.
步骤3：(2-((甲硫基)甲基)吡啶-4-基)氨基甲酸叔丁酯制备
Step 3: Preparation of tert-butyl (2-((methylthio)methyl)pyridin-4-yl)carbamate
将4-氯-2-((甲硫基)甲基)吡啶(70mg)和氨基甲酸叔丁酯(940mg)溶于1,4-二氧六环(10mL)，分别加入碳酸铯(2.6g)、三苄叉丙酮二钯(194mg)和2-二环己基膦-2',4',6'-三异丙基联苯(384mg)，氩气置换三次，90℃下反应5小时。反应液降至室温，滤去不溶物，收集滤液，浓缩，粗品经柱色谱纯化得标题化合物500mg。4-Chloro-2-((methylthio)methyl)pyridine (70mg) and tert-butyl carbamate (940mg) were dissolved in 1,4-dioxane (10mL), cesium carbonate (2.6g ), tribenzylideneacetone dipalladium (194 mg) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (384 mg), replaced with argon three times, and reacted at 90°C for 5 hours. The reaction solution was lowered to room temperature, and the insoluble matter was filtered off. The filtrate was collected and concentrated. The crude product was purified by column chromatography to obtain 500 mg of the title compound.
MS(ESI)m/z(M+H)+＝255.1.MS (ESI) m/z (M+H) + = 255.1.
步骤4：2-((甲硫基)甲基)吡啶-4-胺制备
Step 4: Preparation of 2-((methylthio)methyl)pyridin-4-amine
将2-((甲硫基)甲基)吡啶-4-基)氨基甲酸叔丁酯(500mg)溶于氯化氢/1,4-二氧六环溶液(10mL)，40℃反应1小时。减压浓缩除去溶剂，粗品经反相柱色谱纯化得标题化合物120mg。Dissolve tert-butyl 2-((methylthio)methyl)pyridin-4-yl)carbamate (500 mg) in hydrogen chloride/1,4-dioxane solution (10 mL), and react at 40°C for 1 hour. Concentrate under reduced pressure to remove the solvent, and the crude product is purified by reverse-phase column chromatography to obtain 120 mg of the title compound.
MS(ESI)m/z(M+H)+＝155.1.MS (ESI) m/z (M+H) + = 155.1.
制备例17：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(2-((甲硫基)甲基)吡啶-4-基)喹唑啉-2-胺的制备
Preparation 17: 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(2-((methylthio) Preparation of methyl)pyridin-4-yl)quinazolin-2-amine
氮气氛中，将2-((甲硫基)甲基)吡啶-4-胺(20mg)，7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯喹唑啉(50mg)，(±)-2,2′-双(二苯基膦)-1,1′-联萘(35mg)，三(二亚苄基丙酮)二钯(25mg)和碳酸铯(70mg)溶于甲苯(50mL)，90℃下加热反应6小时。冷却至室温，过滤除掉固体，滤饼用乙酸乙酯洗涤，合并有机相，浓缩，粗品经硅胶柱层析分离得到标题化合物15mg。In a nitrogen atmosphere, 2-((methylthio)methyl)pyridin-4-amine (20 mg), 7-bromo-8-((cis-4-((tert-butyldimethylsilyl) Oxy)cyclohexyl)oxy)-2-chloroquinazoline (50mg), (±)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (35mg), three (di Benzylideneacetone) dipalladium (25mg) and cesium carbonate (70mg) were dissolved in toluene (50mL), and heated at 90°C for 6 hours. Cool to room temperature, remove the solid by filtration, wash the filter cake with ethyl acetate, combine the organic phases, concentrate, and separate the crude product by silica gel column chromatography to obtain 15 mg of the title compound.
MS(ESI)m/z(M+H)+＝589.2,591.2.MS (ESI) m/z (M+H) + = 589.2, 591.2.
制备例18：4-((甲硫基)甲基)吡啶-2-胺的制备
Preparation Example 18: Preparation of 4-((methylthio)methyl)pyridin-2-amine
步骤1：(2-硝基吡啶-4-基)甲醇的制备
Step 1: Preparation of (2-nitropyridin-4-yl)methanol
氮气氛围中，将2-硝基异烟酸(2.0g)溶于四氢呋喃(100mL)，缓慢加入硼烷溶液(40mL)，反应12小时。TLC和LCMS显示反应完全。加水(50mL)，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化，得到的固体再用石油醚洗涤，干燥后得标题化合物1.7g。In a nitrogen atmosphere, 2-nitroisonicotinic acid (2.0 g) was dissolved in tetrahydrofuran (100 mL), and borane solution (40 mL) was slowly added to react for 12 hours. TLC and LCMS showed the reaction was complete. Add water (50 mL), extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate. The obtained crude product is purified by column chromatography, and the obtained solid is washed with petroleum ether and dried to obtain 1.7 g of the title compound.
MS(ESI)m/z(M+H)+＝155.0。MS (ESI) m/z (M+H) + = 155.0.
后续步骤参考制备例1中类似的方法制备得到本制备例的化合物。The following steps refer to the similar method in Preparation Example 1 to prepare the compound of this preparation example.
MS(ESI)m/z(M+H)+＝155.1.MS (ESI) m/z (M+H) + = 155.1.
制备例19：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(4-((甲硫基)甲基)吡啶-2-基)喹唑啉-2-胺的制备
Preparation 19: 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(4-((methylthio) Preparation of methyl)pyridin-2-yl)quinazolin-2-amine
MS(ESI)m/z(M+H)+＝589.2,591.2.MS (ESI) m/z (M+H) + = 589.2, 591.2.
后续步骤参考制备例17中类似的方法制备得到本制备例的化合物。For subsequent steps, refer to the similar method in Preparation Example 17 to prepare the compound of this preparation example.
制备例20：8-(((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-环丙基-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 20: 8-(((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-cyclopropyl-N-(3-((methylsilyl) Preparation of thio)methyl)phenyl)quinazolin-2-amine
氮气氛中，将7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺(200mg)，环丙基硼酸(80mg)，2-二环己膦基-2'-(N,N-二甲胺)-联苯(70mg)，三(二亚苄基丙酮)二钯(70mg)和磷酸钾(210mg)溶于甲苯(50mL)，90℃下加热反应1小时。冷却至室温，过滤除掉固体，滤饼用乙酸乙酯洗涤，合并有机相，浓缩，粗品经制备HPLC纯化得标题化合物45mg。In a nitrogen atmosphere, 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio ) methyl) phenyl) quinazoline-2-amine (200mg), cyclopropyl boronic acid (80mg), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl ( 70 mg), tris(dibenzylideneacetone) dipalladium (70 mg) and potassium phosphate (210 mg) were dissolved in toluene (50 mL), and heated at 90°C for 1 hour. Cool to room temperature, remove the solid by filtration, wash the filter cake with ethyl acetate, combine the organic phases, concentrate, and purify the crude product by preparative HPLC to obtain 45 mg of the title compound.
MS(ESI)m/z(M+H)+＝550.2.MS (ESI) m/z (M+H) + = 550.2.
制备例21：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(2-((甲硫基)甲基)吡啶-4-基)喹唑啉-2-胺的制备
Preparation 21: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methylthio) Preparation of methyl)pyridin-4-yl)quinazolin-2-amine
将8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2,7-二氯喹唑啉(220mg)、2-((甲硫基)甲基)吡啶-4-胺(94mg)、碳酸铯(332mg)、三(二亚苄基丙酮)二钯(23mg)和2-二环己膦基-2'-(N,N-二甲胺)-联苯(40mg)溶于甲苯(7mL)，氩气置换三次后体系于90℃反应5小时。TLC显示原料反应完毕。反应液降至室温，滤去不溶物，收集滤液，浓缩，粗品经柱色谱纯化得标题化合物170mg。8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline (220mg), 2-((methylthio base)methyl)pyridin-4-amine (94mg), cesium carbonate (332mg), tris(dibenzylideneacetone)dipalladium (23mg) and 2-dicyclohexylphosphino-2'-(N,N- Dimethylamine)-biphenyl (40mg) was dissolved in toluene (7mL), and the system was reacted at 90°C for 5 hours after argon replacement three times. TLC showed complete reaction of starting material. The reaction solution was lowered to room temperature, and the insoluble matter was filtered off. The filtrate was collected and concentrated. The crude product was purified by column chromatography to obtain 170 mg of the title compound.
MS(ESI)m/z(M+H)+＝545.1。MS (ESI) m/z (M+H) + = 545.1.
制备例22：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(4-((甲硫基)甲基)吡啶-2-基)喹唑啉-2-胺的制备
Preparation 22: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(4-((methylthio) Preparation of methyl)pyridin-2-yl)quinazolin-2-amine
MS(ESI)m/z(M+H)+＝545.1。MS (ESI) m/z (M+H) + = 545.1.
后续步骤参考制备例17中类似的方法制备得到本制备例的化合物。For subsequent steps, refer to the similar method in Preparation Example 17 to prepare the compound of this preparation example.
制备例23：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-甲基-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 23: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-methyl-N-(3-((methylthio ) methyl) phenyl) quinazoline-2-amine preparation
将7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺(117.73mg)、甲基三氟硼酸钾(35.46mg)、碳酸铯(189.51mg)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(7.17mg)溶于1,4-二氧六环(5mL)和水(1mL)，氮气置换3次，反应体系升温到100℃反应10小时。LC-MS监测显示反应完成，将反应液浓缩，粗品经柱层析纯化得标题化合物120mg。7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl) Phenyl)quinazolin-2-amine (117.73 mg), potassium methyltrifluoroborate (35.46 mg), cesium carbonate (189.51 mg), and [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (7.17 mg) was dissolved in 1,4-dioxane (5 mL) and water (1 mL), replaced with nitrogen three times, and the temperature of the reaction system was raised to 100° C. for 10 hours. LC-MS monitoring showed that the reaction was complete, the reaction solution was concentrated, and the crude product was purified by column chromatography to obtain 120 mg of the title compound.
MS(ESI)m/z(M+H)+＝524.3.MS (ESI) m/z (M+H) + = 524.3.
制备例24：反式-4-((叔丁基二甲基甲硅烷基)氧基)环己-1-醇的制备
Preparation 24: Preparation of trans-4-((tert-butyldimethylsilyl)oxy)cyclohexan-1-ol
将反式-1,4-环己二醇(5.0g)溶于二氯甲烷(100mL)，缓慢加入N-甲基咪唑(2.0g)和叔丁基二甲基氯硅烷(5.3g)，室温反应2小时。TLC和LCMS显示反应完全。加水和二氯甲烷萃取四次，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物6.0g。Dissolve trans-1,4-cyclohexanediol (5.0g) in dichloromethane (100mL), slowly add N-methylimidazole (2.0g) and tert-butyldimethylsilyl chloride (5.3g), React at room temperature for 2 hours. TLC and LCMS showed the reaction was complete. Add water and dichloromethane to extract four times, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and the obtained crude product is purified by column chromatography to obtain 6.0 g of the title compound.
制备例25：7-氰基-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 25: 7-cyano-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio ) methyl) phenyl) quinazoline-2-amine preparation
在惰性气体保护条件下，将7-溴-8-(顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺(200mg)溶于N,N-二甲基甲酰胺(20mL)，加入2-二环己膦基-2'-(N,N-二甲胺)-联苯(120mg)和三(二亚苄基丙酮)二钯(93mg)以及氰化锌(197mg)，90℃加热反应3小时。TLC和LCMS显示反应完全。将反应液加水和二氯甲烷萃取四次，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化，得到的固体再用石油醚洗涤，干燥后得标题化合物100mg。Under inert gas protection conditions, 7-bromo-8-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methyl Thio)methyl)phenyl)quinazolin-2-amine (200mg) was dissolved in N,N-dimethylformamide (20mL), and 2-dicyclohexylphosphino-2'-(N,N -Dimethylamine)-biphenyl (120mg), tris(dibenzylideneacetone)dipalladium (93mg) and zinc cyanide (197mg), reacted by heating at 90°C for 3 hours. TLC and LCMS showed the reaction was complete. The reaction solution was extracted four times with water and dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography, and the obtained solid was washed with petroleum ether and dried to obtain 100 mg of the title compound.
MS(ESI)m/z(M+H)+＝535.3。MS (ESI) m/z (M+H) + = 535.3.
制备例26：5-((甲硫基)甲基)吡啶-3-胺的制备
Preparation 26: Preparation of 5-((methylthio)methyl)pyridin-3-amine
步骤1:5-((叔丁氧羰基)氨基)烟酸甲酯的制备
Step 1: Preparation of 5-((tert-butoxycarbonyl)amino)nicotinic acid methyl ester
将5-氨基烟酸甲酯(7.0g)溶于二氯甲烷(50mL)中，在室温下依次加入三乙胺(13.0 mL)，4-二甲氨基吡啶(560mg)和二碳酸二叔丁酯(12.0g)后继续在室温下反应。搅拌24小时后，直接抽干溶剂，硅胶柱层析分离得到标题化合物(9.2g)。5-aminonicotinic acid methyl ester (7.0g) was dissolved in dichloromethane (50mL), and triethylamine (13.0 mL), 4-dimethylaminopyridine (560 mg) and di-tert-butyl dicarbonate (12.0 g) to continue the reaction at room temperature. After stirring for 24 hours, the solvent was directly sucked dry, and the title compound (9.2 g) was obtained by silica gel column chromatography.
MS(ESI)m/z(M+H)+＝253.1.MS (ESI) m/z (M+H) + = 253.1.
步骤2:(5-(羟甲基)吡啶-3-基)氨基甲酸叔丁酯的制备
Step 2: Preparation of (5-(hydroxymethyl)pyridin-3-yl) tert-butyl carbamate
将5-((叔丁氧羰基)氨基)烟酸甲酯(9.0g)溶于甲醇(100mL)中，在0℃下缓慢加入硼氢化钠(5.4g)然后然后继续在室温下反应。2小时后经LCMS检查反应完全，加入水以及饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并，干燥，过滤，减压抽干溶剂得到标题化合物(6.8g)。Methyl 5-((tert-butoxycarbonyl)amino)nicotinate (9.0 g) was dissolved in methanol (100 mL), sodium borohydride (5.4 g) was slowly added at 0°C and then the reaction was continued at room temperature. After 2 hours, the reaction was checked by LCMS. The reaction was quenched by adding water and saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined, dried, filtered, and the solvent was vacuum-drained to obtain the title compound (6.8 g).
MS(ESI)m/z(M+H)+＝225.1.MS (ESI) m/z (M+H) + = 225.1.
步骤3:(5-(氯甲基)吡啶-3-基)氨基甲酸叔丁酯的制备
Step 3: Preparation of (5-(chloromethyl)pyridin-3-yl)tert-butyl carbamate
将(5-(羟甲基)吡啶-3-基)氨基甲酸叔丁酯(6.0g)溶于无水二甲基亚砜(100mL)中，缓慢加入三聚氯氰(6.0g)，室温反应1小时。TLC检测反应完全，加入水搅拌5分钟，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物4.5g。Dissolve tert-butyl (5-(hydroxymethyl)pyridin-3-yl)carbamate (6.0g) in anhydrous dimethyl sulfoxide (100mL), slowly add cyanuric chloride (6.0g), and React for 1 hour. The reaction was complete as detected by TLC, added water and stirred for 5 minutes, extracted with dichloromethane, combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 4.5 g of the title compound.
MS(ESI)m/z(M+H)+＝243.1.MS (ESI) m/z (M+H) + = 243.1.
步骤4:(5-((甲硫基)甲基)吡啶-3-基)氨基甲酸叔丁酯的制备
Step 4: Preparation of (5-((methylthio)methyl)pyridin-3-yl)tert-butyl carbamate
将(5-(氯甲基)吡啶-3-基)氨基甲酸叔丁酯(4.0g)溶于乙醇(20mL)，在0℃下缓慢滴加甲硫醇钠的水溶液(20％in H2O，5.9mL)，反应20分钟。TLC检测反应完全，加入水，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱层析纯化得标题化合物3.2g。Dissolve tert-butyl (5-(chloromethyl)pyridin-3-yl)carbamate (4.0 g) in ethanol (20 mL), and slowly add an aqueous solution of sodium methylthiolate (20% in H 2 0, 5.9mL), reacted for 20 minutes. TLC detected that the reaction was complete, water was added, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain 3.2 g of the title compound.
MS(ESI)m/z(M+H)+＝255.1.MS (ESI) m/z (M+H) + = 255.1.
步骤5：5-((甲硫基)甲基)吡啶-3-胺的制备
Step 5: Preparation of 5-((methylthio)methyl)pyridin-3-amine
将(5-((甲硫基)甲基)吡啶-3-基)氨基甲酸叔丁酯(3.0g)在室温下溶于盐酸二氧六环溶液(4M,30mL)中，然后加热至60℃反应。1小时后经LCMS检测反应完全，反应液冷却至室温，减压浓缩后反向柱层析得到标题化合物(1.5g)。Dissolve tert-butyl (5-((methylthio)methyl)pyridin-3-yl)carbamate (3.0 g) in dioxane hydrochloride solution (4M, 30 mL) at room temperature, then heat to 60 ℃ reaction. After 1 hour, the reaction was detected by LCMS. The reaction solution was cooled to room temperature, concentrated under reduced pressure and then reversed column chromatography to obtain the title compound (1.5 g).
MS(ESI)m/z(M+H)+＝155.1.MS (ESI) m/z (M+H) + = 155.1.
制备例27：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(5-((甲硫基)甲基)吡啶-3-基)喹唑啉-2-胺的制备Preparation 27: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(5-((methylthio) Preparation of methyl)pyridin-3-yl)quinazolin-2-amine
将8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2,7-二氯喹唑啉(220mg)、5-((甲硫基)甲基)吡啶-3-胺(160mg)、碳酸铯(340mg)、三(二亚苄基丙酮)二钯(80mg)和2-二环己膦基-2'-(N,N-二甲胺)-联苯(61mg)溶于甲苯(30mL)中，氩气置换三次后体系于90℃反应5小时。TLC显示原料反应完毕。反应液降至室温，滤去不溶物，收集滤液，浓缩，粗品经柱色谱纯化得标题化合物170mg。8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloroquinazoline (220mg), 5-((methylthio base)methyl)pyridin-3-amine (160mg), cesium carbonate (340mg), tris(dibenzylideneacetone)dipalladium (80mg) and 2-dicyclohexylphosphino-2'-(N,N- Dimethylamine)-biphenyl (61 mg) was dissolved in toluene (30 mL), and the system was reacted at 90° C. for 5 hours after argon replacement three times. TLC showed complete reaction of starting material. The reaction solution was lowered to room temperature, and the insoluble matter was filtered off. The filtrate was collected and concentrated. The crude product was purified by column chromatography to obtain 170 mg of the title compound.
MS(ESI)m/z(M+H)+＝545.2.MS (ESI) m/z (M+H) + = 545.2.
制备例28：4-(4-甲基哌嗪-1-基)-3-((甲硫基)甲基)苯胺的制备
Preparation 28: Preparation of 4-(4-methylpiperazin-1-yl)-3-((methylthio)methyl)aniline
步骤1：(2-(4-甲基哌嗪-1-基)-5-硝基苯基)甲醇的制备
Step 1: Preparation of (2-(4-methylpiperazin-1-yl)-5-nitrophenyl)methanol
将2-氟-5-硝基苄醇(2.0g)与N-甲基哌嗪(3.5g)置于微波管中，然后在100℃下反应。2小时后经LCMS监测反应完全，加入水以及饱和碳酸氢钠水溶液搅拌10分钟，二氯甲 烷萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩得到标题化合物(1.5g)。2-Fluoro-5-nitrobenzyl alcohol (2.0 g) and N-methylpiperazine (3.5 g) were placed in a microwave tube, and reacted at 100°C. After 2 hours, the reaction was monitored by LCMS, and water and saturated aqueous sodium bicarbonate solution were added and stirred for 10 minutes, dichloromethane Extract with alkane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the title compound (1.5 g).
MS(ESI)m/z(M+H)+＝252.1。MS (ESI) m/z (M+H) + = 252.1.
步骤2：1-(2-(溴甲基)-4-硝基苯基)-4-甲基哌嗪的制备
Step 2: Preparation of 1-(2-(bromomethyl)-4-nitrophenyl)-4-methylpiperazine
参考制备例6中类似的方法制备得到本标题化合物。The title compound was prepared by referring to the similar method in Preparation Example 6.
MS(ESI)m/z(M+H)+＝314.0,316.0。MS (ESI) m/z (M+H) + = 314.0, 316.0.
步骤3：1-甲基-4-(2-((甲硫基)甲基)-4-硝基苯基)哌嗪的制备
Step 3: Preparation of 1-methyl-4-(2-((methylthio)methyl)-4-nitrophenyl)piperazine
参考制备例6中类似的方法制备得到本标题化合物。The title compound was prepared by referring to the similar method in Preparation Example 6.
MS(ESI)m/z(M+H)+＝282.1。MS (ESI) m/z (M+H) + = 282.1.
步骤4：4-(4-甲基哌嗪-1-基)-3-((甲硫基)甲基)苯胺的制备
Step 4: Preparation of 4-(4-methylpiperazin-1-yl)-3-((methylthio)methyl)aniline
将1-甲基-4-(2-((甲硫基)甲基)-4-硝基苯基)哌嗪(510mg)在室温下溶于醋酸(5mL)中，然后加入锌粉(500mg)并于室温下反应。15分钟后经过LCMS监测反应完全，过滤除掉多余固体后，减压抽干溶剂得到固体粗品。固体粗品溶于二氯甲烷，加入饱和碳酸氢钠水溶液调节溶液至碱性，分离有机相，水相用二氯甲烷萃取多次，合并，干燥，过滤，减压浓缩得到标题化合物(350mg)。1-Methyl-4-(2-((methylthio)methyl)-4-nitrophenyl)piperazine (510 mg) was dissolved in acetic acid (5 mL) at room temperature, then zinc powder (500 mg ) and react at room temperature. After 15 minutes, the completion of the reaction was monitored by LCMS. After the excess solid was removed by filtration, the solvent was dried under reduced pressure to obtain a crude solid. The crude solid was dissolved in dichloromethane, and saturated aqueous sodium bicarbonate solution was added to adjust the solution to basicity. The organic phase was separated, and the aqueous phase was extracted several times with dichloromethane, combined, dried, filtered, and concentrated under reduced pressure to obtain the title compound (350 mg).
MS(ESI)m/z(M+H)+＝282.1。MS (ESI) m/z (M+H) + = 282.1.
制备例29：7-溴-8-(顺式-4-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(4-(4-甲基哌嗪-1-基)-3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 29: 7-Bromo-8-(cis-4-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(4- Preparation of (4-methylpiperazin-1-yl)-3-((methylthio)methyl)phenyl)quinazolin-2-amine
后续相关步骤参考制备例3中类似的方法制备得到本制备例的化合物。 For subsequent related steps, refer to the similar method in Preparation Example 3 to prepare the compound of this Preparation Example.
MS(ESI)m/z(M+H)+＝686.2,688.2.MS (ESI) m/z (M+H) + = 686.2, 688.2.
制备例30：2-氨基-6-氟-3-甲氧基苯甲酸的制备
Preparation 30: Preparation of 2-amino-6-fluoro-3-methoxybenzoic acid
步骤1：3,6-二氟-2-硝基苯甲酸的制备
Step 1: Preparation of 3,6-difluoro-2-nitrobenzoic acid
将2,5-二氟苯甲酸(10.0g)置于圆底烧瓶中，在冰浴环境下加入浓硫酸(30mL)，然后缓慢加入浓硫酸(9mL)和浓硝酸(9mL)的混合液体并继续在室温下搅拌12小时。TLC监测反应完全后，加入水，然后二氯甲烷萃取多次，合并有机相，无水硫酸钠干燥，过滤，浓缩得到标题化合物的混合物(10.0g)。2,5-difluorobenzoic acid (10.0 g) was placed in a round-bottomed flask, concentrated sulfuric acid (30 mL) was added in an ice-bath environment, and then a mixed liquid of concentrated sulfuric acid (9 mL) and concentrated nitric acid (9 mL) was added slowly and Stirring was continued at room temperature for 12 hours. After the reaction was complete as monitored by TLC, water was added, and then dichloromethane was extracted several times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of the title compound (10.0 g).
步骤2：3,6-二氟-2-硝基苯甲酸甲酯的制备
Step 2: Preparation of methyl 3,6-difluoro-2-nitrobenzoate
将3,6-二氟-2-硝基苯甲酸的混合物(21.0g)在氮气环境中溶于干燥的二氯甲烷(200mL)中，在0℃下加入二异丙基乙基胺(30.0g)，然后加入三甲氧鎓四氟硼酸盐(18.5g)并在室温下继续反应10小时。反应完全后，加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析分离得到标题化合物(9.0g)。A mixture of 3,6-difluoro-2-nitrobenzoic acid (21.0 g) was dissolved in dry dichloromethane (200 mL) in a nitrogen atmosphere, and diisopropylethylamine (30.0 g), then trimethoxonium tetrafluoroborate (18.5 g) was added and the reaction was continued for 10 hours at room temperature. After the reaction was complete, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain the title compound (9.0 g).
步骤3：6-氟-3-甲氧基-2-硝基苯甲酸甲酯的制备
Step 3: Preparation of methyl 6-fluoro-3-methoxy-2-nitrobenzoate
将3,6-二氟-2-硝基苯甲酸甲酯(8.5g)在氮气保护下溶于干燥的甲醇(50mL)中，缓慢加入甲醇钠(3.2g)后继续在室温下反应。12小时后经过TLC监测反应完全，加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，硅胶 柱层析分离得到标题化合物(7.0g)。Methyl 3,6-difluoro-2-nitrobenzoate (8.5g) was dissolved in dry methanol (50mL) under nitrogen protection, and sodium methoxide (3.2g) was added slowly to continue the reaction at room temperature. After 12 hours, the reaction was monitored by TLC, and the reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and silica gel Separation by column chromatography gave the title compound (7.0 g).
步骤4：6-氟-3-甲氧基-2-硝基苯甲酸的制备
Step 4: Preparation of 6-fluoro-3-methoxy-2-nitrobenzoic acid
将6-氟-3-甲氧基-2-硝基苯甲酸甲酯(6.0g)溶于四氢呋喃(50mL)中，然后加入氢氧化钠(1.6g)并继续在室温下反应。2小时后经TLC监测反应完全，加入水，加入盐酸调节pH<3，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到标题化合物(4.5g)。Methyl 6-fluoro-3-methoxy-2-nitrobenzoate (6.0 g) was dissolved in tetrahydrofuran (50 mL), then sodium hydroxide (1.6 g) was added and the reaction was continued at room temperature. After 2 hours, the reaction was complete as monitored by TLC. Water was added, hydrochloric acid was added to adjust the pH<3, and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (4.5 g).
步骤5：2-氨基-6-氟-3-甲氧基苯甲酸的制备
Step 5: Preparation of 2-amino-6-fluoro-3-methoxybenzoic acid
将6-氟-3-甲氧基-2-硝基苯甲酸(4.0g)溶于溶于乙醇/水(100mL,3:1)，加入铁粉(50.0g)和氯化铵(20.0g)，90℃加热反应1小时。TLC显示反应完毕，过滤除去不溶物，收集滤液，浓缩除去溶剂得标题化合物2.8g。Dissolve 6-fluoro-3-methoxy-2-nitrobenzoic acid (4.0g) in ethanol/water (100mL, 3:1), add iron powder (50.0g) and ammonium chloride (20.0g ), heated at 90°C for 1 hour. TLC showed that the reaction was complete, and the insoluble matter was removed by filtration, the filtrate was collected, and concentrated to remove the solvent to obtain 2.8 g of the title compound.
MS(ESI)m/z(M+H)+＝186.0。MS (ESI) m/z (M+H) + = 186.0.
制备例31：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2,7-二氯-5-氟喹唑啉的制备
Preparation 31: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloro-5-fluoroquinazoline
步骤1：5-氟-8-甲氧基喹唑啉-2,4(1H,3H)-二酮的制备
Step 1: Preparation of 5-fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione
将2-氨基-6-氟-3-甲氧基苯甲酸(20.0g)与尿素(30.0g)均匀混合后，在160℃下加热反 应6小时。TLC和LCMS显示反应完全。趁热加入水(100mL)析出固体，过滤，收集固体，石油醚洗涤，干燥，得标题化合物18.0g。After uniformly mixing 2-amino-6-fluoro-3-methoxybenzoic acid (20.0g) and urea (30.0g), heat reaction at 160°C Should be 6 hours. TLC and LCMS showed the reaction was complete. Water (100 mL) was added while hot to precipitate a solid, which was collected by filtration, washed with petroleum ether, and dried to obtain 18.0 g of the title compound.
MS(ESI)m/z(M+H)+＝211.0。MS (ESI) m/z (M+H) + = 211.0.
步骤2：2,4-二氯-5-氟-8-甲氧基喹唑啉的制备
Step 2: Preparation of 2,4-dichloro-5-fluoro-8-methoxyquinazoline
将5-氟-8-甲氧基喹唑啉-2,4(1H,3H)-二酮(18.0g)溶于三氯氧磷(100mL)，逐滴加入N,N-二甲基苯胺(30.0g)，130℃下回流反应3小时。TLC和LCMS显示反应完全。将反应液浓缩除去多余三氯氧磷，残留物缓慢加入到饱和碳酸氢钠的冰水溶液中，二氯甲烷萃取四次，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物14.0g。Dissolve 5-fluoro-8-methoxyquinazoline-2,4(1H,3H)-dione (18.0 g) in phosphorus oxychloride (100 mL), and add N,N-dimethylaniline dropwise (30.0 g), reflux reaction at 130° C. for 3 hours. TLC and LCMS showed the reaction was complete. Concentrate the reaction solution to remove excess phosphorus oxychloride, slowly add the residue into saturated ice solution of sodium bicarbonate, extract four times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the obtained crude product is passed through the column Purified by chromatography to obtain 14.0 g of the title compound.
MS(ESI)m/z(M+H)+＝247.0。MS (ESI) m/z (M+H) + = 247.0.
步骤3：2-氯-5-氟-8-甲氧基喹唑啉的制备
Step 3: Preparation of 2-chloro-5-fluoro-8-methoxyquinazoline
将2,4-二氯-5-氟-8-甲氧基喹唑啉(13.5g)，四三苯基膦钯(13.5g)和三正丁基锡氢(18.2g)置于圆底烧瓶中，氮气保护后加入无水四氢呋喃(50mL)后继续在室温下反应。24小时后经TLC监测反应完全，直接浓缩除去溶剂后硅胶柱层析纯化得到标题化合物(11.3g)。2,4-Dichloro-5-fluoro-8-methoxyquinazoline (13.5 g), tetrakistriphenylphosphine palladium (13.5 g) and tri-n-butyltin hydrogen (18.2 g) were placed in a round bottom flask , After nitrogen protection, anhydrous tetrahydrofuran (50 mL) was added and the reaction was continued at room temperature. After 24 hours, the reaction was complete as monitored by TLC. The solvent was directly concentrated and purified by silica gel column chromatography to obtain the title compound (11.3 g).
MS(ESI)m/z(M+H)+＝213.0。MS (ESI) m/z (M+H) + = 213.0.
步骤4：2-氯-5-氟喹唑啉-8-醇的制备
Step 4: Preparation of 2-chloro-5-fluoroquinazolin-8-ol
将2-氯-5-氟-8-甲氧基喹唑啉(2.0g)在氮气环境下溶于干燥的二氯甲烷(10mL)中，缓慢加入三溴化硼(1M in CH2Cl2，15mL)，移至室温反应过夜。TLC和LCMS显示反应完全。将反应液加水淬灭，加入饱和碳酸氢钠水溶液调节pH>9，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物1.5g。2-Chloro-5-fluoro-8-methoxyquinazoline (2.0 g) was dissolved in dry dichloromethane (10 mL) under nitrogen atmosphere, and boron tribromide (1M in CH 2 Cl 2 , 15 mL), moved to room temperature and reacted overnight. TLC and LCMS showed the reaction was complete. The reaction solution was quenched with water, and saturated aqueous sodium bicarbonate solution was added to adjust the pH>9, and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography to obtain 1.5 g of the title compound.
MS(ESI)m/z(M+H)+＝199.0。 MS (ESI) m/z (M+H) + = 199.0.
步骤5：2,7-二氯-5-氟喹唑啉-8-醇的制备
Step 5: Preparation of 2,7-dichloro-5-fluoroquinazolin-8-ol
将2-氯-5-氟喹唑啉-8-醇(1.3g)溶于干燥的二氯甲烷(10mL)中，依次加入三氯化铝(92mg)和N-氯代丁二酰亚胺(1.1g)并继续在室温下反应。24小时后经LCMS监测反应完全，加入饱和碳酸氢钠水溶液淬灭反应，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物0.96g。Dissolve 2-chloro-5-fluoroquinazolin-8-ol (1.3g) in dry dichloromethane (10mL), add aluminum trichloride (92mg) and N-chlorosuccinimide successively (1.1 g) and continue to react at room temperature. After 24 hours, the reaction was monitored by LCMS. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography to obtain 0.96 g of the title compound .
MS(ESI)m/z(M+H)+＝233.0。MS (ESI) m/z (M+H) + = 233.0.
步骤6：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2,7-二氯-5-氟喹唑啉的制备
Step 6: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,7-dichloro-5-fluoroquinazoline
参考前述制备例2中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 2.
MS(ESI)m/z(M+H)+＝445.1。MS (ESI) m/z (M+H) + = 445.1.
制备例32：3-((甲基亚磺酰基)甲基)苯胺的制备
Preparation 32: Preparation of 3-((methylsulfinyl)methyl)aniline
步骤1：(3-溴苯基)甲醇的制备
Step 1: Preparation of (3-bromophenyl)methanol
将3-溴苯甲醛(6.8g)溶于甲醇(100mL)中，室温下加入硼氢化钠(1.8g)然后继续在室温下搅拌。反应经过TLC监测反应完全，加入饱和碳酸氢钠水溶液搅拌10分钟，二氯甲烷萃取、合并、干燥、过滤并减压抽干溶剂得到标题化合物(6.7g)。 3-Bromobenzaldehyde (6.8 g) was dissolved in methanol (100 mL), sodium borohydride (1.8 g) was added at room temperature and stirring was continued at room temperature. The completion of the reaction was monitored by TLC, and saturated aqueous sodium bicarbonate solution was added and stirred for 10 minutes, extracted with dichloromethane, combined, dried, filtered, and the solvent was vacuum-drained to obtain the title compound (6.7 g).
步骤2：1-溴-3-(溴甲基)苯的制备
Step 2: Preparation of 1-bromo-3-(bromomethyl)benzene
将(3-溴苯基)甲醇(10.0g)溶于二氯甲烷(150mL)中，在冰浴温度下缓慢加入三溴化磷(8.7g)并继续在室温下反应。反应经过TLC监测结束后，缓慢加入饱和碳酸氢钠水溶液调节溶液至碱性，二氯甲烷萃取、合并、干燥、过滤并减压抽干溶剂，硅胶柱层析分离得到标题化合物(11.5g)。(3-Bromophenyl)methanol (10.0 g) was dissolved in dichloromethane (150 mL), phosphorus tribromide (8.7 g) was slowly added at ice-bath temperature and the reaction was continued at room temperature. After the reaction was monitored by TLC, a saturated aqueous solution of sodium bicarbonate was slowly added to adjust the solution to alkalinity, extracted with dichloromethane, combined, dried, filtered and the solvent was drained under reduced pressure, and the title compound (11.5 g) was obtained by silica gel column chromatography.
步骤3：1-溴-3-((甲硫基)甲基)苯的制备
Step 3: Preparation of 1-bromo-3-((methylthio)methyl)benzene
将1-溴-3-(溴甲基)苯(11.5g)溶于四氢呋喃(120mL)中，在冰浴温度下缓慢加入甲硫醇钠水溶液(20％in H2O,21.4mL)并继续在室温下搅拌。30分钟后经过TLC监测反应完全，加入饱和碳酸氢钠水溶液，二氯甲烷萃取、合并、干燥、过滤并减压抽干溶剂，硅胶柱层析分离得到标题化合物(7.4g)。1-Bromo-3-(bromomethyl)benzene (11.5 g) was dissolved in tetrahydrofuran (120 mL), and an aqueous sodium methylthiolate solution (20% in H 2 O, 21.4 mL) was slowly added at ice-bath temperature and continued Stir at room temperature. After 30 minutes, the reaction was monitored by TLC, and saturated aqueous sodium bicarbonate was added, extracted with dichloromethane, combined, dried, filtered and the solvent was vacuum-drained, and the title compound (7.4 g) was obtained by silica gel column chromatography.
步骤4：1-溴-3-((甲基亚磺酰基)甲基)苯的制备
Step 4: Preparation of 1-bromo-3-((methylsulfinyl)methyl)benzene
将1-溴-3-((甲硫基)甲基)苯(7.4g)溶于乙腈(150mL)中，室温下加入三氯化铁(166mg)后搅拌10分钟，然后加入原高碘酸(8.2g)并继续在室温下反应。TLC监测反应完全后，加入硫代硫酸钠水溶液淬灭反应，二氯甲烷萃取、合并、干燥、过滤并减压抽干溶剂，硅胶柱层析分离得到标题化合物(3.9g)。Dissolve 1-bromo-3-((methylthio)methyl)benzene (7.4g) in acetonitrile (150mL), add ferric chloride (166mg) at room temperature and stir for 10 minutes, then add orthoperiodic acid (8.2 g) and continue to react at room temperature. After the reaction was complete as monitored by TLC, aqueous sodium thiosulfate solution was added to quench the reaction, extracted with dichloromethane, combined, dried, filtered and the solvent was vacuum-drained, and the title compound (3.9 g) was obtained by silica gel column chromatography.
步骤5：叔丁基(3-((甲基亚磺酰基)甲基)苯基)氨基甲酸酯的制备
Step 5: Preparation of tert-butyl(3-((methylsulfinyl)methyl)phenyl)carbamate
将1-溴-3-((甲基亚磺酰基)甲基)苯(200mg)、2-二环己膦基-2'-(N,N-二甲胺)-联苯(120mg)、三(二亚苄基丙酮)二钯(78mg)、碳酸铯(830mg)和氨基甲酸叔丁酯(200mg)在氮气保护下溶于1,4-Dioxane(20mL)中，然后与100℃下反应。6小时后经过LCMS监测反应完全，直接浓缩去除溶剂，硅胶柱层析分离得到标题化合物(120mg)。1-bromo-3-((methylsulfinyl)methyl)benzene (200mg), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (120mg), Tris(dibenzylideneacetone)dipalladium (78mg), cesium carbonate (830mg) and tert-butyl carbamate (200mg) were dissolved in 1,4-Dioxane (20mL) under nitrogen protection, and then reacted with . After 6 hours, the complete reaction was monitored by LCMS. The solvent was directly concentrated to remove, and the title compound (120 mg) was obtained by silica gel column chromatography.
MS(ESI)m/z(M+H)+＝270.1。MS (ESI) m/z (M+H) + = 270.1.
步骤6：3-((甲基亚磺酰基)甲基)苯胺的制备
Step 6: Preparation of 3-((methylsulfinyl)methyl)aniline
将叔丁基(3-((甲基亚磺酰基)甲基)苯基)氨基甲酸酯(100mg)溶于二氯甲烷(10mL)中，然后在室温下加入三氟乙酸(3.5mL)并继续在室温下反应。2小时后经LCMS监测反应完全，直接抽干溶剂得到粗品产物。将粗品产物溶于二氯甲烷中，加入饱和碳酸氢钠水溶液调节水层为碱性，分离有机相，二氯甲烷萃取水相、合并、干燥、过滤并减压抽干溶剂，硅胶柱层析分离得到标题化合物(50mg)。tert-Butyl(3-((methylsulfinyl)methyl)phenyl)carbamate (100 mg) was dissolved in dichloromethane (10 mL), then trifluoroacetic acid (3.5 mL) was added at room temperature And continue to react at room temperature. After 2 hours, the reaction was monitored by LCMS to complete, and the solvent was directly dried to obtain the crude product. Dissolve the crude product in dichloromethane, add saturated aqueous sodium bicarbonate to adjust the aqueous layer to be alkaline, separate the organic phase, extract the aqueous phase with dichloromethane, combine, dry, filter and dry the solvent under reduced pressure, silica gel column chromatography The title compound (50 mg) was isolated.
MS(ESI)m/z(M+H)+＝170.1。MS (ESI) m/z (M+H) + = 170.1.
制备例33：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-5-氟-N-(3-((甲基亚磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 33: 8-((cis-4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-5-fluoro-N-(3-(( Preparation of methylsulfinyl)methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝578.2。MS (ESI) m/z (M+H) + = 578.2.
制备例34：2-氟-5-((甲硫基)甲基)苯胺的制备
Preparation 34: Preparation of 2-fluoro-5-((methylthio)methyl)aniline
参考前述制备例6中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 6.
MS(ESI)m/z(M+H)+＝172.0。MS (ESI) m/z (M+H) + = 172.0.
制备例35：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(2-氟-5-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 35: 8-((cis-4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-fluoro-5-(( Preparation of methylthio)methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝562.1。MS (ESI) m/z (M+H) + = 562.1.
制备例36：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-(1-甲基-1H-吡唑-4-基)-N-(3-((甲基亚磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 36: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(1-methyl-1H-pyrazole-4- base)-N-(3-((methylsulfinyl)methyl)phenyl)quinazolin-2-amine
步骤1：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基亚磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 1: 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfinyl) ) methyl) phenyl) quinazoline-2-amine preparation
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝604.2,606.2。MS (ESI) m/z (M+H) + = 604.2, 606.2.
步骤2：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-(1-甲基-1H-吡唑-4-基)-N-(3-((甲基亚磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 2: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(1-methyl-1H-pyrazol-4-yl Preparation of )-N-(3-((methylsulfinyl)methyl)phenyl)quinazolin-2-amine
室温下，将7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基亚磺酰基)甲基)苯基)喹唑啉-2-胺(131mg)，1-甲基-4-(四甲基-1，3，2-二氧硼杂环戊烷-2-基)-1H-吡唑(68mg)，四三苯基膦钯(25mg)和碳酸钠(69mg)置于圆底烧瓶中，氮气保护后加入1， 4-二氧六环(10mL)和水(2mL)。升温到100℃反应3h，LCMS显示反应完全，减压浓缩后柱层析分离得到标题化合物(60mg)。At room temperature, 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfinyl Acyl)methyl)phenyl)quinazolin-2-amine (131mg), 1-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (68 mg), tetrakistriphenylphosphine palladium (25 mg) and sodium carbonate (69 mg) were placed in a round bottom flask, and 1 was added after nitrogen protection. 4-Dioxane (10 mL) and water (2 mL). The temperature was raised to 100° C. for 3 h. LCMS showed that the reaction was complete. After concentration under reduced pressure, the mixture was separated by column chromatography to obtain the title compound (60 mg).
MS(ESI)m/z(M+H)+＝606.3。MS (ESI) m/z (M+H) + = 606.3.
制备例37：6-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯喹唑啉的制备
Preparation 37: Preparation of 6-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloroquinazoline
步骤1：2-氨基-5-溴-3-甲氧基苯甲酸的制备
Step 1: Preparation of 2-amino-5-bromo-3-methoxybenzoic acid
将原料2-氨基-3-甲氧基苯甲酸(5.0g)溶于甲醇(60mL)中，冰浴下缓慢加入N-溴代丁二酰亚胺(5.6g)，加毕后将混合物在室温下搅拌过夜。经LCMS监测原料反应完全，将反应液缓慢滴加到冰水中，有固体析出，随后将固体过滤并用二氯甲烷洗涤后干燥得到标题化合物(6.0g)。The raw material 2-amino-3-methoxybenzoic acid (5.0g) was dissolved in methanol (60mL), and N-bromosuccinimide (5.6g) was slowly added under ice-cooling. Stir overnight at room temperature. The complete reaction of the starting material was monitored by LCMS. The reaction solution was slowly added dropwise to ice water, and a solid precipitated out. Then the solid was filtered, washed with dichloromethane and dried to obtain the title compound (6.0 g).
MS(ESI)m/z(M+H)+＝246.0，248.0。MS (ESI) m/z (M+H) + = 246.0, 248.0.
步骤2：(2-氨基-5-溴-3-甲氧基苯基)甲醇的制备
Step 2: Preparation of (2-amino-5-bromo-3-methoxyphenyl)methanol
在冰浴环境下，将原料2-氨基-5-溴-3-甲氧基苯甲酸(6.0g)溶于四氢呋喃(60mL)中，随后加入硼烷-四氢呋喃络合物(1M,125mL)，加毕，将反应液升温至50℃反应过夜。经LCMS监测原料反应完全，然后将混合物冷却至0℃，用MeOH(50mL)淬灭并浓缩至25mL。将残余物用碳酸钠水溶液(200mL)稀释，并用乙酸乙酯萃取，分离有机层，收集合并，用 无水Na2SO4干燥，过滤并浓缩得标题化合物(4.5g)。In an ice-bath environment, the raw material 2-amino-5-bromo-3-methoxybenzoic acid (6.0 g) was dissolved in tetrahydrofuran (60 mL), and then borane-tetrahydrofuran complex (1M, 125 mL) was added, After the addition was complete, the temperature of the reaction solution was raised to 50° C. to react overnight. The starting material was monitored for completion by LCMS, then the mixture was cooled to 0 °C, quenched with MeOH (50 mL) and concentrated to 25 mL. The residue was diluted with aqueous sodium carbonate (200 mL), and extracted with ethyl acetate, the organic layer was separated, collected and combined, and used Dry over anhydrous Na2SO4 , filter and concentrate to give the title compound (4.5g).
MS(ESI)m/z(M+H)+＝232.0，234.0。MS (ESI) m/z (M+H) + = 232.0, 234.0.
步骤3：2-氨基-5-溴-3-甲氧基苯甲醛的制备
Step 3: Preparation of 2-amino-5-bromo-3-methoxybenzaldehyde
将(2-氨基-5-溴-3-甲氧基苯基)甲醇(5.0g)溶于二氯甲烷(150mL)中，随后向反应液中加入二氧化锰(9.1g)，加毕，室温下反应过夜。经LCMS监测原料反应完全后，反应液过滤，收集滤液，减压浓缩得到标题化合物(1.52g)。(2-Amino-5-bromo-3-methoxyphenyl)methanol (5.0g) was dissolved in dichloromethane (150mL), then manganese dioxide (9.1g) was added to the reaction solution, and the addition was completed. React overnight at room temperature. After the complete reaction of the raw materials was monitored by LCMS, the reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the title compound (1.52 g).
MS(ESI)m/z(M+H)+＝230.0，232.0。MS (ESI) m/z (M+H) + = 230.0, 232.0.
步骤4：6-溴-8-甲氧基喹唑啉-2(1H)-酮的制备
Step 4: Preparation of 6-bromo-8-methoxyquinazolin-2(1H)-one
将2-氨基-5-溴-3-甲氧基苯甲醛(2.8g)溶于溶剂N-甲基吡咯烷酮(80mL)中，随后加入尿素(3.5g)并在180℃下反应5小时。经LCMS监测原料反应完全，将反应液冷却至100℃，随后缓慢加入水，有固体析出，过滤，滤饼用水洗涤，干燥得到标题化合物(2.5g)。2-Amino-5-bromo-3-methoxybenzaldehyde (2.8 g) was dissolved in solvent N-methylpyrrolidone (80 mL), followed by adding urea (3.5 g) and reacting at 180° C. for 5 hours. The complete reaction of the raw materials was monitored by LCMS. The reaction liquid was cooled to 100° C., and then water was slowly added, and solids were precipitated. After filtration, the filter cake was washed with water and dried to obtain the title compound (2.5 g).
MS(ESI)m/z(M+H)+＝255.0，257.0。MS (ESI) m/z (M+H) + = 255.0, 257.0.
步骤5：6-溴-2-氯-8-甲氧基喹唑啉的制备
Step 5: Preparation of 6-bromo-2-chloro-8-methoxyquinazoline
在冰浴条件下，将6-溴-8-甲氧基喹唑啉-2(1H)-酮(2.0g)溶于三氯氧磷(7.0mL)中，然后升温到120℃反应2小时。随后经LCMS监测原料反应完全，将反应液冷却至室温，浓缩除去多余三氯氧磷，残留物缓慢加入到饱和碳酸氢钠的冰水溶液中，二氯甲烷萃取四次，合并有机相，无水硫酸钠干燥，过滤，浓缩，所得粗品经柱层析纯化得标题化合物(0.9g)。Under ice-bath conditions, 6-bromo-8-methoxyquinazolin-2(1H)-one (2.0 g) was dissolved in phosphorus oxychloride (7.0 mL), and then heated to 120 ° C for 2 hours . Subsequently, the complete reaction of the raw materials was monitored by LCMS. The reaction solution was cooled to room temperature, concentrated to remove excess phosphorus oxychloride, and the residue was slowly added to an ice-water solution of saturated sodium bicarbonate, extracted four times with dichloromethane, and the organic phases were combined and anhydrous Dry over sodium sulfate, filter and concentrate, and the obtained crude product is purified by column chromatography to obtain the title compound (0.9 g).
MS(ESI)m/z(M+H)+＝273.0，275.0。MS (ESI) m/z (M+H) + = 273.0, 275.0.
剩余步骤参考前述制备例2中类似的方法制备得到本制备例的化合物。For the remaining steps, refer to the similar method in the aforementioned Preparation Example 2 to prepare the compound of this Preparation Example.
MS(ESI)m/z(M+H)+＝471.1，473.1。MS (ESI) m/z (M+H) + = 471.1, 473.1.
制备例38：6-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 38: 6-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio) Preparation of methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝588.2，590.2。MS (ESI) m/z (M+H) + = 588.2, 590.2.
制备例39：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯-7-氟喹唑啉的制备
Preparation 39: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloro-7-fluoroquinazoline
参考前述制备例14中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 14.
MS(ESI)m/z(M+H)+＝411.2。MS (ESI) m/z (M+H) + = 411.2.
制备例40：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氟-N-(2-((甲硫基)甲基)吡啶-4-基)喹唑啉-2-胺的制备
Preparation 40: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-fluoro-N-(2-((methylthio) Preparation of methyl)pyridin-4-yl)quinazolin-2-amine
参考前述制备例21中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 21.
MS(ESI)m/z(M+H)+＝529.2。MS (ESI) m/z (M+H) + = 529.2.
制备例41：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氟-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 41: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-fluoro-N-(3-((methylthio) Preparation of methyl)phenyl)quinazolin-2-amine
将8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-氯-7-氟喹唑啉(330mg)，3-((甲硫基)甲基)苯胺(140mg)，醋酸钯(22mg)，2-二环己基膦-2',4',6'-三异丙基联苯(81 mg)和碳酸铯(550mg)溶于1,4-二氧六环(40mL)，体系于无水无氧氮气保护条件下，90℃加热反应2小时。LCMS检测无原料剩余，过滤，收集滤液，浓缩，粗品经柱层析纯化得标题化合物(310mg)。8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-chloro-7-fluoroquinazoline (330 mg), 3-(( Methylthio)methyl)aniline (140mg), palladium acetate (22mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (81 mg) and cesium carbonate (550 mg) were dissolved in 1,4-dioxane (40 mL), and the system was heated at 90°C for 2 hours under the protection of anhydrous and oxygen-free nitrogen. LCMS detected that there was no remaining raw material. After filtration, the filtrate was collected and concentrated. The crude product was purified by column chromatography to obtain the title compound (310 mg).
MS(ESI)m/z(M+H)+＝528.2。MS (ESI) m/z (M+H) + = 528.2.
制备例42：4-氨基-2-((甲硫基)甲基)苯甲腈的制备
Preparation 42: Preparation of 4-amino-2-((methylthio)methyl)benzonitrile
步骤1：2-(溴甲基)-4-硝基苯甲腈的制备
Step 1: Preparation of 2-(bromomethyl)-4-nitrobenzonitrile
取2-甲基-4-硝基苄腈(1.62g)溶解于四氯化碳(30mL)中，分别加入溴代丁二酰亚胺(3.65g)和偶氮二异丁腈(330mg)，反应于氮气氛围下回流过夜，TLC检测无原料剩余。反应液降至室温，过滤，滤液浓缩后溶于四氢呋喃(30mL)，随后于冰浴下加入N,N-二异丙基乙胺(1.65mL)和亚磷酸二乙酯(1.78g)并于室温搅拌30分钟。反应液浓缩，经柱色谱纯化得到标题化合物(1.90g)。Dissolve 2-methyl-4-nitrobenzonitrile (1.62g) in carbon tetrachloride (30mL), add bromosuccinimide (3.65g) and azobisisobutyronitrile (330mg) respectively , and the reaction was refluxed overnight under a nitrogen atmosphere, and no raw material remained as detected by TLC. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated and dissolved in tetrahydrofuran (30mL), then N,N-diisopropylethylamine (1.65mL) and diethyl phosphite (1.78g) were added under ice-cooling and dissolved in Stir at room temperature for 30 minutes. The reaction solution was concentrated and purified by column chromatography to obtain the title compound (1.90 g).
后续相关步骤参考前述制备例1中类似的方法制备得到本制备例的化合物。Subsequent related steps refer to the similar method in the aforementioned Preparation Example 1 to prepare the compound of this Preparation Example.
MS(ESI)m/z(M+H)+＝179.1。MS (ESI) m/z (M+H) + = 179.1.
制备例43：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(4-氰基-3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 43: 8-((cis-4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(4-cyano-3-( Preparation of (methylthio)methyl)phenyl)quinazolin-2-amine
参考前述制备例41中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 41.
MS(ESI)m/z(M+H)+＝569.2。MS (ESI) m/z (M+H) + = 569.2.
制备例44：6-((甲硫基)甲基)吡啶-2-胺的制备
Preparation 44: Preparation of 6-((methylthio)methyl)pyridin-2-amine
步骤1：6-((叔丁氧羰基)氨基)吡啶甲酸甲酯的制备
Step 1: Preparation of methyl 6-((tert-butoxycarbonyl)amino)picolinate
参考前述制备例26中类似的方法制备得到本标题化合物。The title compound was prepared by referring to the similar method in the aforementioned Preparation Example 26.
MS(ESI)m/z(M+H)+＝253.1。MS (ESI) m/z (M+H) + = 253.1.
步骤2：(6-(羟甲基)吡啶-2-基)氨基甲酸叔丁酯的制备
Step 2: Preparation of tert-butyl (6-(hydroxymethyl)pyridin-2-yl)carbamate
参考前述制备例26中类似的方法制备得到本标题化合物。The title compound was prepared by referring to the similar method in the aforementioned Preparation Example 26.
MS(ESI)m/z(M+H)+＝225.1。MS (ESI) m/z (M+H) + = 225.1.
步骤3：(6-(溴甲基)吡啶-2-基)氨基甲酸叔丁酯的制备
Step 3: Preparation of tert-butyl (6-(bromomethyl)pyridin-2-yl)carbamate
参考前述制备例16中类似的方法制备得到本标题化合物。The title compound was prepared by referring to the similar method in the aforementioned Preparation Example 16.
MS(ESI)m/z(M+H)+＝287.0，289.0。MS (ESI) m/z (M+H) + = 287.0, 289.0.
后续相关步骤参考前述制备例26中类似的方法制备得到本制备例的化合物。For subsequent related steps, refer to the similar method in the aforementioned Preparation Example 26 to prepare the compound of this Preparation Example.
MS(ESI)m/z(M+H)+＝155.1。MS (ESI) m/z (M+H) + = 155.1.
制备例45：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(6-((甲硫基)甲基)吡啶-2-基)喹唑啉-2-胺的制备
Preparation 45: 8-((cis-4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(6-((methylthio) Preparation of methyl)pyridin-2-yl)quinazolin-2-amine
参考前述制备例21中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 21.
MS(ESI)m/z(M+H)+＝545.2。MS (ESI) m/z (M+H) + = 545.2.
制备例46：3-((甲硫基)甲基)-4-吗啉苯胺的制备
Preparation 46: Preparation of 3-((methylthio)methyl)-4-morpholine aniline
参考前述制备例28中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 28.
MS(ESI)m/z(M+H)+＝239.1。MS (ESI) m/z (M+H) + = 239.1.
制备例47：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(3-((甲硫基)甲基)-4-吗啉苯基)喹唑啉-2-胺的制备
Preparation 47: 8-((cis-4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(3-((methylthio) Preparation of methyl)-4-morpholinephenyl)quinazolin-2-amine
参考前述制备例41中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 41.
MS(ESI)m/z(M+H)+＝629.2。MS (ESI) m/z (M+H) + = 629.2.
制备例48：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(2-((甲硫基)甲基)吡啶-4-基)-7-(三氟甲基)喹唑啉-2-胺的制备
Preparation 48: 8-((cis-4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(2-((methylthio)methyl)pyridine Preparation of -4-yl)-7-(trifluoromethyl)quinazolin-2-amine
步骤1：8-氟-N-(2-((甲硫基)甲基)吡啶-4-基)-7-(三氟甲基)喹唑啉-2-胺的制备
Step 1: Preparation of 8-fluoro-N-(2-((methylthio)methyl)pyridin-4-yl)-7-(trifluoromethyl)quinazolin-2-amine
参考前述制备例21中类似的方法制备得到本标题的化合物。The title compound was prepared by referring to the similar method in the aforementioned Preparation 21.
MS(ESI)m/z(M+H)+＝369.1。MS (ESI) m/z (M+H) + = 369.1.
步骤2：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(2-((甲硫基)甲基)吡啶-4-基)-7-(三氟甲基)喹唑啉-2-胺的制备
Step 2: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(2-((methylthio)methyl)pyridine- Preparation of 4-yl)-7-(trifluoromethyl)quinazolin-2-amine
将8-氟-N-(2-((甲硫基)甲基)吡啶-4-基)-7-(三氟甲基)喹唑啉-2-胺(100mg)，顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己-1-醇(62mg)和叔丁醇钠(52mg)溶于四氢呋喃中(15mL)，室温反应5小时。LCMS检测无原料剩余，加水淬灭反应，乙酸乙酯萃取，合并有机相，无 水硫酸钠干燥，过滤，浓缩并经柱层析纯化得到标题化合物(80mg)。8-fluoro-N-(2-((methylthio)methyl)pyridin-4-yl)-7-(trifluoromethyl)quinazolin-2-amine (100mg), cis-4- ((tert-Butyldimethylsilyl)oxy)cyclohexan-1-ol (62 mg) and sodium tert-butoxide (52 mg) were dissolved in tetrahydrofuran (15 mL), and reacted at room temperature for 5 hours. LCMS detects that there is no raw material remaining, adding water to quench the reaction, extracting with ethyl acetate, combining the organic phases, no Dry over sodium sulfate, filter, concentrate and purify by column chromatography to give the title compound (80mg).
MS(ESI)m/z(M+H)+＝579.2。MS (ESI) m/z (M+H) + = 579.2.
制备例49：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2,5,7-三氯喹唑啉的制备
Preparation 49: Preparation of 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2,5,7-trichloroquinazoline
步骤1：2,5,7-三氯喹唑啉-8-醇的制备
Step 1: Preparation of 2,5,7-trichloroquinazolin-8-ol
将原料2-氯喹唑啉-8-醇(100mg)溶于四氢呋喃(3mL)中，随后加入1,3-二氯-5,5-二甲基海因(27mg)，加毕，将反应体系置于65℃下反应2小时。随后经LCMS监测显示反应完成，将反应液直接浓缩，硅胶柱层析分离得到本标题化合物(95mg)。The raw material 2-chloroquinazolin-8-ol (100mg) was dissolved in tetrahydrofuran (3mL), then 1,3-dichloro-5,5-dimethylhydantoin (27mg) was added, and the reaction system was Placed at 65°C for 2 hours. Subsequently, LCMS monitoring showed that the reaction was complete, and the reaction solution was directly concentrated and separated by silica gel column chromatography to obtain the title compound (95 mg).
MS(ESI)m/z(M+H)+＝248.9，250.9。MS (ESI) m/z (M+H) + = 248.9, 250.9.
后续相关步骤参考前述制备例2中类似的方法制备得到制备例的化合物。For subsequent related steps, refer to the similar method in the aforementioned Preparation Example 2 to prepare the compound of the Preparation Example.
MS(ESI)m/z(M+H)+＝461.1，463.1。MS (ESI) m/z (M+H) + = 461.1, 463.1.
制备例50：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-5,7-二氯-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺的制备
Preparation 50: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-5,7-dichloro-N-(3-((methylsilyl)oxy) Preparation of thio)methyl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝578.1。MS (ESI) m/z (M+H) + = 578.1.
制备例51：3-(2-(甲磺酰基)丙烷-2-基)苯胺的制备
Preparation 51: Preparation of 3-(2-(methylsulfonyl)propan-2-yl)aniline
步骤1：1-溴-3-((甲基磺酰基)甲基)苯的制备
Step 1: Preparation of 1-bromo-3-((methylsulfonyl)methyl)benzene
冰水浴中，向1-溴-3-((甲基亚磺酰基)甲基)苯(2.0g)的乙酸乙酯(100mL)溶液中加入间氯过氧苯甲酸(1.9g)，自然升温反应过夜。TLC显示有原料剩余，加水稀释后用乙酸乙酯萃取，随后浓缩，硅胶柱层析纯化得到标题化合物(740mg)。In an ice-water bath, add m-chloroperoxybenzoic acid (1.9 g) to a solution of 1-bromo-3-((methylsulfinyl)methyl)benzene (2.0 g) in ethyl acetate (100 mL), and raise the temperature naturally React overnight. TLC showed that the remaining raw material was diluted with water and extracted with ethyl acetate, then concentrated and purified by silica gel column chromatography to obtain the title compound (740 mg).
步骤2：1-溴-3-(2-(甲磺酰基)丙烷-2-基)苯的制备
Step 2: Preparation of 1-bromo-3-(2-(methylsulfonyl)propan-2-yl)benzene
冰水浴中，向1-溴-3-((甲基磺酰基)甲基)苯(390mg)的四氢呋喃(30mL)溶液中加入氢化钠(240mg)，搅拌5分钟，加入碘甲烷(2.2g)，自然升温反应过夜。TLC显示反应良好，加入碳酸氢钠水溶液淬灭，采用二氯甲烷萃取、合并、干燥、浓缩后得到标题化合物(200mg)。Add sodium hydride (240 mg) to a solution of 1-bromo-3-((methylsulfonyl)methyl)benzene (390 mg) in tetrahydrofuran (30 mL) in an ice-water bath, stir for 5 minutes, add iodomethane (2.2 g) , react overnight with natural heating. TLC showed that the reaction was good, it was quenched by adding aqueous sodium bicarbonate solution, extracted with dichloromethane, combined, dried and concentrated to give the title compound (200 mg).
后续相关步骤参考前述制备例32中类似的方法制备得到本制备例的化合物。For subsequent relevant steps, refer to the similar method in the aforementioned Preparation Example 32 to prepare the compound of this Preparation Example.
MS(ESI)m/z(M+H)+＝214.1。MS (ESI) m/z (M+H) + = 214.1.
制备例52：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-(2-(甲基磺酰基)丙烷-2-基)苯基)喹唑啉-2-胺的制备
Preparation 52: 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(2-(methyl Preparation of sulfonyl)propan-2-yl)phenyl)quinazolin-2-amine
参考前述制备例3中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 3.
MS(ESI)m/z(M+H)+＝648.2，650.2。MS (ESI) m/z (M+H) + = 648.2, 650.2.
制备例53：N-(顺式-4-((2,7-二氯喹啉-8-基)氧基)环己基)乙酰胺的制备
Preparation 53: Preparation of N-(cis-4-((2,7-dichloroquinolin-8-yl)oxy)cyclohexyl)acetamide
在氮气的保护下，将2，7-二氯喹唑啉-8-醇(1.1g)溶于四氢呋喃(25mL)，加入N-(反式-4-羟基环己基)乙酰胺(1.2g)，另将三苯基膦(4.1g)溶解到四氢呋喃(10mL)中，氮气保护下加入偶氮二甲酸二异丙酯(3.2g)，混合好后加入到上述反应液中，室温下反应20分钟。LCMS显示反应完全后，直接减压浓缩，所得粗品用柱层析纯化得标题化合物(170mg)。Under the protection of nitrogen, 2,7-dichloroquinazolin-8-ol (1.1g) was dissolved in tetrahydrofuran (25mL), N-(trans-4-hydroxycyclohexyl)acetamide (1.2g) was added, In addition, triphenylphosphine (4.1g) was dissolved in tetrahydrofuran (10mL), and diisopropyl azodicarboxylate (3.2g) was added under nitrogen protection. After mixing well, it was added to the above reaction solution, and reacted at room temperature for 20 minutes. . After LCMS showed that the reaction was complete, it was directly concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain the title compound (170 mg).
MS(ESI)m/z(M+H)+＝354.1。MS (ESI) m/z (M+H) + = 354.1.
制备例54：8-((顺式-4-(乙酰氨基)环己基)氧基)-7-氯-N-(2-((甲硫基)甲基)吡啶-4-基)-喹唑啉-2-胺的制备
Preparation 54: 8-((cis-4-(acetylamino)cyclohexyl)oxy)-7-chloro-N-(2-((methylthio)methyl)pyridin-4-yl)-quinolin Preparation of oxazolin-2-amine
将N-(顺式-4-((2,7-二氯喹啉-8-基)氧基)环己基)乙酰胺(150mg)溶于甲苯(10mL)，加入2-((甲硫基)甲基)吡啶-4-胺(97mg)，碳酸铯(274mg)，Pd2(dba)3(38mg)，dppf(23mg)氮气置换体系三次，并在氮气的氛围下，升温至90℃反应5h。LCMS显示反应完全后，直接减压浓缩，所得粗品用柱层析纯化得标题化合物(80mg)。Dissolve N-(cis-4-((2,7-dichloroquinolin-8-yl)oxy)cyclohexyl)acetamide (150mg) in toluene (10mL), add 2-((methylthio) Methyl)pyridin-4-amine (97mg), cesium carbonate (274mg), Pd 2 (dba) 3 (38mg), dppf (23mg) nitrogen replacement system three times, and under nitrogen atmosphere, heat up to 90°C for 5h . After LCMS showed that the reaction was complete, it was directly concentrated under reduced pressure, and the resulting crude product was purified by column chromatography to obtain the title compound (80 mg).
MS(ESI)m/z(M+H)+＝472.1。MS (ESI) m/z (M+H) + = 472.1.
制备例55：2,7-二氯-8-(环己基氧基)喹唑啉的制备
Preparation 55: Preparation of 2,7-dichloro-8-(cyclohexyloxy)quinazoline
参考前述制备例53中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 53.
MS(ESI)m/z(M+H)+＝297.1。MS (ESI) m/z (M+H) + = 297.1.
制备例56：7-氯-8-(环己基氧基)-N-(2-((甲硫基)甲基)吡啶-4-基)喹唑啉-2-胺的制备
Preparation 56: Preparation of 7-chloro-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine
参考前述制备例54中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 54.
MS(ESI)m/z(M+H)+＝415.2。MS (ESI) m/z (M+H) + = 415.2.
制备例57：7-氰基-8-(环己基氧基)-N-(2-((甲硫基)甲基)吡啶-4-基)喹唑啉-2-胺的制备
Preparation 57: Preparation of 7-cyano-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine
步骤1：7-溴-2-氯-8-(环己基氧基)喹唑啉的制备
Step 1: Preparation of 7-bromo-2-chloro-8-(cyclohexyloxy)quinazoline
参考前述制备例53中类似的方法制备得到标题化合物。The title compound was prepared by referring to the similar method in the aforementioned Preparation Example 53.
MS(ESI)m/z(M+H)+＝341.0，343.0。MS (ESI) m/z (M+H) + = 341.0, 343.0.
步骤2：7-溴-8-(环己基氧基)-N-(2-((甲硫基)甲基)吡啶-4-基)喹唑啉-2-胺的制备
Step 2: Preparation of 7-bromo-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine
参考前述制备例54中类似的方法制备得到标题化合物。The title compound was prepared by referring to the similar method in the aforementioned Preparation Example 54.
MS(ESI)m/z(M+H)+＝459.1，461.1。MS (ESI) m/z (M+H) + = 459.1, 461.1.
步骤3：7-氰基-8-(环己基氧基)-N-(2-((甲硫基)甲基)吡啶-4-基)喹唑啉-2-胺的制备
Step 3: Preparation of 7-cyano-8-(cyclohexyloxy)-N-(2-((methylthio)methyl)pyridin-4-yl)quinazolin-2-amine
参考前述制备例25中类似的方法制备得到本制备例的化合物。The compound of this preparation example was prepared by referring to the similar method in the aforementioned preparation example 25.
MS(ESI)m/z(M+H)+＝406.2。MS (ESI) m/z (M+H) + = 406.2.
实施例1：(外消旋)-8-((顺式-4-羟基环己基)氧基)-N-(3-((S-甲基磺酰亚胺基)甲基)苯基)喹唑啉-2-胺的制备
Example 1: (racemic)-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonimido)methyl)phenyl) Preparation of quinazolin-2-amine
步骤1：(外消旋)-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((S-甲基磺酰亚胺基)甲基)苯基)喹唑啉-2-胺的制备
Step 1: (rac)-8-((cis-4-((tert-Butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((S-methyl Preparation of sulfonylimido)methyl)phenyl)quinazolin-2-amine
将8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基)喹唑啉-2-胺(50mg)溶于甲醇(10mL)，依次加入氨基甲酸铵(18mg)和醋酸碘苯(70mg)，室温反应20分钟。TLC检测反应完全，减压浓缩，粗品经柱层析纯化得标题化合物30mg。8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl)phenyl)quinone Azolin-2-amine (50mg) was dissolved in methanol (10mL), ammonium carbamate (18mg) and iodobenzene acetate (70mg) were added successively, and reacted at room temperature for 20 minutes. TLC detected that the reaction was complete, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 30 mg of the title compound.
MS(ESI)m/z(M+H)+＝541.3.MS (ESI) m/z (M+H) + = 541.3.
步骤2：(外消旋)-8-((顺式-4-羟基环己基)氧基)-N-(3-((S-甲基磺酰亚胺基)甲基)苯基)喹唑啉-2-胺的制备
Step 2: (rac)-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonimido)methyl)phenyl)quinone Preparation of oxazolin-2-amine
将(外消旋)-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((S-甲基磺酰亚胺基)甲基)苯基)喹唑啉-2-胺(20mg)溶于二氯甲烷(5mL)，加入盐酸(0.1mL,4M in dioxane)，室温反应10分钟。TLC检测反应完全，减压浓缩，粗品经制备HPLC纯化得标题化合物10mg。(racemic)-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((S-methylsulfonyl Imido)methyl)phenyl)quinazolin-2-amine (20mg) was dissolved in dichloromethane (5mL), hydrochloric acid (0.1mL, 4M in dioxane) was added, and reacted at room temperature for 10 minutes. TLC detected that the reaction was complete, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 10 mg of the title compound.
MS(ESI)m/z(M+H)+＝427.1.MS (ESI) m/z (M+H) + = 427.1.
1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.26(s,1H),8.49(d,J＝8.4Hz,1H),7.82(s,1H),7.48–7.46(m,1H),7.39–7.34(m,2H),7.30–7.26(m,1H),7.05–7.03(m,1H),4.73(s,1H),4.62(d,J＝3.6Hz,1H),4.34(q,J＝13.2Hz,2H),3.66–3.62(m,1H),3.55(s,1H),2.84(s,3H),2.02–1.96(m,2H),1.82–1.62(m,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.93(s, 1H), 9.26(s, 1H), 8.49(d, J=8.4Hz, 1H), 7.82(s, 1H), 7.48–7.46( m,1H),7.39–7.34(m,2H),7.30–7.26(m,1H),7.05–7.03(m,1H),4.73(s,1H),4.62(d,J＝3.6Hz,1H) ,4.34(q,J＝13.2Hz,2H),3.66–3.62(m,1H),3.55(s,1H),2.84(s,3H),2.02–1.96(m,2H),1.82–1.62(m ,6H).
实施例7：7-溴-8-((顺式-4-羟基环己基)氧基)-N-(3-((S-甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Example 7: 7-bromo-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonyl)methyl)phenyl)quinazoline-2 - Preparation of amines
步骤1：7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 1: 7-Bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl) Preparation of methyl)phenyl)quinazolin-2-amine
将7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲硫基)甲基)苯基) 喹唑啉-2-胺(50mg)溶于二氯甲烷(5mL)，加入间氯过氧苯甲酸(68mg)，室温反应3小时。LCMS显示原料反应完毕。浓缩反应液，粗品经制备TLC纯化得标题化合物20mg。7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylthio)methyl) phenyl) Quinazolin-2-amine (50 mg) was dissolved in dichloromethane (5 mL), m-chloroperoxybenzoic acid (68 mg) was added, and reacted at room temperature for 3 hours. LCMS showed complete reaction of starting material. The reaction solution was concentrated, and the crude product was purified by preparative TLC to obtain 20 mg of the title compound.
MS(ESI)m/z(M+H)+＝620.1,622.1.MS (ESI) m/z (M+H) + = 620.1, 622.1.
步骤2：7-溴-8-((顺式-4-羟基环己基)氧基)-N-(3-((S-甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 2: 7-Bromo-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((S-methylsulfonyl)methyl)phenyl)quinazoline-2- Amine preparation
将7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺(20mg)溶于1,4-二氧六环(5mL)和盐酸/1,4-二氧六环(1mL)的混合溶剂中，室温反应30分钟。LCMS检测无原料剩余，浓缩反应液，粗品经制备HPLC纯化得标题化合物2mg。7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl ) phenyl) quinazoline-2-amine (20mg) was dissolved in 1,4-dioxane (5mL) and a mixed solvent of hydrochloric acid/1,4-dioxane (1mL), and reacted at room temperature for 30 minutes . LCMS detected that there was no remaining raw material. The reaction solution was concentrated, and the crude product was purified by preparative HPLC to obtain 2 mg of the title compound.
MS(ESI)m/z(M+H)+＝506.1,508.1.MS (ESI) m/z (M+H) + = 506.1, 508.1.
1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.33(s,1H),8.36–8.19(m,1H),7.66(t,J＝1.9Hz,1H),7.57(d,J＝2.0Hz,2H),7.36(t,J＝7.9Hz,1H),7.11–7.06(m,1H),5.13–5.06(m,1H),4.52–4.42(m,3H),3.68–3.59(m,1H),2.96(s,3H),2.06–1.92(m,2H),1.82–1.73(m,2H),1.71–1.60(m,2H),1.46–1.38(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.11(s, 1H), 9.33(s, 1H), 8.36–8.19(m, 1H), 7.66(t, J=1.9Hz, 1H), 7.57( d,J=2.0Hz,2H),7.36(t,J=7.9Hz,1H),7.11–7.06(m,1H),5.13–5.06(m,1H),4.52–4.42(m,3H),3.68 –3.59(m,1H),2.96(s,3H),2.06–1.92(m,2H),1.82–1.73(m,2H),1.71–1.60(m,2H),1.46–1.38(m,2H) .
实施例13：8-((顺式-4-羟基环己基)氧基)-7-氯-N-(2-((甲基磺酰亚胺基)甲基)吡啶-4-基)喹唑啉-2-胺的对映异构体A制备
Example 13: 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(2-((methylsulfonimido)methyl)pyridin-4-yl)quinone Preparation of Enantiomer A of Azolin-2-amine
步骤1：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(2-((甲基磺酰亚胺基)甲基)吡啶-4-基)喹唑啉-2-胺的制备(异构体13-1和13-2)
Step 1: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methylsulfonyl Preparation of amino)methyl)pyridin-4-yl)quinazolin-2-amine (isomers 13-1 and 13-2)
将8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(2-((甲硫基)甲基)吡啶-4-基)喹唑啉-2-胺(170mg)溶于甲醇(5mL)，加入氨基甲酸铵(60mg)和碘苯二乙酸(200mg)，室温反应30分钟。TLC显示原料反应完毕。反应液加5％硫代硫酸钠水溶液(10mL)淬灭，乙酸乙酯(3*15mL)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，粗品经柱色谱纯化得标题化合物60mg。将标题化合物通过手性制备HPLC分离成对映异构体。8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methylthio)methyl) Pyridin-4-yl)quinazolin-2-amine (170mg) was dissolved in methanol (5mL), ammonium carbamate (60mg) and iodobenzenediacetic acid (200mg) were added, and reacted at room temperature for 30 minutes. TLC showed complete reaction of starting material. The reaction solution was quenched by adding 5% aqueous sodium thiosulfate solution (10 mL), extracted with ethyl acetate (3*15 mL), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain 60 mg of the title compound. The title compound was separated into the enantiomers by chiral preparative HPLC.
MS(ESI)m/z(M+H)+＝576.2。
MS (ESI) m/z (M+H) + = 576.2.
步骤2：8-((顺式-4-羟基环己基)氧基)-7-氯-N-(2-((甲基磺酰亚胺基)甲基)吡啶-4-基)喹唑啉-2-胺的对映异构体A制备
Step 2: 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(2-((methylsulfonimido)methyl)pyridin-4-yl)quinazole Preparation of Enantiomer A of Lin-2-amine
将8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(2-((甲基磺酰亚胺基)甲基)吡啶-4-基)喹唑啉-2-胺(10mg，异构体13-1)溶于1,4-二氧六环(1mL)，加入氯化氢/1,4-二氧六环(4M,5mL)，室温反应30分钟。LCMS显示无原料剩余。减压浓缩除去溶剂，粗品经反相柱色谱纯化得标题化合物4mg。 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methylsulfonylimide )methyl)pyridin-4-yl)quinazolin-2-amine (10 mg, isomer 13-1) was dissolved in 1,4-dioxane (1 mL), and hydrogen chloride/1,4-diox Hexacyclic (4M, 5mL), react at room temperature for 30 minutes. LCMS showed no starting material remaining. Concentrate under reduced pressure to remove the solvent, and the crude product is purified by reverse-phase column chromatography to obtain 4 mg of the title compound.
MS(ESI)m/z(M+H)+＝462.1。MS (ESI) m/z (M+H) + = 462.1.
1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),9.44(s,1H),8.42(d,J＝5.6Hz,1H),8.26(dd,J＝5.7,2.0Hz,1H),7.79–7.70(m,2H),7.54(d,J＝8.6Hz,1H),5.04–4.95(m,1H),4.52(d,J＝3.3Hz,1H),4.45(s,2H),3.79(s,1H),3.68–3.60(m,1H),2.96(s,3H),2.03(q,J＝10.8,9.4Hz,2H),1.81–1.74(m,2H),1.74–1.67(m,2H),1.51–1.41(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ10.59(s, 1H), 9.44(s, 1H), 8.42(d, J=5.6Hz, 1H), 8.26(dd, J=5.7, 2.0Hz, 1H),7.79–7.70(m,2H),7.54(d,J＝8.6Hz,1H),5.04–4.95(m,1H),4.52(d,J＝3.3Hz,1H),4.45(s,2H ),3.79(s,1H),3.68–3.60(m,1H),2.96(s,3H),2.03(q,J＝10.8,9.4Hz,2H),1.81–1.74(m,2H),1.74– 1.67(m,2H),1.51–1.41(m,2H).
实施例14：8-((顺式-4-羟基环己基)氧基)-7-氯-N-(2-((甲基磺酰亚胺基)甲基)吡啶-4-基)喹唑啉-2-胺的对映异构体B制备
Example 14: 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(2-((methylsulfonimido)methyl)pyridin-4-yl)quinone Preparation of Enantiomer B of Azolin-2-amine
将8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-氯-N-(2-((甲基磺酰亚胺基)甲基)吡啶-4-基)喹唑啉-2-胺(10mg，异构体13-2)溶于1,4-二氧六环(1mL)，加入氯化氢/1,4-二氧六环(4M,5mL)，室温反应30分钟。LCMS显示无原料剩余。减压浓缩除去溶剂，粗品经反相柱色谱纯化得标题化合物4mg。8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(2-((methylsulfonylimide )methyl)pyridin-4-yl)quinazolin-2-amine (10 mg, isomer 13-2) was dissolved in 1,4-dioxane (1 mL), and hydrogen chloride/1,4-diox Hexacyclic (4M, 5mL), react at room temperature for 30 minutes. LCMS showed no starting material remaining. Concentrate under reduced pressure to remove the solvent, and the crude product is purified by reverse-phase column chromatography to obtain 4 mg of the title compound.
MS(ESI)m/z(M+H)+＝462.1。MS (ESI) m/z (M+H) + = 462.1.
1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),9.44(s,1H),8.42(d,J＝5.7Hz,1H),8.26(dd,J＝5.7,2.0Hz,1H),7.79–7.70(m,2H),7.54(d,J＝8.6Hz,1H),5.04–4.95(m,1H),4.52(d,J＝3.3Hz,1H),4.45(s,2H),3.79(s,1H),3.68–3.60(m,1H),2.96(s,3H),2.09–1.96(m,2H),1.84–1.74(m,2H),1.74–1.64(m,2H),1.51–1.41(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ10.59(s, 1H), 9.44(s, 1H), 8.42(d, J=5.7Hz, 1H), 8.26(dd, J=5.7, 2.0Hz, 1H),7.79–7.70(m,2H),7.54(d,J＝8.6Hz,1H),5.04–4.95(m,1H),4.52(d,J＝3.3Hz,1H),4.45(s,2H ),3.79(s,1H),3.68–3.60(m,1H),2.96(s,3H),2.09–1.96(m,2H),1.84–1.74(m,2H),1.74–1.64(m,2H ),1.51–1.41(m,2H).
实施例21：8-((顺式-4-羟基环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)-7-乙烯基喹唑啉-2-胺的制备

Example 21: 8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl)-7-vinylquinazoline-2- Amine preparation

步骤1：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)-7-乙烯基喹唑啉-2-胺的制备
Step 1: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)benzene Base)-7-vinylquinazolin-2-amine preparation
将7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺(50mg)，2-二环己膦基-2'-(N,N-二甲胺)-联苯(10mg)，三(二亚苄基丙酮)二钯(11mg)，氯化锂(10mg)和三丁基乙烯基锡(38mg)置于圆底烧瓶中，氮气保护后加入无水甲苯(20mL)然后在90℃下反应。经LCMS监测反应完全后，冷却至室温，过滤除掉固体，滤液减压浓缩，硅胶柱层析分离得到标题化合物(30mg)。7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl )phenyl)quinazolin-2-amine (50mg), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (10mg), tris(dibenzylideneacetone) Dipalladium (11mg), lithium chloride (10mg) and tributylvinyltin (38mg) were placed in a round bottom flask, and anhydrous toluene (20mL) was added after nitrogen protection and then reacted at 90°C. After the completion of the reaction was monitored by LCMS, it was cooled to room temperature, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain the title compound (30 mg).
MS(ESI)m/z(M+H)+＝568.2。MS (ESI) m/z (M+H) + = 568.2.
步骤2：8-((顺式-4-羟基环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)-7-乙烯基喹唑啉-2-胺的制备
Step 2: 8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl)-7-vinylquinazolin-2-amine preparation of
将8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)-7-乙烯基喹唑啉-2-胺(30mg)在室温下溶于二氯甲烷(10mL)中，加入氯化氢/1,4-二氧六环(4M,0.2mL)，室温反应30分钟。LCMS显示无原料剩余。减压浓缩除去溶剂，粗品经反相柱色谱纯化得标题化合物18mg。8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl) -7-vinylquinazolin-2-amine (30mg) was dissolved in dichloromethane (10mL) at room temperature, hydrogen chloride/1,4-dioxane (4M, 0.2mL) was added, and the reaction was carried out at room temperature for 30 minutes . LCMS showed no starting material remaining. Concentrate under reduced pressure to remove the solvent, and the crude product is purified by reverse-phase column chromatography to obtain 18 mg of the title compound.
MS(ESI)m/z(M+H)+＝454.1。MS (ESI) m/z (M+H) + = 454.1.
1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.25(s,1H),8.35(d,J＝8.0Hz,1H),7.65–7.59(m,3H),7.36–7.29(m,2H),7.04(d,J＝7.6Hz,1H),6.02(dd,J＝18.0,1.2Hz,1H),5.49(d,J＝ 11.2Hz,1H),4.95–4.92(m,1H),4.48(d,J＝3.6Hz,1H),4.44(s,2H),3.62(s,1H),2.95(s,3H),1.94–1.86(m,2H),1.69–1.63(m,4H),1.42–1.36(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ9.99(s,1H),9.25(s,1H),8.35(d,J＝8.0Hz,1H),7.65–7.59(m,3H),7.36– 7.29(m,2H),7.04(d,J=7.6Hz,1H),6.02(dd,J=18.0,1.2Hz,1H),5.49(d,J= 11.2Hz, 1H), 4.95–4.92(m, 1H), 4.48(d, J＝3.6Hz, 1H), 4.44(s, 2H), 3.62(s, 1H), 2.95(s, 3H), 1.94– 1.86(m,2H),1.69–1.63(m,4H),1.42–1.36(m,2H).
实施例26：(外消旋)-8-((顺式-4-羟基环己基)氧基)-N-(3-((甲基磺酰亚胺基)甲基)苯基)-7-乙烯基喹唑啉-2-胺的制备
Example 26: (rac)-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-((methylsulfonimido)methyl)phenyl)-7 -Preparation of vinyl quinazoline-2-amine
步骤1：(外消旋)-7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((S-甲基磺酰亚胺基)甲基)苯基)喹唑啉-2-胺的制备
Step 1: (rac)-7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-( Preparation of (S-methylsulfonylimido)methyl)phenyl)quinazolin-2-amine
参考前述实施例1中类似的方法制备得到本标题化合物。The title compound was prepared by referring to the similar method in the aforementioned Example 1.
MS(ESI)m/z(M+H)+＝619.1，621.1。MS (ESI) m/z (M+H) + = 619.1, 621.1.
后续相关步骤参考前述实施例21中类似的方法制备得到本实施例化合物。Subsequent related steps refer to the similar method in the aforementioned Example 21 to prepare the compound of this example.
MS(ESI)m/z(M+H)+＝453.2。MS (ESI) m/z (M+H) + = 453.2.
1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.25(s,1H),8.31(d,J＝8.0Hz,1H),7.65–7.59(m,3H),7.37–7.30(m,2H),7.07(d,J＝8.0Hz,1H),6.02(d,J＝18.0Hz,1H),5.49(d,J＝11.6Hz,1H),4.94(t,J＝8.0Hz,1H),4.48(d,J＝3.2Hz,1H),4.34(q,J＝13.2Hz,2H),3.63(s,1H),3.59(s,1H),2.83(s,3H),1.94–1.87(m,2H),1.68–1.64(m,4H),1.42–1.35(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ9.94(s,1H),9.25(s,1H),8.31(d,J=8.0Hz,1H),7.65–7.59(m,3H),7.37– 7.30(m, 2H), 7.07(d, J=8.0Hz, 1H), 6.02(d, J=18.0Hz, 1H), 5.49(d, J=11.6Hz, 1H), 4.94(t, J=8.0 Hz,1H),4.48(d,J=3.2Hz,1H),4.34(q,J=13.2Hz,2H),3.63(s,1H),3.59(s,1H),2.83(s,3H), 1.94–1.87(m,2H),1.68–1.64(m,4H),1.42–1.35(m,2H).
实施例27：8-((顺式-4-羟基环己基)氧基)-7-乙炔基-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备

Example 27: 8-((cis-4-hydroxycyclohexyl)oxy)-7-ethynyl-N-(3-((methylsulfonyl)methyl)phenyl)quinazoline-2- Amine preparation

步骤1：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-甲醛基-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 1: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-carbaldehyde-N-(3-((methylsulfonyl ) methyl) phenyl) quinazoline-2-amine preparation
室温下，向8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)-7-乙烯基喹唑啉-2-胺(330mg)的丙酮(20mL)和水(20mL)的混合溶液中加入二水合锇酸钾(22mg)和高碘酸钠(250mg)，室温下反应半小时。LCMS显示反应良好，加入水和硫代硫酸钠水溶液淬灭反应，乙酸乙酯萃取，有机相用无水硫酸钠干燥、过滤、浓缩后得到粗品，柱层析纯化得到标题化合物(150mg)。At room temperature, to 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl) Add potassium osmate dihydrate (22 mg) and sodium periodate (250 mg) to a mixed solution of phenyl)-7-vinylquinazolin-2-amine (330 mg) in acetone (20 mL) and water (20 mL), React at room temperature for half an hour. LCMS showed that the reaction was good. The reaction was quenched by adding water and aqueous sodium thiosulfate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography to obtain the title compound (150 mg).
MS(ESI)m/z(M+H)+＝570.2。MS (ESI) m/z (M+H) + = 570.2.
步骤2：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-乙炔基-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 2: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-ethynyl-N-(3-((methylsulfonyl ) methyl) phenyl) quinazoline-2-amine preparation
室温下，向8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-甲醛基-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺(140mg)的甲醇(50mL)溶液中加入(1-重氮-2-氧代丙基)膦酸二甲酯(100mg)和碳酸钾(110mg)。室温下反应过夜，LCMS显示反应良好。加入硫代硫酸钠水溶液淬灭反应，乙酸乙酯萃取，有机相减压浓缩得到粗品，柱层析得到目标产物(100mg)。At room temperature, to 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-formaldehyde-N-(3-((methylsulfonyl) Acyl)methyl)phenyl)quinazolin-2-amine (140mg) in methanol (50mL) solution was added (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (100mg) and potassium carbonate (110mg). The reaction was carried out overnight at room temperature, and LCMS showed a good reaction. An aqueous solution of sodium thiosulfate was added to quench the reaction, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was obtained by column chromatography (100 mg).
MS(ESI)m/z(M+H)+＝566.2。MS (ESI) m/z (M+H) + = 566.2.
步骤3：8-((顺式-4-羟基环己基)氧基)-7-乙炔基-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 3: 8-((cis-4-hydroxycyclohexyl)oxy)-7-ethynyl-N-(3-((methylsulfonyl)methyl)phenyl)quinazolin-2-amine preparation of
冰水浴中，向8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-乙炔基-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺(30mg)的二氯甲烷(5mL)溶液中加入HCl的1,4-dioxane溶液(4M,0.5mL)，自然升温反应约30分钟。LCMS显示反应完全后，直接减压浓缩除去溶剂，反向制备柱层析得到标题化合物(12mg)。In an ice-water bath, to 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-ethynyl-N-(3-((methyl Add HCl in 1,4-dioxane solution (4M, 0.5mL) to a solution of sulfonyl)methyl)phenyl)quinazolin-2-amine (30mg) in dichloromethane (5mL) and react with natural temperature for about 30 minutes . After LCMS showed that the reaction was complete, the solvent was directly concentrated under reduced pressure, and the title compound (12 mg) was obtained by reverse preparative column chromatography.
MS(ESI)m/z(M+H)+＝452.2。MS (ESI) m/z (M+H) + = 452.2.
1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),9.31(s,1H),8.29(d,J＝8.0Hz,1H),7.67(s,1H),7.60(d,J＝8.4Hz,1H),7.37–7.33(m,2H),7.06(d,J＝7.6Hz,1H),5.02–4.98(m,1H),4.57(s,1H),4.47(d,J＝3.2Hz,1H),4.45(s,2H),3.62–3.60(m,1H),2.95(s,3H),2.03–1.95(m,2H),1.83–1.77(m,2H),1.67–1.62(m,2H),1.45–1.40(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.08(s, 1H), 9.31(s, 1H), 8.29(d, J=8.0Hz, 1H), 7.67(s, 1H), 7.60(d, J=8.4Hz,1H),7.37–7.33(m,2H),7.06(d,J=7.6Hz,1H),5.02–4.98(m,1H),4.57(s,1H),4.47(d,J ＝3.2Hz,1H),4.45(s,2H),3.62–3.60(m,1H),2.95(s,3H),2.03–1.95(m,2H),1.83–1.77(m,2H),1.67– 1.62(m,2H),1.45–1.40(m,2H).
实施例29：2-(8-((顺式-4-羟基环己基)氧基)-2-((3-((甲基磺酰基)甲基)苯基)氨基)喹唑啉-7-基)乙腈的制备
Example 29: 2-(8-((cis-4-hydroxycyclohexyl)oxy)-2-((3-((methylsulfonyl)methyl)phenyl)amino)quinazoline-7 - base) the preparation of acetonitrile
步骤1：8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-(异恶唑-4-基)-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 1: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(isoxazol-4-yl)-N-(3 Preparation of -((methylsulfonyl)methyl)phenyl)quinazolin-2-amine
室温下，将7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺(322mg)、4-异恶唑硼酸频那醇酯(202mg)、氟化钾(91mg)、双三苯基膦二氯化钯(50mg)、DMSO(20mL)和水(3mL)加入到单口瓶中，氮气置换后升温到110℃反应2h。LCMS显示反应良好，直接反相柱层析得到标题化合物(153mg)。At room temperature, 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-((methylsulfonyl )methyl)phenyl)quinazolin-2-amine (322mg), 4-isoxazole borate pinacol ester (202mg), potassium fluoride (91mg), bistriphenylphosphine palladium dichloride (50mg ), DMSO (20mL) and water (3mL) were added into a one-necked flask, replaced with nitrogen, and heated to 110°C for 2h. LCMS showed that the reaction was good, and the title compound (153 mg) was obtained by direct reverse phase column chromatography.
MS(ESI)m/z(M+H)+＝609.3。MS (ESI) m/z (M+H) + = 609.3.
步骤2：2-(8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-((3-((甲基磺酰基)甲基)苯基)氨基)喹唑啉-7-基)乙腈的制备
Step 2: 2-(8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-((3-((methylsulfonyl) Preparation of methyl)phenyl)amino)quinazolin-7-yl)acetonitrile
室温下，向8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-7-(异恶唑-4-基)-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺(60mg)的甲醇(10mL)和水(10mL)混合溶液中加入氟化钾(57mg)，升温到90℃反应1h。LCMS显示反应完全，减压浓缩后，加水和乙酸乙酯分层，分离有机相，水相用二氯甲烷萃取、合并有机相、干燥、过滤并浓缩后柱层析纯化得到标题化合物(47mg)。At room temperature, to 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-(isoxazol-4-yl)-N-( Potassium fluoride (57 mg) was added to a mixed solution of 3-((methylsulfonyl)methyl)phenyl)quinazolin-2-amine (60 mg) in methanol (10 mL) and water (10 mL), and the temperature was raised to 90° C. Reaction 1h. LCMS showed that the reaction was complete. After concentration under reduced pressure, water and ethyl acetate were added to separate the layers, and the organic phase was separated. The aqueous phase was extracted with dichloromethane, the organic phases were combined, dried, filtered and concentrated, and purified by column chromatography to obtain the title compound (47 mg) .
MS(ESI)m/z(M+H)+＝581.3。MS (ESI) m/z (M+H) + = 581.3.
步骤3：2-(8-((顺式-4-羟基环己基)氧基)-2-((3-((甲基磺酰基)甲基)苯基)氨基)喹唑啉-7-基)乙腈的制备
Step 3: 2-(8-((cis-4-hydroxycyclohexyl)oxy)-2-((3-((methylsulfonyl)methyl)phenyl)amino)quinazoline-7- base) the preparation of acetonitrile
室温下，将2-(8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-2-((3-((甲基磺酰基)甲基)苯基)氨基)喹唑啉-7-基)乙腈(47mg)溶于二氯甲烷(10mL)中，室温下加入HCl(4M in 1,4-Dioxane,0.5mL)。10分钟后经LCMS监测反应完全，加入饱和碳酸氢钠水溶液调节溶液至碱性。分离有机相，水相用二氯甲烷萃取，合并有机相，干燥，过滤并浓缩后反相制备 柱层析纯化得到标题化合物(8mg)。At room temperature, 2-(8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-2-((3-((methylsulfonyl )methyl)phenyl)amino)quinazolin-7-yl)acetonitrile (47 mg) was dissolved in dichloromethane (10 mL), and HCl (4M in 1,4-Dioxane, 0.5 mL) was added at room temperature. After 10 minutes, the reaction was monitored by LCMS, and saturated aqueous sodium bicarbonate solution was added to adjust the solution to basicity. Separate the organic phase, extract the aqueous phase with dichloromethane, combine the organic phases, dry, filter and concentrate and prepare in reverse phase Purification by column chromatography gave the title compound (8 mg).
MS(ESI)m/z(M+H)+＝467.2。MS (ESI) m/z (M+H) + = 467.2.
1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.31(s,1H),8.30(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.58(s,1H),7.39–7.33(m,2H),7.07(d,J＝7.6Hz,1H),5.13–5.08(m,1H),4.52(d,J＝3.2Hz,1H),4.44(s,2H),4.12(s,2H),3.64(s,1H),2.95(s,3H),1.98–1.88(m,2H),1.68–1.65(m,4H),1.43–1.38(m,2H). 1 H NMR (400MHz,DMSO-d 6 )δ10.04(s,1H),9.31(s,1H),8.30(d,J=8.0Hz,1H),7.68(d,J=8.0Hz,1H) ,7.58(s,1H),7.39–7.33(m,2H),7.07(d,J＝7.6Hz,1H),5.13–5.08(m,1H),4.52(d,J＝3.2Hz,1H), 4.44(s,2H),4.12(s,2H),3.64(s,1H),2.95(s,3H),1.98–1.88(m,2H),1.68–1.65(m,4H),1.43–1.38( m,2H).
实施例45：7-溴-8-((顺式-4-羟基环己基)氧基)-N-(3-(2-(甲基磺酰基)丙烷-2-基)苯基)喹唑啉-2-胺的制备
Example 45: 7-Bromo-8-((cis-4-hydroxycyclohexyl)oxy)-N-(3-(2-(methylsulfonyl)propan-2-yl)phenyl)quinazole Preparation of phen-2-amine
冰水浴中，向7-溴-8-((顺式-4-((叔丁基二甲基甲硅烷基)氧基)环己基)氧基)-N-(3-(2-(甲基磺酰基)丙烷-2-基)苯基)喹唑啉-2-胺(46mg)的二氯甲烷(10mL)溶液中加入盐酸(4M in Dioxane，0.2mL)，自然升温反应。LCMS显示反应良好，直接减压除去溶剂，反相制备HPLC纯化得到标题化合物(10mg)。In an ice-water bath, to 7-bromo-8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-N-(3-(2-(methyl Hydrochloric acid (4M in Dioxane, 0.2mL) was added to a solution of sulfonyl)propan-2-yl)phenyl)quinazolin-2-amine (46mg) in dichloromethane (10mL), and the reaction was heated naturally. LCMS showed that the reaction was good, the solvent was removed under reduced pressure, and purified by reverse-phase preparative HPLC to obtain the title compound (10 mg).
MS(ESI)m/z(M+H)+＝534.1，536.1。MS (ESI) m/z (M+H) + = 534.1, 536.1.
1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.32(s,1H),8.42(d,J＝9.2Hz,1H),7.74(s,1H),7.58–7.53(m,2H),7.36(t,J＝8.0Hz,1H),7.28(d,J＝8.0Hz,1H),5.08–5.04(m,1H),4.46(s,1H),3.63(s,1H),2.72(s,3H),2.01–1.93(m,2H),1.77–1.72(m,8H),1.67–1.63(m,2H),1.43–1.37(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.03(s, 1H), 9.32(s, 1H), 8.42(d, J=9.2Hz, 1H), 7.74(s, 1H), 7.58–7.53( m,2H),7.36(t,J=8.0Hz,1H),7.28(d,J=8.0Hz,1H),5.08–5.04(m,1H),4.46(s,1H),3.63(s,1H ),2.72(s,3H),2.01–1.93(m,2H),1.77–1.72(m,8H),1.67–1.63(m,2H),1.43–1.37(m,2H).
实施例46：(外消旋)-8-((顺式-4-(乙酰氨基)环己基)氧基)-7-氯-N-(2-((S-甲基磺酰亚胺基)甲基)吡啶-4-基)-喹唑啉-2-胺的制备

Example 46: (rac)-8-((cis-4-(acetylamino)cyclohexyl)oxy)-7-chloro-N-(2-((S-methylsulfonylimide )methyl)pyridin-4-yl)-quinazolin-2-amine preparation

将8-((顺式-4-(乙酰氨基)环己基)氧基)-7-氯-N-(2-((甲硫基)甲基)吡啶-4-基)-喹唑啉-2-胺(80mg)溶于甲醇(20mL)，加入氨基甲酸铵(20mg)和PIDA(130mg)，室温下反应30分钟。LCMS显示反应有产物生成，但原料剩余较多，减压浓缩，所得粗品用制备板分离纯化，最后用反相制备HPLC纯化得到标题化合物(5mg)。8-((cis-4-(acetylamino)cyclohexyl)oxy)-7-chloro-N-(2-((methylthio)methyl)pyridin-4-yl)-quinazoline- 2-Amine (80 mg) was dissolved in methanol (20 mL), ammonium carbamate (20 mg) and PIDA (130 mg) were added, and reacted at room temperature for 30 minutes. LCMS showed that a product was formed in the reaction, but there was a lot of raw material remaining. Concentration under reduced pressure, the obtained crude product was separated and purified by a preparative plate, and finally purified by reverse-phase preparative HPLC to obtain the title compound (5 mg).
MS(ESI)m/z(M+H)+＝503.2。MS (ESI) m/z (M+H) + = 503.2.
1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),9.43(s,1H),8.43(d,J＝5.6Hz,1H),8.20–8.19(m,1H),7.85(d,J＝7.2Hz,1H),7.73(d,J＝8.4Hz,1H),7.65(s,1H),7.52(d,J＝8.4Hz,1H),5.15(s,1H),4.43(s,2H),3.78(s,1H),3.64(s,1H),2.94(s,3H),2.01–1.98(m,2H),1.81(s,5H),1.73–1.70(m,2H),1.57–1.55(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.54(s, 1H), 9.43(s, 1H), 8.43(d, J=5.6Hz, 1H), 8.20–8.19(m, 1H), 7.85( d,J=7.2Hz,1H),7.73(d,J=8.4Hz,1H),7.65(s,1H),7.52(d,J=8.4Hz,1H),5.15(s,1H),4.43( s,2H),3.78(s,1H),3.64(s,1H),2.94(s,3H),2.01–1.98(m,2H),1.81(s,5H),1.73–1.70(m,2H) ,1.57–1.55(m,2H).
实施例49：7-氯-8-((4-羟基-4-甲基环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Example 49: 7-Chloro-8-((4-hydroxy-4-methylcyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl)quinazoline-2 - Preparation of amines
步骤1：8-((顺式-4-((叔丁基二甲基甲硅基)氧基)环己基)氧基)-7-氯-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 1: 8-((cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-7-chloro-N-(3-((methylsulfonyl) Preparation of methyl)phenyl)quinazolin-2-amine
参考前述实施例7中类似的方法制备得到本标题化合物。The title compound was prepared by referring to the similar method in the aforementioned Example 7.
MS(ESI)m/z(M+H)+＝576.2。MS (ESI) m/z (M+H) + = 576.2.
步骤2：8-((顺式-4-羟基环己基)氧基)-7-氯-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 2: 8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(3-((methylsulfonyl)methyl)phenyl)quinazolin-2-amine preparation
参考前述实施例7中类似的方法制备得到本标题化合物。The title compound was prepared by referring to the similar method in the aforementioned Example 7.
MS(ESI)m/z(M+H)+＝462.1。MS (ESI) m/z (M+H) + = 462.1.
步骤3：4-((7-氯-2-((3-((甲基磺酰基)甲基)苯基)氨基)喹唑啉-8-基)氧基)环己烷-1-酮的制备
Step 3: 4-((7-Chloro-2-((3-((methylsulfonyl)methyl)phenyl)amino)quinazolin-8-yl)oxy)cyclohexane-1-one preparation of
将8-((顺式-4-羟基环己基)氧基)-7-氯-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺(50mg)溶于二氯甲烷(15mL)中，加入戴斯-马丁试剂(47mg)和碳酸氢钠(20mg)，室温反应2小时。TLC检测反应完全，加入硫代硫酸钠水溶液和饱和碳酸氢钠水溶液淬灭反应，分离有机相，水相用二氯甲烷萃取，合并，干燥，过滤并浓缩，粗品经柱层析纯化得标题化合物(30mg)。8-((cis-4-hydroxycyclohexyl)oxy)-7-chloro-N-(3-((methylsulfonyl)methyl)phenyl)quinazolin-2-amine (50mg) Dissolve in dichloromethane (15 mL), add Dess-Martin reagent (47 mg) and sodium bicarbonate (20 mg), and react at room temperature for 2 hours. TLC detected that the reaction was complete, adding aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate to quench the reaction, separating the organic phase, extracting the aqueous phase with dichloromethane, combining, drying, filtering and concentrating, the crude product was purified by column chromatography to obtain the title compound (30mg).
MS(ESI)m/z(M+H)+＝460.1.MS (ESI) m/z (M+H) + = 460.1.
步骤4：7-氯-8-((4-羟基-4-甲基环己基)氧基)-N-(3-((甲基磺酰基)甲基)苯基)喹唑啉-2-胺的制备
Step 4: 7-Chloro-8-((4-hydroxy-4-methylcyclohexyl)oxy)-N-(3-((methylsulfonyl)methyl)phenyl)quinazoline-2- Amine preparation
在惰性气体保护条件下，将4-((7-氯-2-((3-((甲基磺酰基)甲基)苯基)氨基)喹唑啉-8-基)氧基)环己烷-1-酮(30mg)溶于THF(10mL)中，随后在室温下加入甲基溴化镁(1mL，3M in THF)并继续在室温下反应2小时。TLC检测反应完全，加入饱和碳酸氢钠水溶液淬灭反应，溶液用二氯甲烷萃取，无水硫酸钠干燥，过滤并浓缩得到粗品。随后经制备HPLC纯化得到标题化合物，分别为前峰化合物A(5mg)和后峰化合物B(5mg)。Under inert gas protection conditions, 4-((7-chloro-2-((3-((methylsulfonyl)methyl)phenyl)amino)quinazolin-8-yl)oxy)cyclohexyl The alkan-1-one (30 mg) was dissolved in THF (10 mL), then methylmagnesium bromide (1 mL, 3M in THF) was added at room temperature and the reaction was continued at room temperature for 2 hours. TLC detected that the reaction was complete, and the reaction was quenched by adding saturated aqueous sodium bicarbonate solution, and the solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. Subsequent purification by preparative HPLC afforded the title compounds, which were pre-peak compound A (5 mg) and post-peak compound B (5 mg), respectively.
化合物A：MS(ESI)m/z(M+H)+＝476.1.Compound A: MS (ESI) m/z (M+H) + = 476.1.
1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.33(s,1H),8.40(d,J＝8.4Hz,1H),7.68–7.66(m,2H),7.43(d,J＝8.4Hz,1H),7.35(t,J＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),4.86–4.79(m,1H),4.47(s,2H),4.15(s,1H),2.97(s,3H),2.05–1.96(m,3H),1.79–1.75(m,2H),1.63–1.60(m,2H),1.24–1.20(m,1H),1.07(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.15(s, 1H), 9.33(s, 1H), 8.40(d, J=8.4Hz, 1H), 7.68–7.66(m, 2H), 7.43( d,J=8.4Hz,1H),7.35(t,J=8.0Hz,1H),7.09(d,J=8.0Hz,1H),4.86–4.79(m,1H),4.47(s,2H), 4.15(s,1H),2.97(s,3H),2.05–1.96(m,3H),1.79–1.75(m,2H),1.63–1.60(m,2H),1.24–1.20(m,1H), 1.07(s,3H).
化合物B：MS(ESI)m/z(M+H)+＝476.1.Compound B: MS (ESI) m/z (M+H) + = 476.1.
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.33(s,1H),8.27(d,J＝8.4Hz,1H),7.67–7.63(m,2H),7.42(d,J＝8.4Hz,1H),7.37(t,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),5.21(s,1H),4.46(s,2H),4.15(s,1H),2.96(s,3H),1.91–1.86(m,2H),1.80–1.70(m,4H),1.38–1.33(m,2H),1.17(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.12(s, 1H), 9.33(s, 1H), 8.27(d, J=8.4Hz, 1H), 7.67–7.63(m, 2H), 7.42( d,J=8.4Hz,1H),7.37(t,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),5.21(s,1H),4.46(s,2H),4.15( s,1H),2.96(s,3H),1.91–1.86(m,2H),1.80–1.70(m,4H),1.38–1.33(m,2H),1.17(s,3H).
参照前述制备例中类似的方法制备起始原料，同时参考前述实施例中类似的方法制备得到下表中实施例的化合物：













The starting materials were prepared by referring to the similar methods in the previous preparation examples, and the compounds in the examples in the following table were prepared by referring to the similar methods in the previous examples:













生物试验biological test
测试例1：TNIK酶学活性测试Test example 1: TNIK enzymatic activity test
利用ADP-Glo Kinase Assay的方法检测受试化合物对TNIK的IC50值。The IC 50 value of the test compound against TNIK was detected by ADP-Glo Kinase Assay.
具体步骤为：化合物测试起始浓度为1μM，3倍梯度稀释成10个浓度点。分别取10个不同浓度的待测化合物溶液50nL，加入384孔板备用。用酶缓冲液(40mM Tris,20mM MgCl2,0.1mg/mL BSA,50μM DTT)配制1.25ng/μL的TNIK酶(Signalchem，货号#T27-11G-10)溶液。在不同浓度的待测化合物孔中分别加入TNIK酶溶液2.5μL；在阴性对照孔中加2.5μL的酶缓冲液；在阳性对照中加入2.5μL的STS(MCE，货号HY-15141)。振荡混匀后室温孵育10分钟。用酶缓冲液配制反应混合溶液(含0.2mg/mL MBP，及40μM ATP)，在阳性对照孔、待测化合物孔、阴性对照孔中分别加入2.5μL的反应混合溶液，振荡混匀后室温孵育120分钟。随后加入4μL ADP-Glo(Promega，货号#V9102)室温孵育40分钟，加入8μL酶检测试剂室温孵育40分钟。Envision 2104multi-label Reader(PerkinElmer，货号#Oct-04)读取Luminescence signal，处理数据。The specific steps are as follows: the initial concentration of the compound test is 1 μM, and the 3-fold serial dilution is made into 10 concentration points. Take 50 nL of 10 solutions of the compound to be tested at different concentrations and add them to a 384-well plate for later use. Prepare a 1.25 ng/μL solution of TNIK enzyme (Signalchem, catalog #T27-11G-10) in enzyme buffer (40mM Tris, 20mM MgCl2, 0.1mg/mL BSA, 50μM DTT). Add 2.5 μL of TNIK enzyme solution to the test compound wells with different concentrations; add 2.5 μL of enzyme buffer solution to the negative control well; add 2.5 μL of STS (MCE, product number HY-15141) to the positive control well. Shake to mix and incubate at room temperature for 10 minutes. Prepare reaction mixture solution (containing 0.2mg/mL MBP and 40μM ATP) with enzyme buffer, add 2.5μL reaction mixture solution to positive control wells, test compound wells, and negative control wells, shake and mix well, and incubate at room temperature 120 minutes. Then add 4 μL ADP-Glo (Promega, product number #V9102) and incubate at room temperature for 40 minutes, add 8 μL enzyme detection reagent and incubate at room temperature for 40 minutes. Envision 2104multi-label Reader (PerkinElmer, Cat. No. #Oct-04) reads the Luminescence signal and processes the data.
计算公式：Calculation formula:
％Inhibition＝100-(Signal化合物-Signal阳性对照孔)/(Signal阴性对照孔Signal阳性对照孔)×100%Inhibition=100-(Signal compound-Signal positive control well)/(Signal negative control well Signal positive control well)×100
以浓度的log值作为X轴，百分比抑制率(％Inhibition)为Y轴，采用分析软件GraphPad Prism 6的dose response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。Taking the log value of the concentration as the X-axis, and the percentage inhibition rate (%Inhibition) as the Y-axis, the dose response-Variable slope of the analysis software GraphPad Prism 6 was used to fit the dose-effect curve, thereby obtaining the IC50 value of each compound on the enzyme activity.
TNIK酶学活性数据TNIK enzymatic activity data
实施例编号Example number IC50(nM)IC50(nM) 实施例编号Example number IC50(nM)IC50(nM)
11 11.7311.73 22 23.7523.75
33 37.3737.37 44 75.0975.09
55 25.0425.04 66 15.1615.16
77 9.959.95 88 31.6731.67
99 39.1039.10 1010 38.6738.67
1212 7.887.88 1313 84.5384.53
1414 73.4573.45 1616 60.3260.32
1717 83.4183.41 1818 19.6819.68
1919 7.017.01 2020 24.6124.61
测试例2：CDK9/CycT1酶学活性测试Test Example 2: CDK9/CycT1 enzymatic activity test
利用Mobility shift assay的方法检测受试化合物对CDK9/CycT1的IC50值。The IC 50 value of the test compound against CDK9/CycT1 was detected by Mobility shift assay.
具体步骤为：化合物测试起始浓度为1μM，3倍梯度稀释成10个浓度点。分别取不同浓度的待测化合物溶液250nL，加入384孔板备用。用酶缓冲液(20Mm HEPES,0.01％Triton,pH7.5)配制12.5nM的CDK9激酶(Carna，货号#04-110)溶液，在不同浓度的待测化合物孔中分别加入CDK9激酶溶液10μL；在阴性对照孔中加10μL的酶缓冲液，1000rpm离心30秒，振荡混匀后室温孵育10分钟。用酶缓冲液配制反应混合溶液(含26.67μM ATP,16.67mM MgCl2及5μM Peptide CTD3)，在待测化合物孔和阴性对照孔中分别加入15μL的反应混合溶液，开始反应，1000rpm离心30秒，振荡混匀后室温孵育120分钟。随后加入30μL终止反应液(BIOMOL GreenTM Reagent，Enzo lifesciences，货号BML-AK111-1000)停止激酶反应，1000rpm离心30秒，震荡混匀。用酶标仪(Perkin Elmer，型号Caliper EZ Reader II)读取转化率，处理数据。The specific steps are as follows: the initial concentration of the compound test is 1 μM, and the 3-fold serial dilution is made into 10 concentration points. Take 250 nL of the compound solution to be tested at different concentrations and add it to a 384-well plate for later use. Prepare 12.5nM CDK9 kinase (Carna, Cat. No. #04-110) solution with enzyme buffer (20Mm HEPES, 0.01% Triton, pH7.5), add 10 μL of CDK9 kinase solution to the test compound wells with different concentrations; Add 10 μL of enzyme buffer to the negative control well, centrifuge at 1000 rpm for 30 seconds, shake and mix well, and incubate at room temperature for 10 minutes. Prepare a reaction mixture solution (containing 26.67 μM ATP, 16.67 mM MgCl 2 and 5 μM Peptide CTD3) with an enzyme buffer, add 15 μL of the reaction mixture solution to the test compound well and the negative control well respectively, start the reaction, and centrifuge at 1000 rpm for 30 seconds. Shake to mix and incubate at room temperature for 120 minutes. Then, 30 μL of stop reaction solution (BIOMOL Green ™ Reagent, Enzo lifesciences, Cat. No. BML-AK111-1000) was added to stop the kinase reaction, centrifuged at 1000 rpm for 30 seconds, and vortexed to mix. The conversion rate was read with a microplate reader (Perkin Elmer, model Caliper EZ Reader II), and the data was processed.
计算公式：Calculation formula:
％Inhibition＝(Conversion％阳性对照孔-Conversion％待测化合物孔)/(Conversion％阳性对照孔-Conversion％阴性对照孔)×100%Inhibition=(Conversion% positive control wells-Conversion% test compound wells)/(Conversion% positive control wells-Conversion% negative control wells)×100
以浓度的log值作为X轴，百分比抑制率(％Inhibition)为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。Taking the log value of the concentration as the X-axis, and the percentage inhibition rate (%Inhibition) as the Y-axis, the log (inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-effect curve to obtain the effect of each compound on the enzyme. The IC50 value of the activity.
CDK9酶学活性数据CDK9 enzymatic activity data
实施例编号Example number IC50(nM)IC50(nM) 实施例编号Example number IC50(nM)IC50(nM)
11 6868 22 1.31.3
33 17.917.9 44 12.512.5
55 1.81.8 66 1.31.3
77 1.631.63 88 1.121.12
99 1.11.1 1010 1.211.21
1111 5.395.39 1212 1.071.07
1313 1.101.10 1414 1.231.23
1616 1.121.12 1717 1.391.39
1818 0.840.84 1919 1.451.45
2020 1.461.46 21twenty one 0.80.8
22twenty two 2.02.0 24twenty four 0.770.77
2626 0.960.96 2727 1.21.2
2828 0.850.85 2929 0.360.36
3232 0.530.53 3333 0.340.34
3434 0.500.50 3535 1.71.7
3636 1.221.22 3737 0.990.99
3838 0.680.68 4040 1.491.49
4141 0.980.98 4242 0.760.76
4343 63.163.1 4545 3.763.76
4646 1.421.42 4747 1.081.08
4848 0.870.87 4949 1.31(A)/1.46(B)1.31(A)/1.46(B)
测试例3：HCT116细胞(来源：南京科佰生物科技有限公司)活性抑制测试Test example 3: HCT116 cell (source: Nanjing Kebai Biotechnology Co., Ltd.) activity inhibition test
利用CellTiter-Glo发光活细胞检测系统检测受试化合物对HCT116细胞增殖抑制的IC50值。The IC50 value of the test compound on HCT116 cell proliferation inhibition was detected by CellTiter-Glo luminescent living cell detection system.
具体步骤为：第一天，胰蛋白酶消化处于对数生长期的细胞，用含10％FBS(PAN，货号ST30-3302)的McCoy's 5A培养基(Sigma，货号M9309)将细胞重悬至合适的密度，混 合均匀，100μL每孔加入到96孔板中，细胞密度为3000～5000个细胞每孔，在37℃，5％CO2培养箱过夜生长使其贴壁。第二天，将受试化合物从10mM的母液用DMSO稀释为2mM，然后3.33倍和3倍交叉梯度稀释成8个浓度点(200×)，随后用完全培养基将化合物稀释为2×，加入100μL含2×化合物的完全培养基至96孔板中(使测试起始浓度为10μM，DMSO含量为0.5％)，在37℃，5％CO2培养箱孵育3天。第5天，取出化合物处理后的细胞平衡至室温，每孔留50μL上清液，然后加入50μL的CellTiter-Glo(Promega，货号#G7571)试剂，室温振荡5分钟使细胞充分裂解，再静置5分钟，酶标仪(BMG，型号FSX)检测Luminescence signal，处理数据。The specific steps are: on the first day, trypsinize the cells in the logarithmic growth phase, and resuspend the cells in McCoy's 5A medium (Sigma, product number M9309) containing 10% FBS (PAN, product number ST30-3302) to a suitable density, mixed Mix evenly, add 100 μL per well into a 96-well plate, the cell density is 3000-5000 cells per well, and grow overnight at 37°C in a 5% CO2 incubator to make it adhere to the wall. The next day, the test compound was diluted to 2 mM from the 10 mM stock solution with DMSO, then 3.33 times and 3 times cross-gradient dilution to 8 concentration points (200×), and then the compound was diluted to 2× with complete medium, adding Put 100 μL of complete medium containing 2× compounds into a 96-well plate (making the test initial concentration 10 μM, DMSO content 0.5%), and incubate at 37° C. in a 5% CO 2 incubator for 3 days. On the 5th day, remove the compound-treated cells and equilibrate to room temperature, leave 50 μL of supernatant in each well, then add 50 μL of CellTiter-Glo (Promega, Cat. No. G7571) reagent, shake at room temperature for 5 minutes to fully lyse the cells, and then let stand 5 minutes, microplate reader (BMG, model FSX) detects Luminescence signal and processes data.
计算公式：Calculation formula:
％cell viability＝Signal化合物/Signal阴性对照×100。%cell viability=Signal compound/Signal negative control×100.
以浓度的log值作为X轴，％cell viability为Y轴，在采用分析软件GraphPad Prism 8的中采用log(inhibitor)vs.dose response-Variable slope(four parameters)拟合量效曲线并计算IC50值。Taking the log value of the concentration as the X-axis, % cell viability as the Y-axis, using the analysis software GraphPad Prism 8, using log (inhibitor) vs. dose response-Variable slope (four parameters) to fit the dose-effect curve and calculate the IC 50 value.
HCT116细胞活性数据HCT116 cell viability data
实施例编号Example number IC50(nM)IC50(nM) 实施例编号Example number IC50(nM)IC50(nM)
11 148.4148.4 22 15.1515.15
33 262.4262.4 44 273.8273.8
55 31.2431.24 66 20.820.8
77 14.214.2 88 16.0916.09
99 16.516.5 1010 21.721.7
1111 643.7643.7 1212 73.573.5
1313 41.341.3 1414 32.9732.97
1616 3939 1717 10.210.2
1818 1.91.9 1919 40.840.8
2020 22.822.8 21twenty one 12.312.3
22twenty two 174.2174.2 24twenty four 3636
2626 34.634.6 2727 32.832.8
2828 36.636.6 2929 30.430.4
3030 556.5556.5 3131 206.3206.3
3232 137.6137.6 3333 41.741.7
3434 45.745.7 3535 39.339.3
3636 45.945.9 3737 12.312.3
3838 12.112.1 4040 139.6139.6
4141 10.210.2 4242 38.938.9
4545 632.4632.4 4646 405.5405.5
4747 42.442.4 4848 2.72.7
4949 41.6(A)/45.5(B)41.6(A)/45.5(B)  the  the

Claims (16)

  1. 通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体：

    其中，    Compounds of general formula (I) or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers:

    in,
    Q选自5-6元芳基、5-6元取代芳基、5-6元杂芳基或5-6元取代杂芳基；Q is selected from 5-6-membered aryl, 5-6-membered substituted aryl, 5-6-membered heteroaryl or 5-6-membered substituted heteroaryl;
    所述5-6元取代芳基或5-6元取代杂芳基各自任选地具有一个或多个取代基，所述取代基任意地选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；所述3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；所述Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；所述Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；所述R5或R6选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；所述3元到5元环烷基、4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；所述C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:烷基、卤素、氨基、氰基或羟基的取代基所取代；Each of the 5-6-membered substituted aryl or 5-6-membered substituted heteroaryl optionally has one or more substituents, and the substituents are arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, Haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; the 3-7 membered substituted Heterocycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; said R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; said R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; said R 5 or R 6 is selected from H, C 1 -C 3 alkyl , halogen, or alternatively R 5 and R 6 together with the carbon atoms to which they are attached optionally form a 3- to 5-membered cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; said 3- to 5-membered cycloalkane group, 4-membered to 6-membered heterocycloalkyl, which can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; said C 1 -C 6 alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further selected from: alkyl, halogen, amino, cyano or hydroxyl substituents replace;
    所述5-6元杂芳基、5-6元取代杂芳基、4-7元杂环烷基、杂芳基、4元到6元杂环烷基或3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；The 5-6 membered heteroaryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, heteroaryl, 4 to 6 membered heterocycloalkyl or 3-7 membered heterocycloalkyl Or 3-7 membered substituted heterocycloalkyl, which has one or more heteroatoms, the heteroatoms are arbitrarily selected from N, O or S;
    所述m是0、1、2或3；said m is 0, 1, 2 or 3;
    R1、R2、R3或R4各自独立地选自H、卤素、氨基、羟基、氰基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、5-6元杂芳基、5-6元取代杂芳基、C1-C6取代烷基、4-7元杂环烷基；所述5-6元取代杂芳基，其取代基任意地选自卤素、氨基、羟基或C1-C6烷基；所述C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl group, 4-7 membered heterocycloalkyl group; said 5-6 membered substituted heteroaryl group, the substituents of which are arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; said C 1 -C 6 Substituted alkyl, whose substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl;
    B表示O、NH、S或CH2；B represents O, NH, S or CH2 ;
    W表示5-7元的饱和环烷基，其中所述5-7元的饱和环烷基任选具有一个或多个取代基，所述取代基选自：H、卤素、氨基、羟基、乙酰氨基、卤代烷基、C1-C6烷基或C1-C6烷氧基； 所述C1-C6烷基或C1-C6烷氧基，各自任意地被选自:卤素、氨基、氰基或羟基的取代基所取代。W represents a 5-7 membered saturated cycloalkyl group, wherein the 5-7 membered saturated cycloalkyl group optionally has one or more substituents selected from: H, halogen, amino, hydroxyl, acetyl Amino, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; Each of the C 1 -C 6 alkyl or C 1 -C 6 alkoxy is optionally substituted by a substituent selected from halogen, amino, cyano or hydroxyl.
  2. 根据权利要求1所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其具有式(Ia)

    其中，    The compound of general formula (I) or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer according to claim 1, which has formula (Ia)

    in,
    X1表示O或NR8，所述R8选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；所述C1-C6烷基、C1-C6烷氧基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:烷基、卤素、氨基、氰基或羟基的取代基所取代；X 1 represents O or NR 8 , and the R 8 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered hetero Cycloalkyl, aryl or heteroaryl; said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted by a substituent selected from: alkyl, halogen, amino, cyano or hydroxyl;
    X2、X3、X4或X5各自独立地选自N或CR9，所述R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；所述3-7元取代杂环烷基,其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；所述3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；X 2 , X 3 , X 4 or X 5 are each independently selected from N or CR 9 , and the R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 Cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl ; The 3-7-membered substituted heterocycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; the 3-7-membered heterocycloalkyl or 3- 7-membered substituted heterocycloalkyl having one or more heteroatoms arbitrarily selected from N, O or S;
    R1、R2、R3或R4各自独立地选自H、卤素、氨基、羟基、氰基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基或C2-C7炔基、5-6元杂芳基、5-6元取代杂芳基、C1-C6取代烷基或4-7元杂环烷基；所述5-6元杂芳基、5-6元取代杂芳基、4-7元杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；所述5-6元取代杂芳基，其取代基任意地选自卤素、氨基、羟基或C1-C6烷基；所述C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, amino, hydroxyl, cyano, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered substituted heteroaryl, C 1 -C 6 substituted alkyl Base or 4-7 membered heterocycloalkyl; the 5-6 membered heteroaryl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, which have one or more heteroatoms, the The heteroatom is arbitrarily selected from N, O or S; the 5-6 membered substituted heteroaryl, the substituent is arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; the C 1 -C 6 substituted alkyl, whose substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl;
    R5或R6各自独立选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；所述3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；所述C1-C6烷基或C1-C6烷氧基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；所述4元到6元杂环烷基，其杂原子选自N、O或S；R or R are each independently selected from H, C 1 -C 3 alkyl, halogen, or alternatively R and R together with the carbon atom to which they are attached optionally form a 3- to 5 -membered cycloalkyl or 4 Yuan to 6-membered heterocycloalkyl; said 3- to 5-membered cycloalkyl or 4- to 6-membered heterocycloalkyl can be further replaced by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or Halogen substitution; the C 1 -C 6 alkyl or C 1 -C 6 alkoxy is further substituted by a substituent selected from: halogen, amino, cyano or hydroxyl; the 4-6-membered hetero Cycloalkyl, whose heteroatoms are selected from N, O or S;
    R7选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基； 所述C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；R 7 is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; The C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl are further selected from: Substituents of halogen, amino, cyano or hydroxy;
    B表示O、NH、S或CH2；B represents O, NH, S or CH2 ;
    Z表示H、卤素、氨基、羟基、乙酰氨基、卤代烷基、C1-C6烷基或C1-C6烷氧基；所述C1-C6烷基或C1-C6烷氧基，各自任意地被选自:卤素、氨基、氰基或羟基的取代基所取代；Z represents H, halogen, amino, hydroxyl, acetamido, haloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; said C 1 -C 6 alkyl or C 1 -C 6 alkoxy groups, each arbitrarily substituted by a substituent selected from: halogen, amino, cyano or hydroxyl;
    r是0、1、2或3；r is 0, 1, 2 or 3;
    m是0、1、2或3；m is 0, 1, 2 or 3;
    n是0、1或2。n is 0, 1 or 2.
  3. 根据权利要求1所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，所述Q为取代或非取代苯基、取代或非取代的6元杂芳基；所述取代苯基或取代的6元杂芳基，其取代基各自任意选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；所述3-7元取代杂环烷基,其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；所述Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；所述Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；所述R5或R6选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；所述3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；所述C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；所述取代或非取代的6元杂芳基、3-7元杂环烷基、3-7元取代杂环烷基或4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；所述m是0、1、2或3。According to the compound of general formula (I) or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer according to claim 1, said Q is substituted or unsubstituted phenyl, substituted Or unsubstituted 6-membered heteroaryl; said substituted phenyl or substituted 6-membered heteroaryl, the substituents of which are each arbitrarily selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 - C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) mSO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; the 3-7 membered substituted Heterocycloalkyl, whose substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; said R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; said R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; said R 5 or R 6 is selected from H, C 1 -C 3 alkyl , halogen, or alternatively R 5 and R 6 together with the carbon atoms to which they are attached optionally form a 3- to 5-membered cycloalkyl group or a 4- to 6-membered heterocycloalkyl group; said 3- to 5-membered cycloalkane or 4- to 6-membered heterocycloalkyl, which may be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; said C 1 -C 6 alkyl, C 3 -C 7 Cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted by a substituent selected from halogen, amino, cyano or hydroxyl; The substituted or unsubstituted 6-membered heteroaryl, 3-7-membered heterocycloalkyl, 3-7-membered substituted heterocycloalkyl or 4-7-membered heterocycloalkyl, heteroaryl or 4-6 membered heterocycloalkyl Cycloalkyl having one or more heteroatoms arbitrarily selected from N, O or S; said m is 0, 1, 2 or 3.
  4. 根据权利要求1所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，所述Q为6元杂芳基，其具有以下取代或非取代的结构：
    The compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I) according to claim 1, said Q is a 6-membered heteroaryl group, which has The following substituted or non-substituted structures:
    所述取代基任意地选自卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、-(CR5R6)mSO2Ra、SF5、3-7元环烷基、3-7元杂环烷基； 所述3-7元杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；所述Ra选自H、C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基；所述Rb选自H、C1-C6烷基、C1-C6烷氧基、氰基、C3-C7环烷基、4-7元杂环烷基、芳基或杂芳基；所述R5或R6选自H、C1-C3烷基、卤素，或作为选择R5与R6与其所连接的碳原子一起任选地形成3元到5元环烷基或4元到6元杂环烷基；所述3元到5元环烷基或4元到6元杂环烷基，可进一步被C1-C6烷基、C1-C6烷氧基或卤素取代；所述C1-C6烷基、C3-C7环烷基、C1-C6烷氧基、4-7元杂环烷基、芳基或杂芳基，进一步地被选自:卤素、氨基、氰基或羟基的取代基所取代；所述4-7元杂环烷基、杂芳基或4元到6元杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；所述m是0、1、2或3。The substituent is optionally selected from halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CR 5 R 6 ) m SO 2 R a , SF 5 , 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl; The 3-7 membered heterocycloalkyl group has one or more heteroatoms, and the heteroatoms are arbitrarily selected from N, O or S; the R a is selected from H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl; said R b is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, C 3 -C 7 cycloalkyl, 4-7 membered heterocycloalkyl, aryl or heteroaryl; said R 5 or R 6 is selected from H, C 1 -C 3 alkyl, halogen, or alternatively R 5 and R 6 together with the carbon atom to which they are attached optionally form a 3- to 5-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl; the 3-membered to 5-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, which can be further substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; said C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, 4-7 membered heterocycloalkyl, aryl or heteroaryl, further substituted by halogen, amino, cyano or hydroxyl The 4-7 membered heterocycloalkyl, heteroaryl or 4-6 membered heterocycloalkyl has one or more heteroatoms, and the heteroatoms are arbitrarily selected from N, O or S; said m is 0, 1, 2 or 3.
  5. 根据权利要求2所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，所述X2、X3、X4或X5各自独立地为CR9，所述R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；所述3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；所述3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；或者所述X2、X3、X4、X5其中一个为N，其余为CR9，所述R9选自H、卤素、氰基、氨基、羟基、卤代烷基、卤代烷氧基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、SF5、3-7元环烷基、3-7元杂环烷基或3-7元取代杂环烷基；所述3-7元取代杂环烷基，其取代基选自C1-C6烷基、C1-C6烷氧基或卤素；所述3-7元杂环烷基或3-7元取代杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；作为优选所述R9选自H、F、Cl、Br、CH3、OCH3、 The compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I) according to claim 2, said X 2 , X 3 , X 4 or X 5 are each independently CR 9 , and the R 9 is selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7-membered cycloalkyl, 3-7-membered heterocycloalkyl or 3-7-membered substituted heterocycloalkyl; the 3-7-membered substituted heterocycloalkyl, Its substituent is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen; the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl has one or more heteroatoms, the heteroatoms are arbitrarily selected from N, O or S; or one of the X 2 , X 3 , X 4 , and X 5 is N, and the rest are CR 9 , and the R 9 is selected from H, Halogen, cyano, amino, hydroxyl, haloalkyl, haloalkoxy, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, SF 5 , 3-7 membered ring Alkyl, 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl; the 3-7 membered substituted heterocycloalkyl, the substituents are selected from C 1 -C 6 alkyl, C 1 - C 6 alkoxy or halogen; the 3-7 membered heterocycloalkyl or 3-7 membered substituted heterocycloalkyl has one or more heteroatoms, and the heteroatoms are arbitrarily selected from N, O or S; preferably, the R 9 is selected from H, F, Cl, Br, CH 3 , OCH 3 ,
  6. 根据权利要求1-5中任一项所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1、R2、R3或R4各自独立地选自H、卤素、氰基、氨基、羟基、卤代烷基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、5-6元杂芳基、5-6元取代杂芳基、C1-C6取代烷基或4-7元杂环烷基；所述5-6元杂芳基、5-6元取代杂芳基或4-7元杂环烷基，其具有一个或多个杂原子，所述杂原子任意地选自N、O或S；所述5-6元取代杂芳基，其取代基任意地选自卤素、氨基、羟基或C1-C6烷基；所述C1-C6取代烷基，其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基。According to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I) according to any one of claims 1-5, R 1 , R 2 , R 3 or R 4 are each independently selected from H, halogen, cyano, amino, hydroxyl, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl, C 1 -C 6 substituted alkyl or 4-7 membered heterocycloalkyl ; The 5-6-membered heteroaryl, 5-6-membered substituted heteroaryl or 4-7-membered heterocycloalkyl has one or more heteroatoms, and the heteroatoms are arbitrarily selected from N, O or S; the 5-6 membered substituted heteroaryl, whose substituents are arbitrarily selected from halogen, amino, hydroxyl or C 1 -C 6 alkyl; the C 1 -C 6 substituted alkyl, whose substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl.
  7. 根据权利要求6所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1选自H、卤素、氰基、氨基、羟基、卤代烷基、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、C2-C7烯基、C2-C7炔基、C1-C6取代烷基或6元杂芳基；所述C1-C6取代烷基， 其取代基任意地选自卤素、氨基、氰基、羟基或C3-C7环烷基；所述6元杂芳基，选自以下取代或非取代的结构：
    According to the compound of general formula (I) or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer according to claim 6, R is selected from H, halogen, cyano, amino , hydroxy, haloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 6 substituted alkyl or 6-membered heteroaryl; said C 1 -C 6 substituted alkyl, Its substituents are arbitrarily selected from halogen, amino, cyano, hydroxyl or C 3 -C 7 cycloalkyl; the 6-membered heteroaryl is selected from the following substituted or unsubstituted structures:
    所述6元杂芳基取代基任意的选自CH3、C2H6。The 6-membered heteroaryl substituent is optionally selected from CH 3 and C 2 H 6 .
  8. 根据权利要求7所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，R1选自H、F、Cl、Br、CF3、CN、CH3、OCH3、环丙基、CH2CN或 According to the compound of general formula (I) or stereoisomer, pharmaceutically acceptable salt, solvate or tautomer according to claim 7, R is selected from H, F, Cl, Br, CF 3 , CN, CH 3 , OCH 3 , cyclopropyl, CH 2 CN or
  9. 根据权利要求2、5、6、7或8中任一项所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，Z可任意选自H、乙酰氨基、甲基或4-羟基；n是1；r是0、1或2。The compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the compound of general formula (I) according to any one of claims 2, 5, 6, 7 or 8, Z can be optionally selected from H, acetamido, methyl or 4-hydroxyl; n is 1; r is 0, 1 or 2.
  10. 根据权利要求1或2任一项所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，m是1。According to the compound of general formula (I) or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer according to any one of claims 1 or 2, m is 1.
  11. 根据权利要求1-10中任一项所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，其特征在于具有以下结构：


    The compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I) according to any one of claims 1-10, is characterized in that having the following structure :


  12. 一种药物组合物，其包含权利要求1-11中任一项所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，以及药物可接受的辅料。A pharmaceutical composition comprising the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I) described in any one of claims 1-11 , and pharmaceutically acceptable excipients.
  13. 根据权利要求1-11中任一项所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体，或根据权利要求12所述的药物组合物，其在制备CDK9和/或TNIK介导疾病中的用途。According to the compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of the general formula (I) according to any one of claims 1-11, or according to claim 12 The pharmaceutical composition described above is used in the preparation of CDK9 and/or TNIK-mediated diseases.
  14. 根据权利要求13所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，所述的CDK9和/或TNIK介导疾病为过度增生性疾病。The compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, or pharmaceutical composition of the general formula (I) according to claim 13, said CDK9 and/or TNIK-mediated diseases are hyperproliferative diseases.
  15. 根据权利要求13或14中任一项所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，所述CDK9和/或TNIK介导疾病为癌症，进一步地为实体瘤和/或血液瘤。The compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, or pharmaceutical composition of the general formula (I) according to any one of claims 13 or 14, so The above-mentioned CDK9 and/or TNIK-mediated disease is cancer, further solid tumor and/or blood tumor.
  16. 根据权利要求15所述的通式(I)的化合物或立体异构体、药学上可接受的盐、溶剂合物、或互变异构体、或药物组合物，所述的CDK9和/或TNIK介导的癌症可选自乳腺癌、卵巢癌、肺癌、胃癌、胰腺癌、结直肠癌、非小细胞肺癌、前列腺癌、甲状腺癌、肝癌、急性髓细胞白血病、多发性骨髓瘤、慢性淋巴细胞性白血病、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或神经细胞瘤。 The compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer, or pharmaceutical composition of the general formula (I) according to claim 15, said CDK9 and/or TNIK-mediated cancer may be selected from breast cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, liver cancer, acute myeloid leukemia, multiple myeloma, chronic lymphoid Cellular leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or neuroblastoma.
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