WO2023143135A1 - Dérivé de quinazoline et son utilisation - Google Patents

Dérivé de quinazoline et son utilisation Download PDF

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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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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/fr

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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

La présente invention concerne un dérivé de quinazoline représenté par la formule générale (I) ou un stéréoisomère, un sel pharmaceutiquement acceptable, un solvate ou un tautomère. Le composé peut inhiber sélectivement CDK9 et/ou TNIK.
PCT/CN2023/072121 2022-01-28 2023-01-13 Dérivé de quinazoline et son utilisation WO2023143135A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2004065378A1 (fr) * 2003-01-17 2004-08-05 Warner-Lambert Company Llc Heterocycles 2-aminopyridines substitues utilises comme inhibiteurs de la proliferation cellulaire
CN101454294A (zh) * 2006-04-06 2009-06-10 诺华公司 用于pdk1抑制的喹唑啉
CN114315798A (zh) * 2020-09-29 2022-04-12 深圳智药信息科技有限公司 喹唑啉类化合物及其药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004065378A1 (fr) * 2003-01-17 2004-08-05 Warner-Lambert Company Llc Heterocycles 2-aminopyridines substitues utilises comme inhibiteurs de la proliferation cellulaire
CN101454294A (zh) * 2006-04-06 2009-06-10 诺华公司 用于pdk1抑制的喹唑啉
CN114315798A (zh) * 2020-09-29 2022-04-12 深圳智药信息科技有限公司 喹唑啉类化合物及其药物组合物

Non-Patent Citations (1)

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Title
BURSAVICH, M.G. ET AL.: "Novel Mps1 Kinase Inhibitors: From Purine to Pyrrolopyrimidine and Quinazoline Leads", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, no. 24, 11 October 2013 (2013-10-11), XP028788008, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2013.10.008 *

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