WO2022078309A1 - Dérivé de bis(pyridin-2-yl)amine substitué, sa composition et son utilisation médicale - Google Patents

Dérivé de bis(pyridin-2-yl)amine substitué, sa composition et son utilisation médicale Download PDF

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WO2022078309A1
WO2022078309A1 PCT/CN2021/123189 CN2021123189W WO2022078309A1 WO 2022078309 A1 WO2022078309 A1 WO 2022078309A1 CN 2021123189 W CN2021123189 W CN 2021123189W WO 2022078309 A1 WO2022078309 A1 WO 2022078309A1
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alkyl
alkoxy
partially unsaturated
membered
membered saturated
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Chinese (zh)
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赵志明
吴盛华
刘阳
华默嘉
郝生雷
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Priority to CN202180064381.8A priority Critical patent/CN116249701A/zh
Publication of WO2022078309A1 publication Critical patent/WO2022078309A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to the technical field of medicine, in particular to a substituted bis(pyridin-2-yl)amine derivative, its pharmaceutically acceptable salts, solvates, stereoisomers, prodrugs, pharmaceutical compositions, and its medicinal use.
  • the cyclin-dependent kinase (CDK) protein family consists of members of the key regulators of the cell division cycle (cell cycle CDKs) involved in the regulation of gene transcription (transcriptional CDKs) and members with other functions. CDKs are required to activate binding to cyclin regulatory subunits.
  • the cell cycle CDKs CDK1/Cyclin B, CDK2/Cyclin A, CDK2/Cyclin E, CDK4/Cyclin D and CDK6/Cyclin D are sequentially activated to drive cells into and through the cell division cycle.
  • the transcribed CDKs CDK9/cyclin T and CDK7/cyclin H regulate the activity of RNA polymerase II through phosphorylation of the carboxy-terminal domain (CTD).
  • CDK9 is the catalytic subunit in the positive transcription elongation factor b (P-TEFb) complex, which regulates gene transcription elongation by phosphorylating the carbon-terminal region of RNA complexase II, which is located in the RNA transcription elongation regulation of chromosome 9q34.1 kinase.
  • CDK9 kinase is highly expressed in cardiomyocytes, hepatocytes, hematopoietic tissues, adipocytes, neurons and muscle cells, and is generally highly expressed in tumor cells. CDK9 is also an important factor in tumor cell progression and maintenance. CDK9 is widely expressed and expressed in a variety of eukaryotic cells and human tissues.
  • CDK9 inhibitors down-regulate the expression of related oncoprotein (MYC) and apoptosis inhibitor protein Mcl-1 by inhibiting the transcriptional elongation of genes, thereby promoting the apoptosis of cancer cells.
  • CDK9 inhibitors reactivate silenced genes, including the activation of ERVs in tumor cells, by modulating the epigenetic factor BRG1, promoting interferon expression, and making tumor cells more sensitive to immunotherapy.
  • CDK9 inhibitors including the selective CDK9 inhibitor BAY1251152 developed by Bayer, the selective CDK9 inhibitor AZD4573 developed by AstraZeneca, the non-selective CDK9 inhibitor TP-1287 developed by Tolero and The non-selective CDK9 inhibitor QHRD107 developed by Changzhou Qianhong Pharmaceutical Company, etc.
  • BAY1251152 is more toxic and is administered by injection.
  • the kinase selectivity and metabolism of AZD4573 are not good, which limits its better efficacy. Therefore, it is of great clinical significance to develop new CDK9 inhibitors with high activity and high selectivity to meet clinical medication needs and improve patient compliance.
  • the object of the present invention is to provide a substituted bis(pyridin-2-yl)amine derivative with high activity, good selectivity, excellent pharmacokinetic parameters, low toxicity and oral administration.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof:
  • (R 01 ) n is that the hydrogen on the pyridine ring is replaced by n R 01 , and n is 0, 1, 2 or 3; each R 01 is the same or different, and is independently cyano, hydroxyl, carboxyl, Halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl) , -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), 5- to 10-membered heteroaryl (preferably 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1- 8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); or two R 01 are connected to form
  • R 02 m is that the hydrogen on the pyridine ring is substituted by m R 02 , and m is 0, 1, 2 or 3; each R 02 is the same or different, and is independently cyano, hydroxyl, carboxyl, halogen (preferably is fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC (O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), 5- to 10-membered heteroaryl (preferably 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy group (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); or two R 02 are connected to form a 3-
  • Q is a 5- to 10-membered heteroaryl group that is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy base, NR a0 R b0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl , -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3- to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or Unsubstituted benzy
  • Z 1 is CR a R b or C(O);
  • R a and R b are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 Alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC ( O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), 5- to 10-membered heteroaryl (preferably 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl ), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); or R a , R b and the connected carbon atoms together form a 3- to 7-membered saturated or partially unsatur
  • Z 2 is (CR c R d ) t0 , -(CR c R d ) t1 -O- or -(CR c R d ) t2 -NR g -; each R c is the same or different, and each R d is the same or different, and R c and R d are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably is -OC(O)C 1-3 alkyl), 5- to 10-membered heteroaryl (preferably 5- to 6-membered heteroaryl and 8- to 10-membered heteroaryl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C
  • R g is hydrogen or C 1-3 alkyl
  • t0, t1, t2 are each independently 1, 2, 3, 4 or 5;
  • R 1a and R 2a are each independently hydrogen or C 1-3 alkyl; or R 1a and R 2a are connected to form a 5- to 8-membered saturated or partially unsaturated monoheterocycle; the 5- to 8-membered saturated or partially unsaturated monocycle Saturated monoheterocycles are unsubstituted or substituted with 1, 2, 3 or 4 R s1 ; wherein each R s1 is the same or different, independently selected from: halogen, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy; or any two R s1 on the same ring atom or on different ring atoms are connected to form a 3- to 7-membered saturated or Partially unsaturated monoheterocycle or 3- to 7-membered saturated or partially unsaturated monocycle; the 3- to 7-membered saturated or partially unsaturated monoheterocycle and 3- to 7-membere
  • R 3a and R 4a are each independently hydrogen, cyano, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)NR a0 R b0 Or -C(O)OC 1-3 alkyl; or R 3a and R 4a are connected to form a 5- to 8-membered heterocycloalkenyl ring or a 5- to 6-membered heteroaryl ring; the 5- to 8-membered heterocycloalkene
  • the base ring and the 5- to 6-membered heteroaryl ring are unsubstituted or substituted with 1, 2, 3 or 4 Rs2 ; wherein each Rs2 is the same or different and independently selected from: halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy; or any two R s2 on the same ring atom or on different ring atoms are connected
  • R 5a is hydrogen or C 1-3 alkyl
  • R 6a and R 7a are each independently hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl); or R 6a and R 7a are connected to form a 5- to 8-membered group Heterocyclenyl rings or 5- to 6-membered heteroaryl rings; the 5- to 8-membered heterocyclenyl rings and 5- to 6-membered heteroaryl rings are unsubstituted or separated by 1, 2, 3 or 4 R s3 is substituted; wherein each R s3 is the same or different, and is independently selected from: halogen, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogen Substituted C 1-3 alkoxy; or any two R s3 on the same ring atom or on different ring atoms are connected to form a 3- to 7-membered saturated or partially unsaturated mono-heterocycle or a 3- to 7-membered
  • L is a bond or (CR e R f ) s ; each R e is the same or different, each R f is the same or different, and R e and R f are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen ( Preferably it is fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1- 3 alkoxy); or R e , R f and the connected carbon atoms together form a 3- to 7-membered saturated or partially unsaturated mono-heterocycle or a 3- to 7-membered saturated or partially unsaturated monocycle; wherein the C 1- 8 alkyl, C 1-8 alkoxy, 3 to 7 membered
  • s is 1, 2 or 3;
  • R 1 , R 2 , R 3 are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); wherein the C 1-8 alkyl and C 1-8 alkoxy are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 Alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0
  • R 4 and R 5 are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 Alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); wherein the C 1-8 alkyl, C 1-8 alkoxy are unsubstituted or 1-8 , 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 ,
  • R 4 and R 5 are connected to form a fused 3- to 7-membered saturated or partially unsaturated monoheterocycle or a fused 3- to 7-membered saturated or partially unsaturated monocycle; the fused 3- to 7-membered saturated or partially unsaturated monocycle Partially unsaturated monoheterocycles, fused 3 to 7 membered saturated or partially unsaturated monocycles are unsubstituted or substituted with 1, 2, 3 or 4 Rs4 ; wherein each Rs4 is the same or different, independently Selected from: halogen, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy; or the same ring atom or different Any two R s4 on the ring atom are connected to form a 3- to 6-membered saturated or partially unsaturated monoheterocycle or a 3- to 6-membered saturated or partially unsaturated monocycle; the 3- to 6-membered saturated
  • R a0 , R b0 are each independently hydrogen, C 1-3 alkyl or acetyl; or R a0 , R b0 and the connected nitrogen atom together form a 4- to 6-membered saturated monoheterocycle; the 4- to 6-membered saturated monocycle
  • the monoheterocycle is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxy, C1-3alkyl , C1-3alkoxy , C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3 -6
  • n is 1; R 01 is fluorine.
  • m is 0 or 1; R 02 is methoxy.
  • m is zero.
  • L is a bond or (CR e R f ) s ; R e , R f are each independently hydrogen.
  • L is CH2 .
  • Z 1 is CH 2 or C(O).
  • Z 2 is (CH 2 ) t0 ; t0 is 1, 2, 3, or 4.
  • formula (a) is a structure represented by formula (a1) or formula (a2):
  • formula (b) is a structure represented by formula (b1):
  • R 3a ', R 4a ' are each independently hydrogen, cyano, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)NR a0 R b0 or -C(O)OC 1-3 alkyl;
  • R 1a , R 2a , R a0 , R b0 are as defined in the specification.
  • formula (b) is a structure represented by formula (b2):
  • E 1 is CR E1a R E1b , C(O) or SO 2 ;
  • E 2 is CR E2a R E2b , O, NR E2c , C(O) or SO 2 ;
  • E 3 is a bond, (CR E3a R E3b ) q , (CR E3a R E3b ) q -O, C(O) or SO 2 ;
  • R E1a and R E1b are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC (O) C 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1 -6 alkoxy, more preferably C 1-3 alkoxy); or R E1a and R E1b together with the attached carbon atoms form a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or Partially unsaturated monocycle; wherein the C 1-8 alkyl, C 1-8 alkoxy, 3- to
  • R E2a and R E2b are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC (O) C 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1 -6 alkoxy, more preferably C 1-3 alkoxy); or R E2a and R E2b together with the attached carbon atoms form a 3- to 7-membered saturated or partially unsaturated mono-heterocycle or a 3- to 7-membered saturated or Partially unsaturated monocycle; wherein the C 1-8 alkyl, C 1-8 alkoxy, 3-
  • R E2c is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) , 3- to 8-membered heterocycloalkyl, -C 1-4 alkyl-3 to 8-membered heterocycloalkyl, -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more Preferably -SO 2 C 1-3 alkyl), -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more Preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl) or C(O)NR a1 R b1 ; wherein the C 1-8 al
  • each R E3a is the same or different, each R E3b is the same or different, and R E3a and R E3b are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1- 3 alkyl) or C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); or R E3a and R E3b attached to the same carbon atom are attached, or Connect with R E3a and R E3b connected to different carbon atoms to form a 3- to 7-membered saturated or partially unsaturated mono
  • q 1, 2 or 3;
  • R a1 and R b1 are each independently hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl; R c1 is hydrogen or C 1-3 alkyl;
  • R 1a , R 2a , R a0 , R b0 are as defined in the specification.
  • formula (b2) is a structure represented by formula (b21):
  • R 1a ', R 2a ' are each independently hydrogen or C 1-3 alkyl; E 1 , E 2 , and E 3 are as defined in formula (b2).
  • formula (b2) is a structure represented by formula (b22):
  • W is (CR W1 R W2 ) u ; each R W1 is the same or different, each R W2 is the same or different, and R W1 and R W2 are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably Fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC ( O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), C 1-8 alkyl (preferably C 1 -6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); or with the same carbon Atom-linked R W1 and R W2 are linked, or linked to R W1 and R W2 linked to different carbon atoms to form a 3- to 7-member
  • u 1, 2, 3 or 4;
  • R a0 , R b0 are as defined in the above specification;
  • E 1 , E 2 , E 3 are as defined in formula (b2).
  • formula (c) is a structure represented by formula (c1):
  • G 1 is CR G1a R G1b , C(O) or SO 2 ;
  • G 2 is CR G2a R G2b , O, NR G2c , C(O) or SO 2 ;
  • G 3 is a bond, (CR G3a R G3b ) p , C(O) or SO 2 ;
  • R G1a and R G1b are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC (O) C 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1 -6 alkoxy, more preferably C 1-3 alkoxy); or R G1a and R G1b together with the attached carbon atoms form a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or Partially unsaturated monocycle; wherein the C 1-8 alkyl, C 1-8 alkoxy, 3- to
  • R G2a and R G2b are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC (O) C 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1 -6 alkoxy, more preferably C 1-3 alkoxy); or R G2a , R G2b together with the attached carbon atoms form a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or Partially unsaturated monocycle; wherein the C 1-8 alkyl, C 1-8 alkoxy, 3-
  • R G2c is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) , 3- to 8-membered heterocycloalkyl, -C 1-4 alkyl-3 to 8-membered heterocycloalkyl, -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more Preferably -SO 2 C 1-3 alkyl), -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more Preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl) or C(O)NR a1 R b1 ; wherein the C 1-8 al
  • Each R G3a is the same or different, each R G3b is the same or different, and R G3a and R G3b are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1- 3 alkyl) or C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); or R G3a and R G3b attached to the same carbon atom are attached, or R G3a and R G3b connected with different carbon atoms are connected to form a 3- to 7-membered saturated or partially unsaturated mono
  • p 1, 2 or 3;
  • R a1 and R b1 are each independently hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl; R c1 is hydrogen or C 1-3 alkyl;
  • R 5a , R a0 , R b0 are as defined in the specification.
  • the structure It is the structure shown by formula (d) or formula (e):
  • R 4 ', R 5 ' are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); wherein the C 1-8 alkyl and C 1-8 alkoxy are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 Alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0
  • X 1 is CR X1a R X1b , NR X1c or O;
  • X 2 is CR X2a R X2b ;
  • X3 is a key or CR X3a R X3b ;
  • X 4 is CR X4a R X4b , NR X4c or O;
  • R X1a , R X1b , R X2a , R X2b , R X3a , R X3b , R X4a , R X4b are each independently hydrogen, cyano, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), -C(O ) OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl ( Preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy); wherein the C 1-8 alkyl, C 1- 8 alkoxy is unsubstituted or substituted with 1, 2 or
  • R X1c and R X4c are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3 -6 cycloalkyl), 3- to 8-membered heterocycloalkyl, -C 1-4 alkyl-3 to 8-membered heterocycloalkyl, -SO 2 C 1-8 alkyl (preferably -SO 2 C 1 -6 alkyl, more preferably -SO 2 C 1-3 alkyl), -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably -C(O)C 1 -6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl) or C(O)NR a1 R b1
  • R X1a , R X1b and the connected carbon atoms together form a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or partially unsaturated monocycle; wherein the 3- to 7-membered saturated or partially unsaturated monocycle Monoheterocycles and 3 to 7 membered saturated or partially unsaturated monocycles are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C
  • R X2a , R X2b and the connected carbon atoms together form a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or partially unsaturated monocycle; wherein the 3- to 7-membered saturated or partially unsaturated monocycle Monoheterocycles and 3 to 7 membered saturated or partially unsaturated monocycles are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C
  • R X3a , R X3b and the connected carbon atoms together form a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or partially unsaturated monocycle; wherein the 3- to 7-membered saturated or partially unsaturated monocycle Monoheterocycles and 3 to 7 membered saturated or partially unsaturated monocycles are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C
  • R X4a , R X4b and the connected carbon atoms together form a 3- to 7-membered saturated or partially unsaturated monoheterocycle or a 3- to 7-membered saturated or partially unsaturated monocycle; wherein the 3- to 7-membered saturated or partially unsaturated monocycle Monoheterocycles and 3 to 7 membered saturated or partially unsaturated monocycles are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C
  • R X4c and R X3a are linked to form a fused 4- to 7-membered saturated or partially unsaturated monoheterocycle; wherein the 4- to 7-membered saturated or partially unsaturated monoheterocycle is unsubstituted or is replaced by 1, 2 or 3 substituted with substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, - C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl,
  • R X1c and R X2a are linked to form a fused 4- to 7-membered saturated or partially unsaturated monoheterocycle; wherein the 4- to 7-membered saturated or partially unsaturated monoheterocycle is unsubstituted or replaced by 1, 2 or 3 substituted with substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxy, carboxyl, C1-3 alkyl, C1-3 alkoxy, C2-4 alkenyl, C2-4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, - C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, C
  • R a1 and R b1 are each independently hydrogen, C 1-3 alkyl or C 3-6 cycloalkyl; R c1 is hydrogen or C 1-3 alkyl;
  • R 1 , R 2 , R 3 , R a0 , R b0 are as defined in the above specification.
  • X 1 is NR X1c or O
  • X 2 is CR X2a R X2b
  • X 3 is a bond or CR X3a R X3b
  • X 4 is NR X4c or O.
  • X 1 is NR X1c ;
  • X 2 is CR X2a R X2b ;
  • X 3 is a bond or CR X3a R X3b ;
  • X 1 is O;
  • X 2 is CR X2a R X2b ;
  • X 3 is a bond or CR X3a R X3b ;
  • X 4 is NR X4c or O.
  • the 3- to 7-membered saturated or partially unsaturated monoheterocycles described in each group are 4- to 6-membered saturated or partially unsaturated monoheterocycles, each independently selected from: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thiomorpholine-1, 1-Dioxide, tetrahydropyran ring, 1,2-dihydroazetadiene ring, 1,2-dihydrooxetadiene ring, 2,5-dihydro-1H-pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4
  • the 3- to 7-membered saturated or partially unsaturated monocyclic ring in each group is a 3- to 6-membered saturated or partially unsaturated monocyclic ring, each independently selected from: cyclopropyl base ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring and cyclohexadienyl ring; more preferably a 3- to 6-membered saturated monocyclic ring.
  • the 5- to 6-membered heteroaryl groups in each group are independently selected from: thienyl, furyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, Pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl base, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4 - oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl.
  • the 3- to 6-membered heterocycloalkyl in each group is a 4- to 6-membered heterocycloalkyl, each independently selected from: azetidinyl, oxygen Hetetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxane, thio morpholinyl, thiomorpholine-1,1-dioxide, tetrahydropyranyl, pyrrolidin-2-one, dihydrofuran-2(3H)-one, morpholin-3-one , piperazin-2-one, piperidin-2-one.
  • the 5- to 8-membered saturated or partially unsaturated mono-heterocyclic rings in each group are independently selected from: imidazolidine, hexahydropyrimidine ring, 1,3-diazepine Heterocyclic ring, 2,3-dihydro-1H-imidazole ring, 1,2,3,4-tetrahydropyrimidine ring, 2,3,4,5-tetrahydro-1H-1,3-diazepine ring, 2,3,4,7-tetrahydro-1H-1,3-diazepine ring.
  • the 5- to 8-membered heterocycloalkenyl ring in each group is selected from: 4,5-dihydro-1H-imidazole ring, 1,4,5,6- tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro- 1H-1,3-diazepine ring, 2,5,6,7-tetrahydro-1,3,5-oxadiazepine ring, 4,5-dihydrooxazole ring, 5,6- Dihydro-4H-1,3-oxazine ring, 6H-1,3-oxazine ring, 4,5,6,7-tetrahydro-1,3-oxazepane, 6,7-bis Hydrogen-2H-1,5,3-dioxazepane
  • R 4 and R 5 are linked to form a fused 3- to 7-membered saturated or partially unsaturated monoheterocycle, which is a fused 4- to 6-membered saturated monoheterocycle selected from: azetidine, Oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, 1,4-dioxane, morpholine, sulfur morpholine ring, tetrahydropyran ring, morpholin-3-one ring, piperazin-2-one ring, piperidin-2-one ring.
  • R 4 and R 5 are connected to form a fused 3- to 7-membered saturated or partially unsaturated monocyclic ring, which is a fused 3- to 6-membered saturated monocyclic ring selected from: cyclopropyl ring, cyclobutyl ring, Cyclopentyl ring, cyclohexyl ring.
  • the 3- to 6-membered saturated or partially unsaturated monoheterocycle formed by the connection of any two Rs4 on the same ring atom or different ring atoms is a 4- to 6-membered saturated monoheterocycle selected from: aza Cyclobutane, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1- Dioxide, tetrahydropyran ring.
  • the 3- to 6-membered saturated or partially unsaturated monocyclic ring formed by the connection of any two R s4 on the same ring atom or different ring atoms is a 3- to 6-membered saturated monocyclic ring, selected from: cyclopropyl ring , cyclobutyl ring, cyclopentyl ring, cyclohexyl ring.
  • the 4- to 6-membered saturated monoheterocycle formed by R a0 , R b0 and the attached nitrogen atom is selected from the group consisting of: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, Tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring.
  • formula (a) is selected from the following structures:
  • formula (a) is selected from the following structures:
  • formula (b1) is selected from the following structures:
  • formula (b2) is selected from the following structures:
  • formula (c1) is selected from the following structures:
  • the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group or an 8- to 10-membered heteroaryl group.
  • the 5- to 6-membered heteroaryl is selected from the group consisting of: thienyl, furyl, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadi oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazole pyridyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazinyl.
  • the 8- to 10-membered heteroaryl group is selected from the group consisting of: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzoyl furyl, benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benziisothiazolyl, benzothiadiazole base, indenazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4, 3-d]Pyrimidyl, 1,8-Naphthyridinyl, 1,7-Naphthyridinyl, 1,6-Naph
  • the 5- to 6-membered heteroaryl is selected from:
  • the above 5- to 6-membered heteroaryl groups are unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, NR a0 R b0 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl base, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl; R a0 , R b0 are as described in the
  • the 5- to 6-membered heteroaryl is selected from:
  • the 8- to 10-membered heteroaryl is selected from:
  • Q is selected from the group consisting of:
  • Q is selected from the group consisting of:
  • formula (e) is selected from the following structures:
  • R 1 , R 2 and R 3 are as defined in the above specification.
  • R 1 is hydrogen or methoxy.
  • R 2 is hydrogen
  • R 3 is fluoro
  • R 4 , R 5 are each independently hydrogen.
  • the structure Choose from the following structures:
  • the compound of formula (I) is any of the following compounds:
  • the compound of formula (I) is any of the following compounds:
  • the compound of formula (I) is any of the following compounds:
  • the compound of formula (I) is any of the following compounds:
  • the second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof , and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, and the compound described in the second aspect of the present invention.
  • the disease is preferably a hyperproliferative disease, a virus-induced infectious disease and/or a cardiovascular disease, more preferably a hyperproliferative disease.
  • a fourth aspect of the present invention provides a method for treating a disease associated with or mediated by CDK9 activity, the method comprising administering to a patient an effective amount of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable amount thereof An accepted salt, or a stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition as described in the second aspect of the present invention.
  • the disease associated with CDK9 activity is a hyperproliferative disease, particularly cancer, such as solid tumors and hematological tumors.
  • diseases associated with or mediated by CDK9 activity include diseases associated with or involving CDK9 activity (eg, overactivity of CDK9), as well as conditions that accompany these diseases.
  • Overactivity of CDK9 refers to increased CDK9 enzymatic activity compared to normal non-disease cells, or it refers to increased CDK9 enzymatic activity resulting in unwanted cell proliferation, or reduced or insufficient programmed cell death (apoptosis) CDK9 activity, or refers to mutations that result in constitutive activation of CDK9.
  • Hyperproliferative diseases include diseases involving undesired or uncontrolled proliferation of cells, and they include diseases involving reduced or insufficient programmed cell death (apoptosis).
  • the compounds of the present invention can be used to prevent, inhibit, block, reduce, reduce, control, etc. cell proliferation and/or cell division, and/or produce apoptosis.
  • the method comprises administering to a subject (including mammals, including humans) in need thereof, an amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, effective to treat or prevent the disease.
  • Hyperproliferative disorders in the context of the present invention include, but are not limited to, for example, angiogenic or vascular proliferative disorders, mesangial cell proliferative disorders, and solid tumors, such as breast, respiratory, brain, reproductive organs, digestive tract, urinary tract, Cancers of the eye, liver, skin, head and neck, thyroid, parathyroid glands and their distant metastases. Those diseases also include lymphoma, sarcoma and leukemia. In some embodiments, the cancer is selected from pancreatic cancer, breast cancer, ovarian cancer, cervical cancer, leukemia.
  • Figure 1 is a graph of the effect of compound Z-1 on animal tumor volume (the horizontal axis is the number of days (days), and the vertical axis is the tumor volume TV (mm 3 );
  • Figure 3 is a graph of the effect of compound Z-1 on the body weight change of tumor-bearing animals (the abscissa is the number of days (days), and the ordinate axis is the animal body weight change rate BW (%)).
  • Alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups.
  • C 1-8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, preferably C 1-6 alkyl, more preferably C 1-3 alkyl; non-limiting examples of alkyl include: Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethyl propylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl
  • Alkynyl refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups having one or more carbon-carbon triple bonds
  • C 2-8 alkynyl refers to alkynyl groups having 2 to 8 carbon atoms, preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl, similarly defined; non-limiting examples include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like .
  • Cycloalkyl and “cycloalkyl ring” are used interchangeably and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group which may be fused to an aryl or heteroaryl group. Cycloalkyl rings can be optionally substituted. In certain embodiments, the cycloalkyl ring contains one or more carbonyl groups, eg, oxo groups.
  • C 3-8 cycloalkyl refers to a monocyclic cycloalkyl having 3 to 8 carbon atoms
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc.
  • C 8-10 cycloalkyl refers to a fused bicyclic cyclic hydrocarbon group having 8 to 10 ring atoms, non-limiting examples of C 8-10 cycloalkyl include
  • Cycloalkenyl and “cycloalkenyl ring” are used interchangeably, and both refer to a monocyclic, bicyclic or polycyclic cyclic hydrocarbon group containing one or more carbon-carbon double bonds in the ring, which may be combined with an aryl or Heteroaryl fused. Cycloalkenyl rings can be optionally substituted. In certain embodiments, the cycloalkenyl ring contains one or more carbonyl groups, eg, oxo groups. "C 3-8 cycloalkenyl” refers to a monocyclic cycloalkenyl having 3 to 8 carbon atoms. Preferred is C 3-6 cycloalkenyl.
  • Non-limiting examples of cycloalkenyl include cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, cyclopentyl-2-en-1-one, cyclohexenyl Hexyl-2,5-dien-1-one, cyclohexyl-2-en-1-one, cyclohex-2-ene-1,4-dione, etc.
  • Heterocycloalkyl and “heterocycloalkyl ring” are used interchangeably and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which group may be combined with an aryl or heteroaryl group fused. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, the heterocycloalkyl ring contains one or more carbonyl or thiocarbonyl groups, eg, oxo- and thio-containing groups.
  • 3- to 8-membered heterocycloalkyl refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, preferably 4 to 8-membered heterocycloalkyl. More preferred are 3 to 6 membered heterocycloalkyl groups having 3 to 6 ring atoms, of which 1 or 2 are heteroatoms selected from nitrogen, oxygen and sulfur. More preferred are 4 to 6 membered heterocycloalkyl groups having 4 to 6 ring atoms, of which 1 or 2 are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl , oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxane, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetra Hydropyranyl, azetidine-2-one, oxetane-2-one, dihydrofuran-2(3H)-one, pyrrolidin-2-one, pyrrolidine- 2,5-dione, dihydrofuran-2,5-dione, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazin-2-one, Lino-3-one group, etc.
  • 6- to 12-membered heterocycloalkyl and “6- to 12-membered fused heterocycloalkyl” are used interchangeably and refer to 6 to 12 ring atoms, wherein 1, 2 or 3 ring atoms are selected from A fused bicyclic cyclic hydrocarbon group of heteroatoms of nitrogen, oxygen and sulfur.
  • 8- to 10-membered heterocycloalkyl and “8- to 10-membered fused heterocycloalkyl” are used interchangeably and refer to 8 to 10 ring atoms, wherein 1, 2 or 3 ring atoms are selected from A fused bicyclic cyclic hydrocarbon group of heteroatoms of nitrogen, oxygen and sulfur.
  • Non-limiting examples of bicyclic heterocycloalkyl include hexahydro-1H-furo[3,4-c]pyrrole, octahydro-1H-cyclopenta[c]pyridine, hexahydro-1H-pyrrolo[2,1 -c][1,4]oxazine, octahydropyrrolo[1,2-a]pyrazine, hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one, octahydrocyclopentanone [c] Pyrrole et al.
  • bicyclic heterocycloalkyl systems In fused bicyclic heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence permits.
  • Bicyclic heterocycloalkyl systems can include one or more heteroatoms in one or both rings.
  • Heterocycloalkenyl and “heterocycloalkenyl ring” are used interchangeably to refer to a heterocycloalkyl group containing one or more carbon-carbon double bonds or carbon-nitrogen double bonds within the ring, but are not intended to include, for example, Heteroaryl moiety as defined herein. This group can be fused to an aryl or heteroaryl group. Heterocycloalkenyl rings can be optionally substituted. In certain embodiments, the heterocycloalkenyl ring contains one or more carbonyl or thiocarbonyl groups, eg, oxo- and thio-containing groups.
  • 5- to 8-membered heterocycloalkenyl ring refers to a heterocycloalkenyl ring having 5 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Preferred is a 5- to 6-membered heterocycloalkenyl ring.
  • heterocycloalkenyl rings include 4,5-dihydro-1H-imidazole rings, 1,4,5,6-tetrahydropyrimidine rings, 3,4,7,8-tetrahydro-2H- 1,4,6-oxadiazosine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diazepine ring, 2,5,6, 7-Tetrahydro-1,3,5-oxadiazepine.
  • Aryl and “aromatic ring” are used interchangeably and both refer to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, the group Can be fused with a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring or heteroaryl.
  • C 6-10 aryl refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, non-limiting examples of aryl groups include phenyl, naphthyl, and the like.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and both refer to a monocyclic, bicyclic, or polycyclic 4n+2 aromatic ring system (eg, having a ring carbon atom and a ring heteroatom) Arrangement of shared 6 or 10 pi electrons) groups wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl or aromatic rings. Heteroaryl rings can be optionally substituted.
  • 5- to 10-membered heteroaryl refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • “5- to 6-membered heteroaryl” refers to a monocyclic heteroaryl having 5 to 6 ring atoms of which 1, 2, 3 or 4 are heteroatoms, non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl oxazolyl, 1,2,5-oxadiazol
  • 8- to 10-membered heteroaryl refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3 or 4 are heteroatoms, non-limiting examples include indolyl, iso Indolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzoisofuryl, benzimidazolyl, benzoxazolyl, benziso oxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido [2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthyridinyl, 1,
  • Heteroatom refers to nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as valence allows. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Fused” refers to a structure in which two or more rings share one or more bonds.
  • Alkoxy refers to -O-alkyl, wherein alkyl is as defined above. Preferred is C 1-8 alkoxy, more preferred is C 1-6 alkoxy, and most preferred is C 1-3 alkoxy. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentoxy, and the like.
  • Cycloalkyloxy refers to -O-cycloalkyl, wherein cycloalkyl is as defined above. C 3-8 cycloalkyloxy is preferred, and C 3-6 cycloalkyloxy is more preferred. Non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • a bond means that the two groups connected by it are joined by a covalent bond.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Halo refers to the replacement of one or more (eg, 1, 2, 3, 4 or 5) hydrogens in a group with a halogen.
  • Amino refers to NH2
  • cyano refers to CN
  • nitro refers to NO2
  • benzyl refers to -CH2 - phenyl
  • oxo O
  • carboxy refers to -C (O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • hydroxyl refers to -OH
  • thiol refers to SH
  • cyclopropylidene structure is:
  • saturated or partially unsaturated monocyclic refers to a saturated or partially unsaturated all-carbon monocyclic ring system, wherein “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond, and “partially unsaturated” is intended to encompass Rings having multiple sites of unsaturation, but are not intended to include aryl or heteroaryl moieties as defined herein.
  • saturated or partially unsaturated monocyclic rings contain one or more carbonyl groups, eg, oxo groups.
  • a "3- to 7-membered saturated or partially unsaturated monocyclic ring” has 3 to 7 ring carbon atoms, preferably a saturated or partially unsaturated monocyclic ring having 3 to 6 ring carbon atoms, more preferably 3 to 6 ring carbon atoms of saturated monocycles.
  • Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, Cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.
  • “Saturated or partially unsaturated monoheterocycle” means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated monocycle are selected from nitrogen, oxygen or S(O) t (wherein t is an integer from 0 to 2 ), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • a "3- to 7-membered saturated or partially unsaturated monoheterocycle” has 3 to 7 ring atoms, wherein 1, 2 or 3 ring atoms are the aforementioned heteroatoms.
  • the atoms are 5- to 6-membered saturated or partially unsaturated monoheterocycles of the above heteroatoms, most preferably 5- or 6-membered saturated monoheterocycles.
  • Non-limiting examples of saturated monoheterocycles include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings , oxazolidine ring, piperazine ring, dioxolane ring, dioxane ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, nitrogen oxetan-2-one ring, oxetan-2-one ring, pyrrolidin-2-one ring, pyrrolidin-2,5-dione ring, piperidin-2-one ring, dihydro Furan-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran
  • Non-limiting examples of partially unsaturated monoheterocycles include 1,2-dihydroazetadiene rings, 1,2-dihydrooxetadiene rings, 2,5-dihydro-1H- Pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2, 3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4 ,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosine ring, 1,6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1,3
  • Substituted means that one or more hydrogen atoms in a group, preferably 1 to 5 hydrogen atoms, independently of each other, are substituted by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independently of each other replaced by a corresponding number of substituents Substituents are substituted. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • substituted substituents independently selected from " in the present invention means that when more than one hydrogen on a group is substituted by a substituent, the types of the substituents may be the same or different, so The selected substituents are each independent species.
  • L is (CR e R f ) s , when s is 2, that is, L is (CR e R f )-(CR e R f ), wherein the two R e or R f may be the same or different, and they are each independent species.
  • any group herein may be substituted or unsubstituted.
  • the substituents are preferably 1 to 5 or less groups, independently selected from cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more Preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, halogenated C 1-8 alkyl substituted amino, acetyl, hydroxy, hydroxymethyl , hydroxyethyl, carboxyl
  • a compound of the present invention may be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, syrups, and the like.
  • the compounds of the invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like.
  • the above dosage forms can be prepared from the active compound and one or more carriers or excipients by conventional methods of pharmacy.
  • the aforementioned carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compounds may be in solution or suspension with the carriers described above.
  • “Pharmaceutically acceptable carrier” means a non-toxic, inert, solid, semi-solid substance or liquid filling machine, diluent, encapsulating material or auxiliary preparation or any type of auxiliary material, which is compatible with the patient, preferably breastfeeding An animal, more preferably a human, is suitable for delivering an active agent to a target of interest without terminating the activity of the agent.
  • Active substance of the present invention or “active compound of the present invention” refers to the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof , which has a high CDK9 selective inhibitory activity.
  • compositions of the present invention are formulated, dosed and administered in a manner consistent with standard medical practice.
  • a "therapeutically effective amount" of a compound to be administered will be determined by such factors as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • a “therapeutically effective amount” refers to an amount of a compound of the invention that will elicit a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or ameliorating symptoms, alleviating a disorder, slowing or delaying disease progression, or preventing disease, and the like.
  • the pharmaceutical composition of the present invention or a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, contained in the pharmaceutical composition of the present invention It is preferably 0.1 mg to 5 g/kg (body weight).
  • Patient means an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • Treatment refers to alleviating, delaying the progression, attenuating, preventing, or maintaining an existing disease or disorder (eg, cancer). Treatment also includes curing, preventing the development or alleviating to some extent one or more symptoms of a disease or disorder.
  • compositions include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • Pharmaceutically acceptable acid addition salts are salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts with inorganic bases and salts with organic bases. These salts can be prepared by methods known in the art.
  • solvate refers to the complex formed by the compound of the present invention and a solvent. They either react in the solvent or are precipitated or crystallized from the solvent. For example, a complex formed with water is called a "hydrate”. Solvates of compounds of formula (I) are within the scope of this invention.
  • the compound represented by the formula (I) of the present invention contains one or more chiral centers, it can exist in different optically active forms.
  • a compound of formula (I) contains one chiral center, the compound contains a pair of enantiomers. Both enantiomers of the compound and mixtures of the pair of enantiomers, such as racemic mixtures, are also within the scope of the present invention. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • the compound includes enantiomers and diastereomers.
  • Enantiomers and diastereomers of this compound and mixtures of enantiomers, mixtures of diastereomers, and mixtures of enantiomers and diastereomers It is also within the protection scope of the present invention. Enantiomers and diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the present invention includes prodrugs of the above compounds.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to yield the parent compound.
  • For specific preparation methods of prodrugs please refer to (Saulnier, M.G.; Frennesson, D.B.; Deshpande, M.S.; Hansel, S.B and Vysa, D.M.Bioorg.Med.Chem Lett.1994, 4, 1985-1990; and Greenwald, R.B.; Y.H.; Conover, C.D.; Shum, K.; Wu, D.; Royzen, M.J. Med. Chem. 2000, 43, 475.).
  • the present invention provides methods for the preparation of compounds of formula (I), which can be synthesized using standard synthetic techniques known to those skilled in the art or using methods known in the art in combination with the methods described herein.
  • the solvents, temperatures and other reaction conditions given in the present invention can be varied according to the skill in the art.
  • the reactions can be used sequentially to provide compounds of the invention, or they can be used to synthesize fragments that are subsequently added by the methods described herein and/or by methods known in the art.
  • the compounds described herein can be synthesized using methods analogous to those described below or exemplified in the Examples, or relevant publications available to those skilled in the art, using appropriate alternative starting materials.
  • Starting materials for the synthesis of the compounds described herein can be synthesized or can be obtained from commercial sources.
  • the compounds described herein and other related compounds having various substituents can be synthesized using techniques and starting materials known to those skilled in the art.
  • the general methods for preparing the compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified to introduce various moieties in the molecules provided herein by reagents and conditions deemed appropriate by those skilled in the art.
  • LC-MS Agilent 1290HPLC System/6130/6150MS Liquid Mass Spectrometer (manufacturer: Agilent), column Waters BEH/CHS, 50 ⁇ 2.1 mm, 1.7 ⁇ m.
  • ISCO Combiflash-Rf75 or Rf200 automatic column passing instrument Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
  • Known starting materials can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Darui Chemicals, etc. company.
  • the progress of the reaction can be monitored by thin-layer chromatography (TLC), and the compound can be purified by column chromatography.
  • TLC thin-layer chromatography
  • the developing solvent system used in column chromatography or TLC can be selected from: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system, etc.
  • the volume ratio of the solvent is based on the polarity of the compound adjust differently.
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • DIEA N,N-diisopropylethylamine
  • EA ethyl acetate
  • PE petroleum Ether
  • BINAP (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinyl Imine
  • Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium
  • Pd(dppf)Cl 2 [1,1'-bis(diphenylphosphonium)ferrocene]palladium dichloride
  • Pd( PPh3 ) 4 tetrakis(triphenylphosphine)palladium
  • PdCl2 CH3CN
  • room temperature refers to about 20-30°C.
  • Step 1 2-Chloro-5-fluoro-4-iodopyridine (20 g, 77.69 mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (17.16 g, 101.00 mmol) under nitrogen , Pd(PPh 3 ) 4 (8.98 g, 7.77 mmol), potassium carbonate (32.16 g, 233.07 mmol), 1,4-dioxane (400 mL) and water (100 mL) were heated to 100 °C for 16 hours.
  • Step 2 Compound 1-1 (7 g, 27.38 mmol), (2-amino-4-pyridyl)methanol (3.57 g, 28.75 mmol), Pd 2 (dba) 3 (2.51 g, 2.74 mmol) were combined under nitrogen protection ), X-PHOS (2.61 g, 5.48 mmol), cesium carbonate (17.85 g, 54.76 mmol) and 1,4-dioxane (150 mL) were placed in a reaction flask and heated at 120° C. for 16 hours.
  • Step 6 Compound 1-5 (1 g, 2.10 mmol), tert-butyl carbamate (369.54 mg, 3.15 mmol), magnesium oxide (339.04 mg, 8.41 mmol), dimerized rhodium acetate (278.86 mg, 630.91 ⁇ mol), Iodobenzenediacetic acid (1.35 g, 4.21 mmol) and DCM (30 mL) were mixed and reacted at 45°C for 3 hours.
  • tert-butyl carbamate (369.54mg, 3.15mmol), magnesium oxide (339.04mg, 8.41mmol), rhodium dipolyacetate (278.86mg, 630.91 ⁇ mol), iodobenzenediacetic acid (1.35g, 4.21mmol) were added.
  • tert-butyl carbamate (369.54mg, 3.15mmol), magnesium oxide (339.04mg, 8.41mmol), rhodium dimerized acetate (278.86mg, 630.91 ⁇ mol), iodobenzenediacetic acid were added.
  • Step 7 Trifluoroacetic acid (2 mL) was added to a solution of compound 1-6 (429.99 mg, 503.05 ⁇ mol) and DCM (6 mL) at 0°C, and the reaction was completed at room temperature for 1 hour. The reaction solution was evaporated to dryness to obtain compound 1-7 (220 mg). MS m/z (ESI): 491.2 [M+1].
  • Step 8 Compound 1-7 (220 mg, 448.50 ⁇ mol) and acetic acid (5 mL) were mixed and heated to 75°C for 8 hours, the reaction solution was evaporated to dryness, the residue was added to DCM (15 mL) and washed with water (10 mL*2).
  • Compound Z-1 (26.89 mg) was purified by HPLC preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm). MS m/z (ESI): 445.0 [M+1].
  • Step 2 Compound 2-1 (146 mg, 249.74 ⁇ mol), trifluoroacetic acid (1.5 mL) and DCM (3 mL) were mixed and reacted at room temperature for 1 hour. The reaction solution was evaporated to dryness and sent to preparative liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm) to purify compound Z-2 (24.96 mg). MS m/z (ESI): 385.1 [M+1].
  • Step 3-6 Refer to the preparation method of step 5-8 of Example 1, except that compound 1-4 is replaced by compound 3-2 to obtain compound Z-3 (3.23 mg). MS m/z (ESI): 459.1 [M+1].
  • Step 1 Combine 2-chloro-4-(chloromethyl)pyridine (500 mg, 3.09 mmol), 3-sulfanylpropan-1-ol (341.30 mg, 3.70 mmol), potassium carbonate (639.78 mg, 4.63 mmol) After mixing with acetonitrile (20 mL), the mixture was heated at 50°C and reacted for 3 hours. The reaction solution was filtered and evaporated to dryness to obtain compound 4-1 (670 mg). MS m/z (ESI): 218.0 [M+1].
  • Step 2 m-chloroperoxybenzoic acid (624.77 mg, 3.08 mmol, 85% purity) was added to a solution of compound 4-1 (670.00 mg, 3.08 mmol) and DCM (20 mL) at 0 °C, and reacted at 0 °C for 10 minute. The reaction solution was filtered and evaporated to dryness to obtain compound 4-2 (650 mg). MS m/z (ESI): 234.0 [M+1].
  • Step 3 tert-butylchlorodimethylsilane (1.26 g, 8.34 mmol) was added to compound 4-2 (650 mg, 2.78 mmol), imidazole (1.14 g, 16.69 mmol), 4-dimethylaminopyridine (339.77 mg, 2.78 mmol) and DCM (30 mL) at room temperature for 2 hours.
  • the reaction solution was added to ice water, extracted with DCM, the organic layer was washed with saturated brine, dried and evaporated to dryness to obtain a crude product.
  • Step 4 Compound 4-3 (600 mg, 1.72 mmol), tert-butyl carbamate (302.99 mg, 2.59 mmol), magnesium oxide (277.98 mg, 6.90 mmol), rhodium dimerized acetate (228.64 mg, 517.28 ⁇ mol), Iodobenzenediacetic acid (1.11g, 3.45mmol) and DCM (20mL) were mixed and reacted at 45°C for 8 hours, and tert-butyl carbamate (302.99mg, 2.59mmol), magnesium oxide (277.98mg, 6.90mmol), di Rhodium polyacetate (228.64 mg, 517.28 ⁇ mol) and iodobenzenediacetic acid (1.11 g, 3.45 mmol) were added and reacted at 45° C.
  • Step 6 Trifluoroacetic acid (3 mL) was added to a solution of compound 4-5 (440 mg, 1.26 mmol) and DCM (9 mL) at 0°C, and reacted at room temperature for 1 hour. The reaction solution was evaporated to dryness to obtain crude product. The crude product was purified by reverse phase column chromatography (aqueous ammonium bicarbonate/acetonitrile) to give compound 4-6 (310 mg). MS m/z (ESI): 249.0 [M+1].
  • Step 7 Methanesulfonyl chloride (87.50 mg, 763.88 ⁇ mol) was added to a mixture of compound 4-6 (200 mg, 804.09 ⁇ mol)), triethylamine (162.73 mg, 1.61 mmol, 224.30 ⁇ L) and DCM (10 mL) at 0 °C In the solution, the reaction was carried out at 0°C for 2 hours after the addition. The reaction solution was quenched with a small amount of ice water at 0°C, and the crude product was obtained after the solution was evaporated to dryness. The crude product was purified by column chromatography (reverse phase, aqueous ammonium bicarbonate/acetonitrile) to give compound 4-7 (138 mg). MS m/z (ESI): 327.0 [M+1].
  • Step 8 Compound 4-7 (138 mg, 422.25 ⁇ mol) and ammonia water (5 mL) were heated to 80° C. to react for 2 hours. The reaction solution was evaporated to dryness to obtain compound 4-8 (95 mg). MS m/z (ESI): 231.0 [M+1].
  • Step 9 Compound 4-8 (45 mg, 195.05 ⁇ mol), Intermediate v1 (32.25 mg, 136.53 ⁇ mol), Pd2(dba)3 (17.87 mg, 19.50 ⁇ mol), XantPhos (22.55 mg, 39.01 ⁇ mol) were combined under nitrogen protection ), potassium carbonate (53.91 mg, 390.09 ⁇ mol) and 1,4-dioxane (5 mL) were heated to 130°C for microwave reaction for 1 hour. After filtering the reaction solution, the filtrate was evaporated to dryness to obtain crude product.
  • Step 2 Compound 5-1 (90 mg, 262.89 ⁇ mol), 2-methylsulfanyl-4,5-dihydro-1H-imidazole (64.17 mg, 262.89 ⁇ mol, hydroiodide) and pyridine (5 mL) Heated to 125°C and reacted for 2 hours. The reaction solution was evaporated to dryness to obtain crude product. The crude product was subjected to preparative HPLC liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm) to obtain compound Z-5 (9.51 mg). MS m/z (ESI): 411.2 [M+1].
  • Step 1 Compound 1-3 (200 mg, 552.83 ⁇ mol) and methylamine/THF (5 mL) were heated to 60° C. and reacted in a sealed tube for 16 hours. The reaction solution was evaporated to dryness and then slurried with DCM, the solid salt was filtered off, filtered and evaporated to dryness to obtain compound 6-1 (190 mg). MS m/z (ESI): 357.1 [M+1].
  • Step 2 Compound 6-1 (50 mg, 140.30 ⁇ mol), 1H-pyrazole-1-carboximide amide hydrochloride (61.70 mg, 420.91 ⁇ mol, HCl), DIEA (72.53 mg, 561.22 ⁇ mol, 97.75 ⁇ L) ) and DMSO (5 mL) were heated to 130 °C for 16 hr.
  • the reaction solution was subjected to preparative HPLC liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm) to prepare compound Z-6 (13.04 mg).
  • Step 2 Compound 7-1 (220 mg, 1.02 mmol), potassium carbonate (281.20 mg, 2.03 mmol) and acetonitrile (10 mL) were mixed, iodomethane (144.40 mg, 1.02 mmol) was added, and the reaction was completed at room temperature for 16 hours. The reaction solution was filtered and evaporated to dryness to obtain the crude product. The crude product was further distilled and beaten, filtered and evaporated to dryness to obtain compound 7-2 (280 mg). MS m/z (ESI): 175.0 [M-56+1].
  • Step 3 Intermediate v2 (50 mg, 146.05 ⁇ mol), compound 7-2 (50.45 mg, 219.08 ⁇ mol), and ethanol (5 mL) were heated at 60° C. to react for 48 hours. The reaction solution was evaporated to dryness to obtain compound 7-3 (76 mg). MS m/z(ESI): 525.2[M+1].
  • Step 4 Trifluoroacetic acid (0.8 mL) was added to a solution of compound 7-3 (71 mg, 135.36 ⁇ mol) and DCM (2 mL), and reacted at room temperature for 1 hour. The reaction solution was evaporated to dryness to obtain crude product. The crude product was prepared by preparative HPLC liquid chromatography (preparative column: 21.2 ⁇ 250 mm C18 column; system: 10 mM NH 4 HCO 3 H 2 O; wavelength: 254/214 nm) to obtain compound Z-7 (5.93 mg). MS m/z (ESI): 425.0 [M+1].
  • Step 1 Under nitrogen protection, 2-chloro-5-methoxypyridine (500 mg, 3.48 mmol) and THF (15 mL) were cooled to -78 °C, lithium diisopropylamide (2M, 3.48 mL) was added, After completion of the reaction at -78°C for 1 hour, DMF (509.11 mg, 6.97 mmol, 539.31 ⁇ L) was added, and the reaction at -78°C was completed for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution, and extracted with extraction (10 mL*2). The organic layer was washed with saturated brine and evaporated to dryness to obtain compound 10-1 (530 mg). MS m/z (ESI): 190.0 [M+18+1].
  • Step 3-9 Refer to the preparation method of step 2-8 of Example 1, except that compound 1-1 is replaced with compound 10-2, and (2-amino-4-pyridyl)methanol is replaced with intermediate v1 to prepare compound Z-10 (1.10 mg). MS m/z (ESI): 475.1 [M+1].
  • Step 2 Under argon protection, compound 13-1 (100 mg, 243.65 ⁇ mol) was dissolved in anhydrous DMF (3 mL), then cesium carbonate (158.77 mg, 487.31 ⁇ mol) was added, and the mixture was stirred at room temperature for half Hour. 1,2-Dibromoethane (68.66 mg, 365.48 ⁇ mol) was then added dropwise to the reaction, which was stirred at room temperature for a further 3 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the solvent was spin-dried to obtain the crude product. The crude product was purified by preparative liquid chromatography to give the product Z-13 (1.54 mg). MS m/z (ESI): 437.5 [M+1].
  • Step 2 Compound 14-1 (400 mg, 835.92 ⁇ mol) was dissolved in dry DMF (5 mL), followed by [3-(aminomethyl)oxetan-3-yl]methanol (195.85 mg, 1.67 mmol) ), triethylamine (169.17 mg, 1.67 mmol) was added. The reaction was stirred at 60°C for 5 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure to obtain compound 14-2 (360 mg). MS m/z (ESI): 502.5 [M+1].
  • Step 3 In a 15 mL sealed tube, compound 14-2 (220 mg, 438.64 ⁇ mol) was dissolved in acetone (5 mL), followed by iodomethane (249.04 mg, 1.75 mmol), DIEA (113.38 mg, 877.28 ⁇ mol, 152.80 ⁇ L) ) are added sequentially. The reaction was stirred at 55°C for 3 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure to obtain compound 14-3 (200 mg). MS m/z(ESI): 516.6[M+1].
  • Step 4 Compound 14-3 (200 mg, 387.9 ⁇ mol) was dissolved in dry THF (10 mL), and sodium hydroxide (31 mg, 775.8 ⁇ mol) was added thereto. The reaction was stirred at room temperature for 5 hours. After the reaction was completed, the inorganic salt was filtered off, diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure to obtain a crude product. The crude product was purified by preparative liquid chromatography to give the product Z-14 (16.05 mg). MS m/z (ESI): 468.5 [M+1].
  • Step 1 Compound (2 g, 5.53 mmol) and triisopropyl(prop-1-ynyl)silane (4.34 g, 22.11 mmol) were dissolved in acetonitrile (30 mL) under nitrogen protection, then PdCl 2 ( CH3CN ) 2 (430.26 mg, 1.66 mmol), XantPhos (789.45 mg, 1.66 mmol), cesium carbonate (3.60 g, 11.06 mmol) were added sequentially. After the reaction was replaced with argon three times at room temperature, the reaction was heated to 75°C for 2 hours.
  • Step 2 Compound 20-2 (1.4 g, 2.76 mmol) was dissolved in water (5 mL), methanol (100 mL), and then ammonium fluoride (5.10 g, 137.88 mmol) was added. The reaction was stirred at reflux for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure to obtain compound 20-2 (750 mg). MS m/z (ESI): 352.4 [M+1].
  • Step 3 Compound 20-2 (100 mg, 284.62 ⁇ mol) and 2-(6-azido-2-pyridyl)propan-2-ol (60.86 mg, 341.54 ⁇ mol) were dissolved in THF under N2 protection (4 mL), tert-butanol (8 mL), water (4 mL), then copper sulfate pentahydrate (56.85 mg, 227.69 ⁇ mol), sodium ascorbate (56.39 mg, 284.62 ⁇ mol), 0.5 mL of triethylamine were added in turn. After the reaction was replaced with argon three times at room temperature, the reaction was heated to 70°C for 6 hours.
  • Step 1 1,2-Difluoro-3-nitro-benzene (9.35 g, 58.77 mmol) and 1-hydroxycyclopropanecarboxylic acid (5 g, 48.98 mmol) were dissolved in DMF (50 mL) and cooled to 0°C , to which was added 60% sodium hydrogen (4.90 g, 122.44 mmol). The reaction was stirred at room temperature for 0.5 hours, then heated to 80°C for 3 hours.
  • Step 2 Compound 24-1 (8.0 g, 33.17 mmol) was dissolved in ethanol (80 mL) and water (15 mL), then reduced iron powder (9.26 g, 165.86 mmol) and ammonium chloride (8.87 g, 165.86 mmol) were dissolved ) into it. The reaction was stirred at 90°C for 2 hours. EA (100 mL) was added to dilute, washed with saturated sodium chloride solution (100 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent 0-30% EA in PE to give compound 24-2 (5.0 g). MS m/z(ESI): 194.1[M+1]
  • Step 3 Compound 24-2 (2.7 g, 13.98 mmol) was dissolved in THF (40 mL) and borane (1 M, 41.93 mL) was added. The reaction was stirred at 50°C for 2 hours. Methanol (15 mL) was added to quench the reaction, the solvent was removed under reduced pressure, 20 mL of 1N hydrochloric acid was added, heated to 50° C. for 10 minutes, cooled to room temperature, added with saturated sodium carbonate solution (50 mL), extracted with EA, filtered, and concentrated under pressure , to obtain compound 24-3 (2.5 g). MS m/z (ESI): 180.1 [M+1].
  • Step 4 Compound 24-3 (2.5 g, 13.95 mmol) was dissolved in acetonitrile (25 mL), then NBS (4.97 g, 27.90 mmol) was added to it. The reaction was stirred at room temperature for 2 hours. EA (80 mL) was added to dilute, washed with saturated sodium chloride solution (60 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent 0-30% EA in PE to give compound 24-4 (2.0 mg). MS m/z (ESI): 337.8 [M+1].
  • Step 5 Compound 24-4 (1.8 g, 5.34 mmol) was dissolved in THF (30 mL), cooled to -78 °C, and n-butyllithium (2.5 M, 4.70 mL) was added. The reaction was stirred at -78°C for 15 minutes, the reaction was stopped, quenched by adding saturated sodium chloride solution (50 mL), extracted with EA (60 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent 0-30% EA in PE to give compound 24-5 (1.05 mg). MS m/z(ESI): 257.9 [M+1].
  • Step 6 Compound 24-5 (550 mg, 2.13 mmol) and pinacol biboronate (1.08 g, 4.26 mmol) were placed in a reaction flask, DMSO (20 mL) was added, and then Pd(dppf)Cl 2 (155.93 mg, 213.11 ⁇ mol) and potassium acetate (627.43 mg, 6.39 mmol) were added. The reaction was stirred at 120°C for 2 hours. EA (60 mL) was added to dilute, washed with saturated sodium chloride solution (60 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-6 (500 mg). MS m/z(ESI): 306.1[M+1]
  • Step 7 Compound 24-6 (500 mg, 1.64 mmol) and 2-chloro-5-fluoro-4-iodo-pyridine (463.99 mg, 1.80 mmol) were dissolved in 1,4-dioxane (12 mL), Then Pd(dppf)Cl2 (59.95 mg , 81.93 ⁇ mol), potassium carbonate (679.36 mg, 4.92 mmol) were added. The reaction was stirred in the microwave at 100°C for 3 hours. EA (80 mL) was added to dilute, washed with saturated sodium chloride solution (80 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent 0-50% EA in PE to give compound 24-7 (300 mg). MS m/z(ESI): 309.0[M+1]
  • Step 8 Compound 24-7 (100 mg, 323.93 ⁇ mol) and (2-amino-4-pyridyl)methanol (60.32 mg, 485.89 ⁇ mol) were dissolved in 1,4-dioxane (6 mL), followed by Pd2(dba) 3 (29.66 mg, 32.39 ⁇ mol), XantPhos (37.49 mg, 64.79 ⁇ mol) and cesium carbonate (211.08 mg, 647.86 ⁇ mol) were added. The reaction was stirred at 100°C for 3 hours.
  • Step 9 Compound 24-8 (80 mg) (80 mg, 201.82 ⁇ mol) was dissolved in DCM (15 mL), then thionyl chloride (120.05 mg, 1.01 mmol, 73.29 ⁇ L) was added. The reaction was stirred at 40°C for 3 hours. EA (80 mL) was added, washed with saturated sodium chloride solution (60 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-9 (80 mg). MS m/z (ESI): 415.0 [M+1].
  • Step 10 Compound 24-9 (80 mg, 192.85 ⁇ mol) and 1H-benzimidazol-2-amine (38.52 mg, 289.27 ⁇ mol) were dissolved in acetone (15 mL) followed by potassium carbonate (53.31 mg, 385.70 ⁇ mol) and potassium hydroxide (21.64 mg, 385.70 ⁇ mol) were added. The reaction was stirred at 60°C for 3 hours. EA (80 mL) was added, washed with saturated sodium chloride solution (80 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 1 Refer to the preparation method of Step 8 of Example 24, except that (2-amino-4-pyridyl)methanol is replaced with diphenylmethaneimide to obtain compound 27-1.
  • Step 2 Compound 27-1 (700 mg, 1.54 mmol) was dissolved in methanol (30 mL), and hydroxylamine hydrochloride (536.3 mg, 7.72 mmol) was added thereto. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, ethyl acetate (50 mL) was added, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 27-2 (350 mg). MS m/z (ESI): 290.1 [M+1].
  • Step 3 Compound 27-2 (100 mg, 345.69 ⁇ mol) and compound 4-8 (171.22 mg, 622.24 ⁇ mol) were placed in a microwave tube, toluene (6 mL), N-methylpyrrolidone (0.6 mL) were added, and then Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)( 51.08 mg, 69.14 ⁇ mol), X-PHOS (32.96 mg, 69.14 ⁇ mol), potassium phosphate (366.89 mg, 1.73 mmol) were added.
  • Step 1-2 Refer to the preparation method of Step 1-2 of Example 3, except that compound 1-3 is replaced with 2-chloro-4-(chloromethyl)pyridine to obtain compound 28-1. MS m/z(ESI): 260.1[M+1].
  • Step 3-4 Refer to the preparation method of step 5-6 of Example 1, except that compound 1-4 is replaced by compound 28-1 to obtain compound 28-4.
  • Step 5 Using compound 28-4 and compound 27-2 as raw materials, referring to the preparation method of step 3 of Example 27, compound 28-5 was obtained, MS m/z (ESI): 644.3 [M+1].
  • Step 6 Referring to the preparation method of Step 7 of Example 1, compound 28-6 was obtained. MS m/z (ESI): 544.2 [M+1].
  • Step 7 Compound 28-6 (160 mg, 294.34 ⁇ mol) was dissolved in methanol (12 mL) and water (3 mL), and sodium hydroxide (58.8 mg, 1.47 mmol) was added thereto. After the reaction was completed, the pH was adjusted to 3-4 with 2N dilute hydrochloric acid, evaporated to dryness under reduced pressure, and dried to obtain compound 28-7 (150 mg). MS m/z (ESI): 530.2 [M+1].
  • Step 8 Compound 28-7 (150.00 mg, 141.63 ⁇ mol) was dissolved in acetonitrile (10 mL), then N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (79.48 mg, 283.26 ⁇ mol) and N-methylimidazole (34.88 mg, 424.88 ⁇ mol) were added. The reaction was stirred at room temperature for 2 hours. Diluted with ethyl acetate (50 mL), the organic phase was washed with saturated sodium chloride solution (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Test Example 1 Activity Inhibition Test on CDK Family Kinases
  • kinase reagents were purchased from Carna Bioscience, reaction substrates and detection reagents were purchased from PerkinElmer, and other reagents were purchased from Thermo scientific.
  • the LANCE Ultra method was used to determine the activity of the analytes on the kinase activities of CDK1/CycB (Carna bioscience, #04-102), CDK2/CycA (Carna bioscience, #04-103), and CDK9/CycT (Carna bioscience, #04-110). inhibition.
  • the kinase activity test uses a 10 ⁇ L system, which contains the following components: CDK kinase dilution, Ulight-Myelic basic protein (Perkin Elmer, #TRF-0109, hereinafter referred to as U-MBP) and ATP (Thermo scientific, #PV3227) mixed Substrate diluent, as well as the compounds (ie analytes) prepared in the above examples of the present invention.
  • U-MBP Ulight-Myelic basic protein
  • ATP Thermo scientific, #PV3227
  • Each kinase in the test includes three test groups: background group (Blank), no inhibition group (PC) and compound test group (Test).
  • the components included in each test group are as follows:
  • test compound The test compound was dissolved in 10 mM at room temperature for gradient dilution with DMSO, and then diluted with deionized water to make 4 ⁇ compound working solution, and the content of DMSO was 2%.
  • Compounds used in CDK1 and CDK2 assays were tested at a maximum concentration of 10 ⁇ M and CDK9 at 1 ⁇ M.
  • 1.33x reaction buffer the composition is 26.7 mM MOPS, 6.67 mM MgCl 2 and 0.0133% Tween-20. After configuration, store it in a refrigerator at 4°C in the dark. Before use, add freshly prepared DTT to a final concentration of 5.33 mM.
  • the working concentration of DMSO in the reaction was 0.5%.
  • test groups including Blank, PC and Test groups
  • 10 ⁇ L assay solution contains: 16mM EDTA (Thermo scientific, #15575), 1nM phosphorylated U-MBP protein antibody (Perkin Elmer, #TRF-0201) and 1x assay buffer (Perkin Elmer, #CR97-100) .
  • the wavelength of excitation light is 320nm
  • the wavelength of emission light is 615nm and 665nm.
  • the method of inhibition rate is as follows:
  • Ratio value 665nm/615nm
  • the median inhibitory concentration IC50 of the compound was calculated using a four-parameter model.
  • MV-4-11 cells (20,000 cells/well) were seeded in 96-well plates (Corning #3916) and cultured in 90 ⁇ L/well (IMDM containing 10% fetal bovine serum (FBS), Gibco #10099-141C). ). After culturing for 16 hours, 10 uL of the compounds of the present invention formulated into different concentrations were added (the final concentration of DMSO was 0.5% (v/v)). After culturing for 3 days, 50 ⁇ L of Cell Titer-Glo (Promega #G7558) was added to each well, placed on a shaker at 80 rpm, 25 °C, 15 min, and the fluorescence value was detected with a Tecan Infinite pro3000. The test results are shown in the table.
  • the LC/MS/MS method was used to measure the drug concentration in the plasma of mice after oral administration of the compound of the present invention at different times, to study the pharmacokinetic behavior of the compound of the present invention in mice, and to evaluate its pharmacokinetic characteristics.
  • Test animals healthy adult male ICR mice (body weight 30-40g, 12 rats in the intragastric administration group fasted overnight, free drinking water and diet 4 hours after administration), provided by Beijing Vital River Laboratory Animal Co.LTD;
  • ICR mice were administered by tail gavage (10 mg/kg, 5% DMSO, pH 4.5, 20% Captisol).
  • Blood sample collection select animals that meet the experimental requirements before administration, weigh and mark. Before collecting blood samples, bind the mice, and each dosed mouse is at a predetermined blood collection time point (gavage administration: 0.083, 0.25, 0.5, 1, 2, 4, 6, 7.5 after administration, respectively). , 24h blood collection, a total of 9 time points), about 100 ⁇ L of blood was collected through the orbit. The blood was transferred to a 1.5 mL test tube pre-added with K 2 EDTA, centrifuged for 4 min (8000 rpm, 4° C.), and the plasma was taken out. The whole process was completed within 15 min after blood collection. All samples need to be stored in a -20°C freezer until sample analysis. The drug concentration was determined by LC/MS/MS method. Under the same dosage and administration mode of some example compounds of the present invention, the pharmacokinetic properties parameters in mice are shown in Table 3:
  • mice Female, 6-10 weeks, weighing approximately 20-23 g, were kept in a special pathogen-free environment and housed in a single ventilated cage (4 mice per cage). , 2 cages of 8 animals in each group). All cages, bedding and water were sterilized before use. All animals had free access to standard certified commercial laboratory diets.
  • a total of 85 mice were purchased from the Laboratory Animal Management Department of the Shanghai Institute of Family Planning Science (No. 3577, Jinke Road, Pudong, Shanghai) for the study. Each mouse was implanted with tumor cells (1 ⁇ 10 7 0.1 ml + Matrigel 0.1 ml) subcutaneously in the right flank for tumor growth. Dosing was initiated when the mean tumor volume reached approximately 165 cubic millimeters. Test compounds were administered orally by gavage daily at a dose of 10 mpk. Antitumor efficacy was determined by dividing the mean tumor increase volume in compound-treated animals by the mean tumor increase volume in untreated animals.
  • Tumor volume was measured twice a week with a two-dimensional caliper, and volume was measured in cubic millimeters.
  • Tumor volume TV 0.5a ⁇ b 2 .
  • a is the long diameter of the tumor and b is the short diameter of the tumor.
  • the relative tumor proliferation rate T/C (%) that is, the percentage value of the relative tumor volume in the treatment group and the control group at a certain time point.
  • the body weight change (%) of tumor-bearing animals was calculated as follows: (body weight at the time of measurement - body weight at the time of grouping)/body weight at the time of grouping x 100.

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Abstract

L'invention concerne un dérivé de bis(pyridin-2-yl)amine substitué représenté par la formule (I), un sel, un solvate, un stéréoisomère, un promédicament et une composition pharmaceutique pharmaceutiquement acceptables de celui-ci, et une application médicale de celui-ci. Le dérivé présente une activité inhibitrice sélective de CDK9 significative et est de grande valeur pratique.
PCT/CN2021/123189 2020-10-12 2021-10-12 Dérivé de bis(pyridin-2-yl)amine substitué, sa composition et son utilisation médicale WO2022078309A1 (fr)

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Citations (6)

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CN104854091A (zh) * 2012-10-18 2015-08-19 拜耳药业股份公司 含砜基团的5-氟-n-(吡啶-2-基)吡啶-2-胺衍生物
CN105102444A (zh) * 2012-11-15 2015-11-25 拜耳医药股份有限公司 含磺亚胺基的5-氟-n-(吡啶-2-基)吡啶-2-胺衍生物
CN105324380A (zh) * 2013-03-14 2016-02-10 艾伯维公司 吡咯并[2,3-b]吡啶cdk9激酶抑制剂
CN105492438A (zh) * 2013-07-04 2016-04-13 拜耳医药股份有限公司 磺亚胺取代的5-氟-n-(吡啶-2-基)吡啶-2-胺衍生物以及其作为cdk9激酶抑制剂的用途
CN106232596A (zh) * 2014-03-13 2016-12-14 拜耳医药股份有限公司 含有砜基团的5‑氟‑n‑(吡啶‑2‑基)吡啶‑2‑胺衍生物
WO2019161224A1 (fr) * 2018-02-15 2019-08-22 GiraFpharma LLC Composés hétérocycliques utilisés en tant qu'inhibiteurs de kinases

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104854091A (zh) * 2012-10-18 2015-08-19 拜耳药业股份公司 含砜基团的5-氟-n-(吡啶-2-基)吡啶-2-胺衍生物
CN105102444A (zh) * 2012-11-15 2015-11-25 拜耳医药股份有限公司 含磺亚胺基的5-氟-n-(吡啶-2-基)吡啶-2-胺衍生物
CN105324380A (zh) * 2013-03-14 2016-02-10 艾伯维公司 吡咯并[2,3-b]吡啶cdk9激酶抑制剂
CN105492438A (zh) * 2013-07-04 2016-04-13 拜耳医药股份有限公司 磺亚胺取代的5-氟-n-(吡啶-2-基)吡啶-2-胺衍生物以及其作为cdk9激酶抑制剂的用途
CN106232596A (zh) * 2014-03-13 2016-12-14 拜耳医药股份有限公司 含有砜基团的5‑氟‑n‑(吡啶‑2‑基)吡啶‑2‑胺衍生物
WO2019161224A1 (fr) * 2018-02-15 2019-08-22 GiraFpharma LLC Composés hétérocycliques utilisés en tant qu'inhibiteurs de kinases

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