WO2018086591A1 - 吡啶胺取代的杂三环化合物、其制法与医药上的用途 - Google Patents

吡啶胺取代的杂三环化合物、其制法与医药上的用途 Download PDF

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WO2018086591A1
WO2018086591A1 PCT/CN2017/110463 CN2017110463W WO2018086591A1 WO 2018086591 A1 WO2018086591 A1 WO 2018086591A1 CN 2017110463 W CN2017110463 W CN 2017110463W WO 2018086591 A1 WO2018086591 A1 WO 2018086591A1
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compound
ring
alkyl
preparation
esi
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PCT/CN2017/110463
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WO2018086591A8 (zh
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刘洋
王江维
张青
陈永刚
席宝信
孙网彬
刘颖涛
陈曦
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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 CA3039012A priority Critical patent/CA3039012C/en
Priority to DK17868712.5T priority patent/DK3505519T3/da
Priority to EP17868712.5A priority patent/EP3505519B1/en
Priority to JP2019544762A priority patent/JP6905069B2/ja
Priority to CN202110481424.4A priority patent/CN113264935B/zh
Priority to AU2017356569A priority patent/AU2017356569B2/en
Priority to NZ752011A priority patent/NZ752011B2/en
Priority to CN201780008595.7A priority patent/CN108699067B/zh
Priority to US16/338,379 priority patent/US11168088B2/en
Publication of WO2018086591A1 publication Critical patent/WO2018086591A1/zh
Publication of WO2018086591A8 publication Critical patent/WO2018086591A8/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medical technology.
  • the invention relates in particular to a pyridylamine substituted heterotricyclic compound, a process for its preparation and its use as a CDK4/6 inhibitor, as well as pharmaceutical compositions prepared therefrom.
  • CDK is a type of serine/threonine protein kinase that activates enzymatic activity only after binding to cyclins, and plays a key role in the initiation of cell cycle and regulation of transformation in various periods.
  • CDK4/6 is an important regulatory protein of the cell cycle, which phosphorylates the tumor suppressor protein Rb and releases the E2F transcription factor, allowing cells to pass through the G1/S detection point of the cell cycle, and the cell cycle can continue.
  • CDK4 single knockout mice have diabetes signs and cell defects
  • CDK6 single knockout mice have mild anemia symptoms due to defects in hematopoietic cell proliferation
  • CDK4 and CDK6 (CDK4/6) double knockouts make hematopoietic precursor cells Impaired proliferative capacity, leading to double knockout of mouse embryonic death.
  • Superactivation of the CDK4/6-cyclin D/Rb signaling pathway is commonly found in tumor cells. Under the stimulation of various mitotic signals inside and outside the cell, cyclin D is highly expressed, regulates the interaction between CDK4/6 protein and cyclin D, and promotes the localization and kinase activity of CDK4/6.
  • Activated CDK4/6 inhibits the activity of Rb tumor suppressor protein by phosphorylation, dissociates the Rb-E2F complex, releases free E2F into the nucleus, regulates protein transcription, and initiates cell cycle progression.
  • Superactivation of CDK4 is often found in epithelial malignancies, whereas superactivation of CDK6 is often found in stromal cell tumors such as sarcomas and hematological cancers. Construction of a breast cancer-bearing mouse model revealed that wild-type nude mice all formed tumors, while CDK4 knockout nude mice were completely unable to form tumors.
  • CDK4 siRNA interfered with the expression of CDK4, and it was found that the tumor growth of nude mice was significantly inhibited.
  • Selective CDK4/6 inhibitors can induce G1 arrest in cells, thereby increasing the tolerance of hematopoietic stem/progenitor cells to DNA damaging agents such as IR, and effectively reducing various hematopoietic toxicities caused by radiation, including myelosuppression and hooliganism.
  • CDK4 can inhibit the growth of tumor cells, while CDK6 is highly expressed in the blood system, and its function is to regulate the growth of hematopoietic cells.
  • the inhibition of CDK6 may cause hematological toxicity, such as neutrophils. Reduce, red blood cell reduction, etc.
  • Palbociclib has the same inhibition on both CDK4 and CDK6, with enzyme activities of 10 nm and 10 nm, respectively, and its toxicity should be related to this.
  • Abemaciclib inhibits CDK4 more strongly than CDK6; weak CDK6 inhibitors cause low hematologic toxicity. Since the homology of CDK4 and CDK6 is very high, about 70%, the development of selective CDK4/6 inhibitors, especially CDK4 inhibitors, is a big challenge.
  • a first aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 , R 3 and R 4 are each independently hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) Or a halogenated C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group);
  • halogen preferably fluorine, chlorine, bromine
  • C 1-8 alkyl preferably C 1-6 alkyl, more preferably C 1-3 alkyl
  • a halogenated C 1-8 alkyl group preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group
  • R 2 is -(CH 2 ) n -Y, wherein Y is a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group), a 3 to 6 membered saturated monoheterocyclic ring (preferably 4 to 6 members) a 5- to 6-membered monocyclic heteroaryl ring, an 8- to 10-membered bicyclic heteroaryl ring, a spiro ring, a spiro heterocyclic ring, a bridged ring or a bridged heterocyclic ring; n is 0, 1 or 2;
  • Z 1 and Z 2 are each independently a bond, CR a R b , NR c , O, S or S(O) 2 , and Z 1 and Z 2 are not simultaneously a bond, NR c , O, S or S (O) 2 ;
  • R a and R b are each independently hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated a C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group);
  • halogen preferably fluorine, chlorine, bromine
  • C 1-8 alkyl preferably C 1-6 alkyl, more preferably C 1-3 alkyl
  • halogenated a C 1-8 alkyl group preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group
  • R a , R b and the attached carbon atoms together form a 3 to 6 membered saturated monoheterocyclic ring, a 3 to 6 membered saturated or partially unsaturated monocyclic ring;
  • R c is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkane) More preferably, it is a halogenated C 1-3 alkyl group, a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group), a C(O)C 1-8 alkyl group (preferably a C (O) group.
  • 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
  • CONR a1 R b1 -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkane Base, -C(O)CH 2 CN, -C(O)CH 2 OH, 3 to 6 membered saturated monoheterocycle, 5 to 6 membered monocyclic heteroaryl ring, 8 to 10 membered bicyclic heteroaryl ring , spiro, spiro heterocycle, bridged or bridged heterocycle;
  • the A ring is a structure represented by the formula (A-1), the formula (A-2), the formula (A-3) or the formula (A-4):
  • R 11 , R 22 , R 32 and R 41 are each independently hydrogen, C 1-8 alkyl, halogenated C 1-8 alkyl, C 3-8 cycloalkyl or 3 to 6-membered saturated mono Ring (preferably 4 to 6 yuan, more preferably 5 to 6 yuan);
  • R 12 , R 21 , R 31 , R 42 are each independently hydrogen, halogen, C 1-8 alkyl, halo C 1-8 alkyl, C 3-8 cycloalkyl or 3 to 6-membered saturated mono Ring (preferably 4 to 6 yuan, more preferably 5 to 6 yuan);
  • the bridged or bridged heterocyclic ring is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of CN, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, halogen, 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 alkane Oxy), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (
  • R a1 , R b1 , R a2 , R b2 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy A substituted C 1-8 alkyl group (preferably a C 1-6 alkoxy-substituted C 1-6 alkyl group, more preferably a C 1-3 alkoxy-substituted C 1-3 alkyl group).
  • Y is a C 3-6 cycloalkyl group, a 4 to 6 membered saturated monoheterocyclic ring, a 5 to 6 membered monocyclic heteroaryl ring, a spiro ring, a spiro heterocyclic ring, a bridged ring or a bridged heterocyclic ring.
  • a cycloalkyl group a 4 to 6 membered saturated monoheterocyclic ring, a 5 to 6 membered monocyclic heteroaryl ring, a spiro ring, a spiro heterocyclic ring, a bridged ring or a bridged heterocyclic ring which is unsubstituted or substituted by -(CH 2 ) m -L 1 substituted;
  • L 1 is CN, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, -C(O)OC 1-6 alkyl, C 1-8 alkyl (preferably C 1) -6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogen C 1 -6 alkyl, more preferably halogenated C 1-3 alkyl), NR a2 R b2 , C 1-8 alkoxy
  • m is 0 or 1.
  • the 4- to 6-membered saturated monoheterocyclic ring is azetidine, oxetane, tetrahydropyrrole, tetrahydrofuran, piperidine, piperazine, morpholine or tetrahydropyran.
  • the C 3-6 cycloalkyl group is a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • the 5- to 6-membered monocyclic heteroaryl ring is thiophene, N-alkylpyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, tetrazole, metabolite An oxazole, an oxadiazole, a thiadiazole, a pyridine, a pyridazine, a pyrimidine or a pyrazine.
  • the spiroheterocycle is a double spiroheterocycle containing 1-2 nitrogen or oxygen atoms.
  • the bridged heterocycle is a bicyclic bridged heterocycle containing 1-2 nitrogen or oxygen atoms.
  • L 1 azetidine, oxetane, tetrahydrothiophene, pyrrolidine, tetrahydrofuran, piperidine, oxazolidine, piperazine, dioxolane, dioxane Hexacyclic, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of: Acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, C 3-6 cycloalkyl, halogen C 1-3 alkoxy, -C(O)OC 1-6 alkyl, NR a3 R b3 ; wherein R a3 and R b3 are each independently hydrogen or C 1-3 alkyl.
  • Y is a group selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, azetidine, tetrahydropyrrole, tetrahydrofuran, piperidine, piperazine, morpholine or tetra Hydropyran, said group being unsubstituted or substituted by L 1 or -CH 2 -L 1 ;
  • L 1 is CN, acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)OC(CH 3 ) 3 , -C(O)OCH(CH 3 ) 2 , methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, cyclopentyl, cyclohexyl, monofluoromethyl, difluoromethyl, trifluoro
  • the azetidine, tetrahydropyrrole, tetrahydrofuran, piperidine, piperazine, morpholine or tetrahydropyran in L 1 is unsubstituted or is selected from 1, 2 or 3 Substituted by the following group of substituents: acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, C 3- 6 cycloalkyl, halo C 1-3 alkoxy, -C(O)OC 1-6 alkyl, NR a3 R b3 ; wherein R a3 , R b3 are each independently hydrogen or C 1-3 alkyl .
  • R c is hydrogen, -C(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl, -CONR a1 R b1 , -SO 2 C 1-3 alkane a group, -C(O)CH 2 CN, -C(O)CH 2 OH or -(CH 2 ) p -L 2 ; wherein L 2 is CN, C 1-8 alkyl (preferably C 1-6 alkane) More preferably, C 1-3 alkyl), NR a1 R b1 , C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated a C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group), a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group), a 4- to 6-membered saturated monohe
  • the alkyl group, alkoxy group, cycloalkyl group, 4 to 6 membered saturated monoheterocyclic ring, 5 to 6 membered monocyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring or bridged heterocyclic ring is unsubstituted Or substituted with one substituent selected from the group consisting of acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, C 1-3 alkyl, C 1 -3 alkoxy, halo C 1-3 alkyl, C 3-6 cycloalkyl, NR a2 R b2 , azetidine, oxetane, tetrahydrothiophene, tetrahydropyrrole, tetrahydrofuran, Piperidine, oxazolidine, piperazine, dioxolane, dioxane,
  • p is 0 or 1.
  • the 4- to 6-membered saturated monoheterocyclic ring is azetidine, oxetane, tetrahydropyrrole, tetrahydrofuran, piperidine, piperazine, morpholine or tetrahydropyran.
  • the 5- to 6-membered monocyclic heteroaryl ring is thiophene, N-alkylpyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, tetrazole, metabolite An oxazole, an oxadiazole, a thiadiazole, a pyridine, a pyridazine, a pyrimidine or a pyrazine.
  • R 11 , R 22 , R 32 , R 41 are each independently hydrogen or -(CH 2 ) q -L 3 ; wherein L 3 is CN, NR a1 R b1 , C 1-8 alkane a group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group), a C 1-8 alkoxy group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group) a halogenated C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group), a C 3-8 cycloalkyl group (preferably a C 3-6 ring)
  • the alkyl group, alkoxy group, cycloalkyl group, 4 to 6 membered saturated monoheterocyclic ring, 5 to 6 membered monocyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring or bridged heterocyclic ring is unsubstituted Or substituted with one substituent selected from the group consisting of acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, C 1-3 alkyl, C 1 -3 alkoxy, halo C 1-3 alkyl, C 3-6 cycloalkyl, NR a2 R b2 , azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, Piperidine, oxazolidine, piperazine, dioxolane, dioxane,
  • q is 0 or 1.
  • the 4- to 6-membered saturated monoheterocyclic ring is azetidine, oxetane, tetrahydropyrrole, tetra Hydrofuran, piperidine, piperazine, morpholine or tetrahydropyran.
  • the 5- to 6-membered monocyclic heteroaryl ring is thiophene, N-alkylpyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, tetrazole, metabolite An oxazole, an oxadiazole, a thiadiazole, a pyridine, a pyridazine, a pyrimidine or a pyrazine.
  • R 12 , R 21 , R 31 , R 42 are each independently hydrogen, halogen or —(CH 2 ) r —L 4 ;
  • L 4 is CN, 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 a C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group), a C 3-8 cycloalkyl group (preferably a C 3-6 cycloalkyl group), NR a1 R b1 , a 4 to 6 membered saturated monoheterocyclic ring, a 5 to 6 membered monocyclic heteroaryl ring, a spiro ring, a spiroheterocyclic ring, a bridged ring or a bridged heterocyclic
  • the alkyl group, alkoxy group, cycloalkyl group, 4 to 6 membered saturated monoheterocyclic ring, 5 to 6 membered monocyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring or bridged heterocyclic ring is unsubstituted Or substituted with one substituent selected from the group consisting of acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, C 1-3 alkyl, C 1 -3 alkoxy, halo C 1-3 alkyl, C 3-6 cycloalkyl, NR a2 R b2 , azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, Piperidine, oxazolidine, piperazine, dioxolane, dioxane,
  • r is 0 or 1.
  • the 4- to 6-membered saturated monoheterocyclic ring is azetidine, oxetane, tetrahydropyrrole, tetrahydrofuran, piperidine, piperazine, morpholine or tetrahydropyran.
  • the 5- to 6-membered monocyclic heteroaryl ring is thiophene, N-alkylpyrrole, furan, thiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, tetrazole, metabolite An oxazole, an oxadiazole, a thiadiazole, a pyridine, a pyridazine, a pyrimidine or a pyrazine.
  • R a and R b are each independently hydrogen, fluorine, chlorine, C 1-3 alkyl, halo C 1-3 alkyl;
  • R a , R b and the attached carbon atom together form propylene oxide, azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole, piperidine ring, tetrahydropyran ring, Cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring.
  • the cyclo, cyclobutyl ring, cyclopentyl ring, cyclohexyl ring is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of acetyl, hydroxy, hydroxymethyl, hydroxyethyl, carboxy, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, C 3-6 cycloalkyl, halo C 1-3 alkoxy, -C(O)OC 1- 6 alkyl, NR a3 R b3 ; wherein R a3 , R b3 are each independently hydrogen or C 1-3 alkyl.
  • R 11 , R 22 , R 32 , R 41 , R 12 , R 21 , R 31 and R 42 are as defined above.
  • Z 1 is a bond
  • Z 2 is CR 1a R 1b , NR c , O, S or S(O) 2
  • R 1a , R 1b are as defined for R a , R b .
  • Z 1 is CR 1a R 1b , NR c , O, S or S(O) 2 ;
  • Z 2 is CR 2a R 2b (preferably CH 2 );
  • R 1a , R 1b , R 2a R 2b is as defined by R a and R b .
  • Z 1 is CR 1a R 1b (preferably CH 2 );
  • Z 2 is CR 2a R 2b , NR c , O, S or S(O) 2 ;
  • R 1a , R 1b , R 2a R 2b is as defined by R a and R b .
  • Z 1 is a bond
  • Z 2 is CR 2a R 2b , NR c , O, S or S(O) 2
  • Z 2 is preferably CR 2a R 2b , more preferably CH 2
  • the structure represented by the formula (B-1), the formula (B-2) or the formula (B-3) (preferably, the formula (B-2)); R 2a and R 2b are as defined for R a and R b .
  • Z 1 is CR 1a R 1b , NR c , O, S or S(O) 2 (Z 1 is preferably CH 2 or O);
  • Z 2 is CR 2a R 2b (Z 2 is preferably CH 2 );
  • the structure represented by the formula (B-1), the formula (B-2) or the formula (B-4); R 1a , R 1b , R 2a and R 2b are as defined for R a and R b .
  • Z 1 is a bond or O;
  • Z 2 is CR 2a R 2b (Z 2 is preferably CH 2 );
  • the structure represented by the formula (B-2); R 2a and R 2b are as defined for R a and R b .
  • Z 1 is CR 1a R 1b (Z 1 is preferably CH 2 );
  • Z 2 is CR 2a R 2b (Z 2 is preferably CH 2 );
  • the structure represented by the formula (B-1); R 1a , R 1b , R 2a , and R 2b are as defined for R a and R b .
  • R 1 , R 3 , and R 4 are each independently hydrogen, halogen, C 1-6 alkyl or halo C 1-6 alkyl.
  • R 1 , R 3 , and R 4 are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
  • R 1 , R 3 , and R 4 are each independently hydrogen.
  • n is 0 or 1.
  • the compound is selected from the following Table A:
  • the compound is selected from the following Table B:
  • a second aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; A pharmaceutically acceptable carrier.
  • a third aspect of the invention provides a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect of the invention
  • a disease or condition selected from the group consisting of cancer, abnormal cell proliferative diseases, infections, inflammatory conditions, autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, radiation-induced Hematopoietic toxic disease, or a combination thereof.
  • the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, Glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, true Polycythemia, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, chorionic epithelial cancer or pediatric tumor.
  • the radiation-induced hematopoietic toxic diseases include, but are not limited to, myelosuppression, neutropenia, leukopenia, anemia.
  • a fourth aspect of the invention provides a method of inhibiting the activity of CDK4 and/or CDK6 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, A construct, solvate or prodrug, or a pharmaceutical composition according to the second aspect of the invention.
  • a fifth aspect of the invention provides an inflammatory condition (eg, rheumatoid arthritis, osteoarthritis, etc.), autoimmune, for treating abnormal cell proliferative diseases, infections (eg, viral infections such as herpes, HIV, fungal infections, etc.) Sexual diseases (eg psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis) Or a method of neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, etc.) comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable thereof a salt, stereoisomer, solvate or prodrug, or a pharmaceutical combination according to the second aspect of the invention
  • the abnormal cell proliferative disorder may be cancer
  • a sixth aspect of the invention provides a method of treating cancer comprising administering a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, solvate thereof, to a subject in need thereof Or a prodrug, or a pharmaceutical composition according to the second aspect of the invention, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, malignant astrocytes and oligos) Glioma of glioblastoma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, original Hair or metastatic squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochond
  • the pyridylamine-substituted heterotricyclic structure of the present invention has high inhibitory activity against CDK4 and CDK6, and has a weak inhibitory activity against CDK1 and CDK2. /6 Selectivity, thus the series of compounds of the invention can be developed as drugs for the treatment of cancer with selective CDK4 and CDK6 inhibitors. On this basis, the inventors completed the present invention.
  • alkyl refers to both straight and branched saturated aliphatic hydrocarbon groups, and C1-8 alkyl is alkyl having from 1 to 8 carbon atoms, preferably C1-6 alkyl, more preferably C 1-3 alkyl, the definition is similar; 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-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3- Methyl butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl Base, 2,2-dimethylbutyl, 1,3-dimethylbut
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon group
  • C 3-8 cycloalkyl refers to a cyclic hydrocarbon group containing from 3 to 8 carbon atoms, preferably a C 3-6 ring. Alkyl, the definition is similar.
  • Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl
  • a cyclooctyl group or the like is preferably a cyclopropyl group, a cyclopentyl group or a cyclohexenyl group.
  • spirocyclic refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the individual rings, which may contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system.
  • the spiro ring is divided into a double spiro ring or a multi-spiral ring depending on the number of rings, preferably a double spiro ring. More preferably, it is preferably a 4 member/5 member, a 5 member/5 member or a 5 member/6 member double screw ring.
  • spiroheterocycle refers to a polycyclic hydrocarbon in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(O) n (where n is an integer) From 0 to 2), the remaining atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spiroheterocycle is classified into a bispiral heterocyclic ring or a polyspirocyclic ring according to the number of rings, preferably a double spiro heterocyclic ring. More preferably, it is 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan / 6 yuan double spiro heterocycle. example
  • bridged ring refers to a polycyclic group that shares two or more carbon atoms.
  • the shared carbon atom is called the bridgehead carbon.
  • the two bridgehead carbons may be carbon chains or a bond. , called the bridge. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably a bicyclic or tricyclic bridged ring.
  • bridge heterocycle refers to a polycyclic group that shares two or more atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) n (where n is an integer from 0 to 2) a hetero atom, the remaining ring atoms being carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably a bicyclic or tricyclic bridge heterocycle. E.g:
  • 8- to 10-membered bicyclic refers to a bridged ring containing two rings of 8 to 10 ring atoms, which may be a saturated all-carbon bicyclic or partially unsaturated all-carbon bicyclic ring, 8 to 10 membered bicyclic rings. Examples include (but are not limited to):
  • 8- to 10-membered bicyclic heterocycle refers to a two-ring-containing bridged heterocyclic ring containing from 8 to 10 ring atoms, wherein 1, 2, 3, 4 or 5 ring carbon atoms are selected from nitrogen Substituted by a hetero atom of oxygen or sulfur.
  • Examples of the 8- to 10-membered bicyclic heterocycle include, but are not limited to, a tetrahydroquinoline ring, a tetrahydroisoquinoline ring, a decahydroquinoline ring, and the like.
  • C 1-8 alkoxy refers to -O-(C 1-8 alkyl), wherein alkyl is as defined above.
  • a C 1-6 alkoxy group is preferred, and a C 1-3 alkoxy group is more preferred.
  • Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, pentyloxy and the like.
  • C 3-8 cycloalkoxy refers to -O-(C 3-8 cycloalkyl), wherein cycloalkyl is as defined above. Preference is given to C 3-6 cycloalkoxy. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • C 6-10 aryl refers to an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, meaning 6 to 10
  • An aryl group of a carbon atom preferably a phenyl group and a naphthyl group, more preferably a phenyl group.
  • a bond refers to the attachment of two groups attached thereto through a covalent bond.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • halo means that one or more (eg 1, 2, 3, 4 or 5) hydrogens in the group are replaced by a halogen.
  • halo C 1-8 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) halo, wherein alkyl is as defined above. It is selected as a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group.
  • halogenated C 1-8 alkyl groups include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, Monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.
  • halo C 1-8 alkoxy means that the alkoxy group is substituted by one or more (eg 1, 2, 3, 4 or 5) halogens, wherein the alkoxy group is as defined above. It is preferably a halogenated C 1-6 alkoxy group, more preferably a halogenated C 1-3 alkoxy group. These include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.
  • halo C 3-8 cycloalkyl refers to a cycloalkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halo, wherein cycloalkyl is as defined above.
  • Preferred is a halogenated C 3-6 cycloalkyl group. These include, but are not limited to, trifluorocyclopropyl, monofluorocyclopropyl, monofluorocyclohexyl, difluorocyclopropyl, difluorocyclohexyl, and the like.
  • deuterated C 1-8 alkyl refers to an alkyl group substituted with one or more (eg 1, 2, 3, 4 or 5) deuterium atoms, wherein alkyl is as defined above. It is preferably a deuterated C 1-6 alkyl group, more preferably a deuterated C 1-3 alkyl group. Examples of deuterated C 1-20 alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, didecanoethyl, triterpene methyl, triterpenoid Base.
  • amino refers to NH 2
  • cyano refers to the CN
  • Niro refers to NO 2
  • benzyl refers to -CH 2 - phenyl
  • carboxy refers to -C (O) OH
  • acetyl means a -C (O) CH 3
  • hydroxymethyl group refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH
  • hydroxy means - OH
  • thiol refers to SH
  • cyclopropylene structure is:
  • heteroaryl ring and “heteroaryl” are used interchangeably and mean having 5 to 10 ring atoms, preferably 5 or 6 membered monocyclic heteroaryl or 8 to 10 membered bicyclic heteroaryl.
  • the ring array shares 6, 10 or 14 ⁇ electrons; and has a group of 1 to 5 hetero atoms in addition to carbon atoms.
  • Hetero atom means nitrogen, oxygen or sulfur.
  • 3- to 6-membered saturated or partially unsaturated monocyclic refers to a saturated or partially unsaturated, all-carbon monocyclic ring containing from 3 to 6 ring atoms.
  • monocyclic rings include, but are not limited to, cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl groups. Ring, cycloheptatrienyl ring, cyclooctyl ring, and the like.
  • 3 to 6 membered saturated monoheterocycle means that 1, 2 or 3 carbon atoms in a 3 to 6 membered monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer 0)
  • the heteroatoms to 2) are substituted, but do not include the ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon; preferably 4 to 6 members, more preferably 5 to 6 members.
  • saturated monoheterocycles include, but are not limited to, propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazolidine, piperazine , dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, and the like.
  • a "5- to 6-membered monocyclic heteroaryl ring” refers to a monoheteroaryl ring containing from 5 to 6 ring atoms, including, for example, but not limited to, a thiophene ring, an N-alkylpyrrole ring, Furan ring, thiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, Pyrimidine ring, pyrazine ring and the like.
  • 8- to 10-membered bicyclic heteroaryl ring refers to a bi-heteroaryl ring containing from 8 to 10 ring atoms, including, for example, but not limited to, benzofuran, benzothiophene, anthracene, Isoindole, quinoline, isoquinoline, carbazole, benzothiazole, benzimidazole, quinazoline, quinoxaline, porphyrin, pyridazine.
  • substituted refers to one or more hydrogen atoms in the group, preferably 1 to 5 hydrogen atoms are independently substituted with each other by a corresponding number of substituents, more preferably 1 to 3 hydrogen atoms are independent of each other. The ground is replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • any of the groups herein may be substituted or unsubstituted.
  • the substituent is preferably a group of 1 to 5 or less, independently selected from the group consisting of CN, halogen, 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 halogen 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 amine, amine, halogenated C 1-8 alkyl substituted amine, 4 Up to 6-membered saturated monoheterocyclic ring, 5-
  • terapéuticaally effective amount refers to a compound of the invention that will elicit a biological or medical response to an individual, such as reducing or inhibiting the activity of an enzyme or protein or ameliorating a condition, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, and the like. the amount.
  • pharmaceutically acceptable carrier means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating or auxiliary formulation or any type of excipient that is compatible with the patient, most Preferably, it is a mammal, more preferably a human, which is suitable for delivering the active agent to a target of interest without terminating the activity of the agent.
  • patient refers to an animal, preferably a mammal, and more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.
  • treating refers to alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing, or alleviating one or more symptoms of the disease or condition to some extent.
  • the present invention provides a process for the preparation of a compound of formula (I).
  • the compounds of the present invention can be prepared by a variety of synthetic procedures, and exemplary methods of preparation of such compounds can include, but are not limited to, the schemes described below.
  • the compounds of formula (I) of the present invention can be prepared by the following schemes and exemplary methods described in the Examples and related publications used by those skilled in the art.
  • the steps in the method can be extended or merged as needed during the specific operation.
  • the compound of the formula (I) is obtained by a carbon-nitrogen coupling reaction of the formula (I-1) with the formula (I-2).
  • the carbon-nitrogen coupling of the arylamine with the aryl halide may be catalyzed by a Pd catalyst, a suitable ligand and a base, preferably potassium or potassium t-butoxide and PdO-, such as the Buchwald-Hartwig reaction.
  • the final compound of formula (I) is obtained.
  • the starting materials of the formula (I-1) and the formula (I-2) can be commercially obtained depending on the specific structure, or can be produced by a method known to a person skilled in the art.
  • the compound of the formula (I-1) can be produced by a method comprising the following steps:
  • the compound of the formula (1.1) and the compound of the formula (1.2) are reacted under heating to obtain a compound of the formula (1.3).
  • the compound of the formula (1.3) and the compound of the formula (1.4) are subjected to ring closure under basic conditions to give a compound of the formula (I-1).
  • the intermediate compound of formula (1.1) can be obtained by two different routes.
  • the compound of formula (1.1) can be prepared by Method 1 comprising the following steps:
  • the compound of the formula (1a.1) is reacted with the corresponding alcohol to give a compound of the formula (1a.2) which can be passed through a halogenating agent such as N-halosuccinimide in a suitable solution such as dichloro
  • a halogenating agent such as N-halosuccinimide
  • a suitable solution such as dichloro
  • the reaction is carried out in methane to give a compound of the formula (1a.3) which is reacted with hydrazine under basic conditions to give a compound of the formula (1a.5).
  • the compound of the formula (1.1) can be modified, such as a nucleophilic substitution, an alkylation reaction or the like.
  • the compound of formula (1.1) can be prepared by Method 2 comprising the following steps:
  • the compound of the formula (1a.1) is reacted with an acylate such as an acid chloride to form an ester to give a compound of the formula (1b.1), a compound of the formula (1b.1) in a base.
  • the compound is deprotected under acidic conditions and the ring is closed to give the compound of formula (1.1).
  • a series of novel pyridylamine substituted heterotricyclic compounds are provided, which have high selective inhibitory activity against CDK4/6, and also have good brain permeability and can be used as a drug for a wide range of cancer treatments.
  • DMB is 2,4-dimethoxybenzyl
  • THF is tetrahydrofuran
  • EA is ethyl acetate
  • PE is petroleum ether
  • Ac 2 O is acetic anhydride
  • NBS is N-bromosuccinimide.
  • DCM is dichloromethane
  • AIBN is azobisisobutyronitrile
  • Pd(dppf)Cl 2 is 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • TFA is trifluoroacetic acid
  • TBSCl Is tert-butyldimethylchlorosilane
  • NCS is N-chlorosuccinimide
  • DHP is dihydropyran
  • LiAlH 4 is lithium aluminum hydride
  • PMB is p-methoxybenzyl
  • LiHMDS is two (three Methylsilyl) lithium amide
  • Pd 2 (dba) 3 is tris(dibenzylideneacetone)dipalladium
  • RuPhos is 2-dicyclohexylphosphorin-2',6'-diisopropoxy-1,1 '-Biphenyl
  • DMAP is 4-dimethylaminopyridine
  • room temperature means about 20-25 °C.
  • Step 3 A solution of compound 1a-3 (200 mg, 1.1 mmol. The reaction mixture was concentrated to give Compound 1a, which was used directly to the next step. MS m/z (ESI): N/A.
  • Step 1 The preparation method is the same as that of the compound 1a-2, except that the compound 1a-1 in the process of the 1a-2 process is replaced with the compound 5a-1.
  • Step 2 A solution of compound 5a-2 (5 g, 29.8 mmol) in EtOAc (EtOAc) (EtOAc) LC-MS was followed until the end of the reaction. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. MS m/z (ESI): 169 [M+H] + .
  • Step 3 The preparation method is the same as Compound 1a except that Compound 1a-3 in Process 1a is replaced by Compound 5a-3.
  • Step 4 Compound 5a-4 (344 mg, 1.85 mmol) in THF (5 mL) EtOAc. . TLC is tracked until the end of the reaction. The reaction solution was concentrated and purified by combiflash to give 309 mg of Compound 5a-5. MS m/z (ESI): 297 [M+H] + .
  • Step 5 A solution of compound 5a-5 (309 mg, 1.04 mmol. LC-MS was followed until the reaction was complete. The reaction mixture was concentrated, EtOAc (EtOAc)EtOAc. MS m/z (ESI): 179 [M+H] + .
  • Step 6 A solution of compound 5a-6 (185 mg, 1.04 mmol) in 5a.3 (3 mL) was stirred at 105 ° C for one hour. The reaction solution was cooled to room temperature, concentrated and dried to give compound 5a-7, which was used directly for the next reaction. MS m/z (ESI): 234 [M+H] + .
  • Step 7 Compound 5a-7 (242 mg, 1.04 mmol) was added EtOAc (EtOAc,EtOAc. LC-MS was followed until the reaction was complete. The reaction solution was cooled to room temperature, concentrated and purified by combiflash to yield 197 g of Compound 5a. MS m/z (ESI): 230 [M+H] + .
  • Step 1 The preparation method is the same as that of the compound 3-2, except that the compound 3-1 in the 3-2 process is replaced with the compound 6a-1.
  • Step 2 The preparation method is the same as the compound 3-3 except that the compound 3-2 in the 3-3 process is replaced with the compound 6a-2.
  • Step 1 A solution of compound 8a-1 (6 g, m. The reaction solution was cooled in an ice-bath, and EtOAc (EtOAc, m. The reaction was quenched by the addition of saturated brine, and THF was evaporated, evaporated, evaporated, evaporated, evaporated. . MS m/z (ESI): 127 [M+H] + .
  • Step 3 Compound 8a-3 (2 g, 10 mmol) in EtOAc (10 mL) The next step is to react. MS m/z (ESI): 193 [M+H] + .
  • Step 4 A solution of compound 8a-4 (1.8 g, 9.3 mmol) eluted eluted eluted eluted eluted eluted The ethyl acetate was dissolved, washed with water and brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated and purified by EtOAc (EtOAc: EtOAc) MS m/z (ESI): 207 [M+H] + .
  • Step 1 The preparation method is the same as that of the compound 1a-2, except that the compound 1a-1 in the process of the 1a-2 process is replaced with the compound 9a-1.
  • Step 2 The preparation method is the same as Compound 1a-3 except that Compound 1a-2 in Process 1a-3 is replaced by Compound 9a-2.
  • Step 3 The preparation method is the same as the compound 8a-4, except that the compound 8a-3 in the 8a-4 process is replaced with the compound 9a-3.
  • Step 4 Compound tetrahydrofuran (100mL) 9a-4 (4.12g , 20mmol) was added methanol (1.21mL, 30mmol), PPh 3 (6.812g, 26mmol), was added DIAD (5.15mL, 26mmol) under ice-cooling, The mixture was stirred at room temperature overnight. LC-MS was followed until the reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with brine, and then evaporated. MS m/z (ESI): 221 [M+H] + .
  • Step 5 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 9a-5. MS m/z (ESI): 276 [M+H] + .
  • Step 6 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of Process 5a is replaced with the compound 9a-6. MS m/z (ESI): 266 [M+H] + .
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 8a and ethyl iodide.
  • Step 2 The preparation method is the same as the compound 5a-7 except that the compound 55a-6 in the process of 5a-7 is replaced with the compound 10a-1.
  • Step 3 The preparation method is the same as that of the compound 5a, except that the compound 5a-7 in the process of 5a is replaced with the compound 10a-2.
  • Step 1 The preparation method is the same as the compound 8a-3 except that the compound 8a-2 in the 8a-3 process is replaced with the compound 11a-1.
  • Step 2 The preparation method is the same as that of the compound 8a-4, except that the compound 8a-3 in the 8a-4 process is replaced with the compound 11a-2.
  • Step 3 The preparation method is the same as that of the compound 8a, except that the compound 8a-4 in the process of Process 8a is replaced with the compound 11a-3.
  • Step 4 The preparation method is the same as that of the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 11a-4 and methyl iodide.
  • Step 5 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 11a-5.
  • Step 6 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of 5a is replaced with the compound 11a-6.
  • Step 1 The preparation method is the same as Compound 1a except that Compound 1a-3 in Process 1a is replaced by Compound 9a-3. MS m/z (ESI): 229 [M+H] + .
  • Step 2 The preparation method is the same as the compound 5a-5 except that the compound 5a-4 and the compound 5a.2 in the process of 5a-5 are replaced with the compound 12a-1 and the compound 2a.
  • Step 3 The preparation method is the same as the compound 5a-6 except that the compound 5a-5 in the process of 5a-6 is replaced with the compound 12a-2.
  • Step 4 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 12a-3.
  • Step 5 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of 5a is replaced with the compound 12a-4.
  • Step 1 The preparation method is the same as that of the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 30-4 and ethyl iodide.
  • Step 2 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 13a-1.
  • Step 3 The preparation method is the same as that of the compound 5a, except that the compound 5a-7 in the process of 5a is replaced with the compound 13a-2.
  • Step 1 The preparation method is the same as that of the compound 1-2, except that the compound 1-1 in the 1-2 method is replaced with the compound 14a-1.
  • Step 2 Under argon atmosphere, Compound 14a-2 (1g, 5.94mmol) in dry THF (6mL) at 0-5 deg.] C was added dropwise LiAlH 4 (90mg, 2.38mmol). The temperature was raised to 25 ° C and stirred for 4 hours. The reaction solution was ice-cooled, quenched with ethyl acetate was added, cooled slowly poured into H 2 SO 4 (2M) solution, the resulting solution was extracted with methyl tert-butyl ether twice, dried over anhydrous sodium sulfate Filtration and concentration under reduced pressure gave crude product 14a-3 directly to next step. MS m/z (ESI): 125 [M+H] + .
  • Step 3 methanol compound 14a-3 (736mg, 5.94mmol) of (5mL) was added dropwise at 0 °C was added H 2 O 2 (3mL, 29.63mmol ), the resulting mixture was added to 2% at 0 °C of NaOH ( 1.6 mL) solution. The reaction was stirred at room temperature for 20 h. LC-MS was followed until the reaction was complete. The mixture was diluted with water and extracted with EtOAc (EtOAc)EtOAc. MS m / z (ESI): 141 [M+H] + .
  • Step 4 Compound 14a-4 (300 mg, 2.14 mmol). LC-MS was followed until the reaction was complete. The mixture was cooled, diluted with water and evaporated with EtOAc EtOAc. MS m/z (ESI): 355 [M+H] + .
  • Step 5 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 14a-5.
  • Step 6 The preparation method is the same as that of the compound 5a, except that the compound 5a-7 and the compound 1.3 in the process of the process 5a are replaced with the compound 14a-6 and the compound 14a.1. MS m/z (ESI): 221 [M+H] + .
  • Step 7 The preparation method is the same as that of the compound 43-3, except that the compound 43-2 in the method of 43-3 is replaced with the compound 14a-7.
  • Step 8 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 14a-8.
  • Step 9 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of 5a is replaced with the compound 14a-9.
  • Step 1 The preparation method is the same as the compound 8a-3 except that the compound 8a-2 in the 8a-3 process is replaced with the compound 15a-1.
  • Step 2 The preparation method is the same as that of the compound 8a-4, except that the compound 8a-3 in the 8a-4 process is replaced with the compound 15a-2.
  • Step 3 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 15a-3 and methyl iodide.
  • Step 4 The preparation method is the same as that of the compound 8a, except that the compound 8a-4 in the process of Process 8a is replaced with the compound 15a-4.
  • Step 5 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 15a-5.
  • Step 6 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of Process 5a is replaced with the compound 15a-6.
  • Step 1 The preparation method is the same as that of the compound 8a-3, except that the compound 8a-2 and the isobutyryl chloride in the 8a-3 process are replaced with the compound 1-2 and acetyl chloride.
  • Step 2 The preparation method is the same as that of the compound 8a-4, except that the compound 8a-3 in the 8a-4 process is replaced with the compound 16a-1.
  • Step 4 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 16a-3 and the bromocyclopentane.
  • Step 5 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 16a-4.
  • Step 6 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of 5a is replaced with the compound 16a-5.
  • Step 1 The preparation method is the same as that of the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 9a-4 and methyl iodide.
  • Step 2 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 17a-1.
  • Step 3 The preparation method is the same as that of the compound 5a, except that the compound 5a-7 in the process of 5a is replaced with the compound 17a-2.
  • Step 1 The preparation method is the same as Compound 1a except that Compound 1a-3 in Process 1a is replaced by Compound 18a-1. MS m/z (ESI): 266 [M+H] + .
  • Step 2 The preparation method is the same as the compound 5a-5 except that the compound 5a-4 in the process of 5a-5 is replaced with the compound 18a-2.
  • Step 3 The preparation method is the same as the compound 5a-6 except that the compound 5a-5 in the process of 5a-6 is replaced with the compound 18a-3.
  • Step 4 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 18a-4.
  • Step 5 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of 5a is replaced with the compound 18a-5.
  • Step 1 To a solution of KOH (14.98 g, 267.6 mmol) in water (3.6 mL) and EtOAc (EtOAc) (EtOAc) The filter cake was washed with EtOAc (EtOAc) elute elute elute elute
  • Step 2 A solution of compound 19a-2 (46.7 g, 259 mmol) and 1,2-dibromoethane in DMSO (376 mL) was stirred at room temperature for 2 days. The mixture was extracted with water, extracted with EtOAc (EtOAc m. MS m/z (ESI): 495 [M+H] + .
  • Step 3 A solution of compound 19a-3 (9 g, 36.3 mmol. The mixture was combined with EtOAc. EtOAc (EtOAc m. MS m/z (ESI): 495 [M+H] + .
  • Step 4 Compound 19a-4 (1g, 5.3mmol) and (2.2g, 15.8mmol) in ethanol K 2 CO 3 (18mL) was heated at reflux for 3h. The mixture was combined with water and extracted with EtOAc.
  • Step 5 The preparation method is the same as the compound 8a-3 except that the compound 8a-2 in the 8a-3 process is replaced with the compound 19a-5.
  • Step 6 The preparation method is the same as the compound 8a-4 except that the compound 8a-3 in the 8a-4 process is replaced with the compound 19a-6. MS m/z (ESI): 177 [M+H] + .
  • Step 7 The preparation method is the same as the compound 8a except that the compound 8a-4 in the process of Process 8a is replaced with the compound 19a-7.
  • Step 8 The preparation method is the same as that of the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 19a-8 and methyl iodide.
  • Step 9 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 19a-9. MS m/z (ESI): 260 [M+H] + .
  • Step 10 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of Process 5a is replaced with the compound 19a-10.
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 20a-1 and the compound 20a.1.
  • Step 2 The preparation method is the same as the compound 65-3, except that the compound 65-2 in the process of the 65-3 process is replaced with the compound 20a-2.
  • Step 3 The preparation method is the same as the compound 65-7, except that the compound 65-6 and acetone in the process of the 65-7 process are replaced with the compound 20a-3 and formaldehyde.
  • Step 4 A solution of compound 20a-4 (1.2 g, EtOAc. LC-MS was followed until the end of the reaction. The reaction mixture was concentrated to give the compound 20a-5, which was used directly to the next reaction. MS m/z (ESI): 184 [M+H] + .
  • Step 5 The preparation method is the same as the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 20a-5 and the compound 20a.2. m/z (ESI): 254 [M+H] + .
  • Step 6 Compound 20a-6 (650 mg, 2.6 mmol) was added to phosphorus oxychloride (30 mL), and the mixture was stirred at 120 ° C for 2 h, and the reaction mixture was concentrated to give compound 20a-7.
  • Step 7 The preparation method is the same as the compound 8a-4 except that the compound 8a-3 in the 8a-4 process is replaced with the compound 20a-7. Purification by combiflash gave 50 mg of compound 20a. m/z (ESI): 250 [M+H] + .
  • Step 1 The preparation method is the same as the compound 3-3 except that the compound 3-2 in the 3-3 process is replaced with the compound 55-2. MS m/z (ESI): 266 [M+H] + .
  • Step 2 Compound 21a-1 (2.5 g, 9.5 mmol) was added compound 21a.1 (5 mL), and the mixture was microwaved at 180 ° C for 30 min. The reaction mixture was concentrated and purified by combiflash to afford compound 21a-2 (1 g, yield 52%). MS m/z (ESI): 495 [M+H] + .
  • Step 3 The preparation method is the same as that of the compound 8a except that the compound 8a-4 in the process of Process 8a is replaced with the compound 21a-2.
  • Step 4 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 in the 3-5 process is replaced with the compound 21a-3. MS m/z (ESI): 265 [M+H] + .
  • Step 5 The preparation method is the same as the compound 5a-7 except that the compound 5a-6 in the process of 5a-7 is replaced with the compound 21a-4.
  • Step 6 The preparation method is the same as the compound 5a except that the compound 5a-7 in the process of Process 5a is replaced with the compound 21a-5.
  • Step 2 Compound 1-2 (17 g, 121 mmol) was added to 60 mL 1.1, and the mixture was stirred at 110 ° C for 2 hr. The reaction solution was cooled to room temperature, concentrated and dried to give Compound 1-3, which was used directly for the next step. MS m/z (ESI): 196 [M+H] + .
  • Step 3 A solution of compound 1-3 (20 g, 103 mmol) in EtOAc (EtOAc) The reaction solution was cooled to room temperature, concentrated and purified by EtOAc (EtOAc/EtOAc) MS m/z (ESI): 137 [M+H] + .
  • Step 5 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 1-5. MS m/z (ESI): 276 [M+H] + .
  • Step 6 Compound 1-6 (220 mg, 0.8 mmol), EtOAc (EtOAc,EtOAc. LC-MS was followed until the reaction was complete. The reaction solution was cooled to room temperature, concentrated and purified by EtOAc (EtOAc/EtOAc) MS m/z (ESI): 266 [M+H] + .
  • Step 7 Compound 1-7 (130 mg, 0.48 mmol), 4a (150 mg, 0.48 mmol) in 1,4-dioxane (5 mL) was added to Xantphos (14 mg, 0.024 mmol), Pd 2 (dba) 3 ( 22 mg, 0.024 mmol) and sodium tert-butoxide (95 mg, 0.96 mmol), and the mixture was subjected to microwave reaction at 150 ° C for 45 minutes under nitrogen atmosphere. LC-MS was followed until the reaction was complete. The reaction was filtered, concentrated and purified with EtOAc EtOAc (EtOAc) MS m/z (ESI): 533 [M+H] + .
  • Step 8 A solution of compound 1-8 (90 mg, 0.169 mmol. LC-MS was followed until the end of the reaction. The reaction mixture was concentrated and purified to purified white crystal crystal crystal crystal MS m/z (ESI): 433 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) 9.92 (s, 1H), 8.73 (s, 2H), 8.36 (s, 1H), 8.02.
  • Step 2 A solution of compound 2-1 (4.6 g, 14.1 mmol) in 1,4-dioxane (12 mL) LC-MS was followed until the reaction was complete. The reaction mixture was concentrated, washed with methylene chloride, washed with sodium sulfate (1 N) and brine, and evaporated. MS m/z (ESI): 207 [M+H] + .
  • Step 3 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 2-2.
  • Step 5 The preparation method is the same as that of the compound 1-8, except that the compounds 1-7 and 4a in the process of 1-8 are replaced with the compounds 2-4 and 3a. Purification by Prep-HPLC gave white solid compound P-2 (52 mg, 67%).
  • Step 1 The preparation method is the same as that of the compound 1-2, except that the compound 1-1 in the 1-2 method is replaced with the compound 3-1.
  • Step 3 To a solution of compound 3-3 (2.5 g, 11.4 mmol The TLC was followed until the reaction was complete. The reaction mixture was concentrated and purified by EtOAc EtOAc (EtOAc:EtOAc) MS m/z (ESI): N/A.
  • Step 4 A solution of compound 3-4 (125 mg, EtOAc, EtOAc, m. LC-MS was followed until the reaction was complete. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. MS m/z (ESI): 207 [M+H] + .
  • Step 5 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 3-5. MS m/z (ESI): 262 [M+H] + .
  • Step 6 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 3-6. MS m/z (ESI): 258 [M+H] + .
  • Step 7 The preparation method is the same as the compound P-2 except that the compound 1-8 in the P-2 process is replaced with the compound 3-7. Purification by Prep-HPLC gave white solid compound P-3 (62mg, 62%). MS m/z (ESI): 461 [M+H] + .
  • Step 1 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the 1-8 process is replaced with the compound 2-4.
  • Step 2 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 4-1.
  • the white solid compound P-4 (1.3 g, 81%).
  • Step 1 The preparation method is the same as that of the compound 3-4, except that the compound 3-3 in the 3-4 process is replaced with the compound 6a.
  • Step 2 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 in the 3-5 process is replaced with the compound 5-1.
  • Step 3 The preparation method is the same as the compound 3-6 except that the compound 3-5 in the 3-6 process is replaced with the compound 5-2. MS m/z (ESI): 248 [M+H] + .
  • Step 4 The preparation method is the same as the compound 3-7 except that the compound 3-6 in the 3-7 process is replaced with the compound 5-3. MS m/z (ESI): 244 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-3 except that the compound 3-7 in the P-3 process is replaced with the compound 5-4. Purification by Prep-HPLC gave white solid compound P-5 (13 mg, 14%). MS m/z (ESI): 447 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.44 (s, 1H), 8.35-8.33 (m, 2H), 8.15 (s, 1H), 7.67 (d, 1H), 4.66-4.63 (m, 1H), 3.49 (s, 2H), 3.42 (s, 2H), 2.86 (q, 2H), 2.49-2.26 (m, 10H), 1.65 (d, 6H) ), 1.27(t,3H), 0.97(t,3H).
  • Step 1 The preparation method is the same as the compound 4a except that the compound N-Boc piperazine in the process of 4a is replaced with the compound 7.1. MS m/z (ESI): 226 [M+H] + .
  • Step 2 The preparation method is the same as the compound P-6 except that the compound 3a in the P-6 process is replaced with the compound 7-2. Purification by Prep-HPLC gave white solid compound P-7 (358 mg, 47%). MS m/z (ESI): 419 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.
  • Step 1 The preparation method is the same as the compound P-6 except that the compound 3a in the P-6 process is replaced with the compound 4a.
  • Step 2 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 8-1. Purification by Prep-HPLC gave white solid compound P-8 (965 mg, 59%). MS m / z (ESI): 391 [M + H] +; 1 H NMR (400MHz, DMSO) ⁇ 9.09 (s, 1H), 8.33 (s, 1H), 8.18 (d, 1H), 7.96 (s , 1H), 7.38 (d, 1H), 3.89 (s, 3H), 3.60 (s, 2H), 3.30-3.25 (m, 1H), 3.05-3.27 (m, 4H), 2.91-2.84 (m, 4H) ), 1.48 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compounds 1-4 and 9.1. MS m/z (ESI): 205 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 9-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 9-2.
  • Step 4 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the 1-8 process is replaced with the compound 9-3. MS m/z (ESI): 517 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 9-4. Purification by Prep-HPLC gave white solid compound P-9 (23 mg, 3%). MS m/z (ESI): 417 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) 9.49 (s, 1H), 8.33 (s, 1H), 7.95-7.96 (d, 1H), 7.84 7.87(d,1H),7.32-7.39(m,2H),6.01-6.09(m,1H),2.97-3.00(t,4H),2.82-2.83(d,4H),2.72-2.77(t,2H ), 2.66-2.69 (t, 2H), 2.02 (s, 2H), 1.81-1.92 (m, 4H), 1.60-1.61 (d, 2H).
  • Step 1 To a solution of compound 7a (400 mg, 3 mmol) in dichlorohexane (30 mL), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc With potassium carbonate (800 mg, 6 mmol), the mixture was stirred at 70 ° C for 4 hours. LC-MS was followed until the reaction was complete. The reaction mixture was concentrated and purified by EtOAc EtOAc (EtOAc:EtOAc) MS m/z (ESI): 177 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 11-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 11-2.
  • Step 4 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 11-3. MS m/z (ESI): 495 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 11-4. Purification by Prep-HPLC gave white solid compound P-11 (13 mg, 55%). MS m/z (ESI): 384 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.
  • Step 1 The preparation method is the same as that of the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 7a and bromopentane.
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 13-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 13-2.
  • Step 4 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 13-3. MS m/z (ESI): 517 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 13-4. Purification by Prep-HPLC gave white solid compound P-13 (313 mg, 64%). MS m/z (ESI): 417 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.08 (s, 1H), 8.24 (s, 1H), 8.00-7.95 (m, 2H), 7.34 (dd, 1H), 4.61-4.55 (m, 1H), 3.41 (s, 2H), 3.00-2.98 (m, 4H), 2.84-2.83 (m, 4H), 2.48-2.47 (m, 3H), 2.25 -2.22 (m, 2H), 2.01-1.97 (m, 5H), 1.66-1.64 (m, 2H).
  • Step 1 The preparation method was the same as that of the compound 2-1 except that the compound 2a in the 2-1 method was replaced with the compound 14.1. MS m/z (ESI): 313 [M+H] + .
  • Step 2 The preparation method is the same as the compound 2-2 except that the compound 2-1 in the 2-2 process is replaced with the compound 14-1.
  • Step 3 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 14-2.
  • Step 4 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 14-3. MS m/z (ESI): 244 [M+H] + .
  • Step 5 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 14-4. MS m/z (ESI): 495 [M+H] + .
  • Step 6 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 14-5. Purification by Prep-HPLC gave white solid compound P-14 (280 mg, 87%). MS m/z (ESI): 405 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 8.97 (s, 1H), 8.17 (s, 1H), 7.95 (d, 1H), 7.92 (d) , 1H), 7.35 (dd, 1H), 3.99 (dt, 1H), 3.81 (s, 3H), 3.06-2.92 (m, 4H), 2.89-2.78 (m, 4H), 2.74 (t, 2H), 2.65 (t, 2H), 1.35 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 7a and ethyl iodide.
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 15-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 15-2.
  • Step 4 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the 1-8 process is replaced with the compound 15-3. MS m/z (ESI): 437 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 15-4. Purification by Prep-HPLC gave white solid compound P-15 (19 mg, 50%). MS m/z (ESI): 377 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.07 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H), 7.93 (s) , 1H), 7.39 (d, 1H), 4.20 (q, 2H), 3.41 (s, 2H), 3.05 (s, 4H), 2.91 (s, 4H), 2.44 (s, 3H), 1.46 (t, 3H).
  • Step 1 The preparation method is the same as that of the compound 1-4, except that the compound 1-3 in the 1-4 process is replaced with the compound 5a-3. MS m/z (ESI): 165 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 16-1 and methyl iodide.
  • Step 3 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 16-2.
  • Step 4 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 16-3. MS m/z (ESI): 230 [M+H] + .
  • Step 5 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 16-4. MS m/z (ESI): 495 [M+H] + .
  • Step 6 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 16-5. Purification by Prep-HPLC gave white solid compound P-16 (14 mg, 23%). MS m/z (ESI): 391 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.04 (s, 1H), 8.30 (s, 1H), 8.22 (d, 1H), 7.95 (s) , 1H), 7.38 (d, 1H), 3.81 (s, 3H), 3.71 (s, 2H), 3.09-3.04 (m, 1H), 3.02-3.98 (m, 4H), 2.89-2.81 (m, 4H) ), 1.41 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 in the 3-5 process is replaced with the compound 16-1.
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 17-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 17-2.
  • Step 4 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 17-3. MS m/z (ESI): 519 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 17-4. Purification by Prep-HPLC gave white solid compound P-15 (35 mg, 50%). MS m/z (ESI): 495 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.10 (s, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.99 (s) , 1H), 7.41 (d, 1H), 4.55-4.45 (m, 1H), 3.82 (s, 2H), 3.12-3.05 (m, 5H), 2.98-2.93 (m, 4H), 1.47 (d, 6H) ), 1.41 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 in the 3-5 process is replaced with the compound 16-1.
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 18-1.2. MS m/z (ESI): 248 [M+H] + .
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 18-2.
  • Step 4 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the 1-8 process is replaced with the compound 18-3. MS m/z (ESI): 495 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 18-4. Purification by Prep-HPLC gave white solid compound P-18 (30 mg, 50%). MS m/z (ESI): 405 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.17 (s, 1H), 8.34 (s, 1H), 8.23 (d, 1H), 7.99 (s) , 1H), 7.41 (d, 1H), 4.23 (q, 2H), 3.61 (s, 2H), 3.31-3.27 (m, 1H), 3.13 - 3.07 (m, 4H), 2.99-2.94 (m, 4H) ), 1.49 (d, 6H), 1.37 (t, 3H).
  • Step 1 The preparation method is the same as that of the compound 13, except that the compound 1-2 in the 13 method is replaced with the compound 18-1.1. MS m/z (ESI): 248 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 19-1.
  • Step 3 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the 1-8 process is replaced with the compound 19-2.
  • Step 4 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 19-3. Purification by Prep-HPLC gave white solid compound P-19 (8 mg, 36%). MS m/z (ESI): 405 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.11 (s, 1H), 8.31 (s, 1H), 8.24 (d, 1H), 7.97 (s) , 1H), 7.39 (d, 1H), 4.13 (q, 2H), 3.76 (s, 2H), 3.10-3.06 (m, 1H), 3.03-2.97 (m, 4H), 2.89-2.83 (m, 4H) ), 1.45-1.38 (m, 9H).
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3- in the 3-5 method is replaced with the compound 7a.
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 20-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 20-2.
  • Step 4 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the process of 1-8 is replaced with the compound 20-3. MS m/z (ESI): 495 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 20-4. Purification by Prep-HPLC gave white solid compound P-20 (7 mg, 30%). MS m/z (ESI): 391 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.07 (s, 1H), 8.24 (s, 1H), 8.17 (d, 1H), 7.93 (s) , 1H), 7.40 (d, 1H), 4.77-4.44 (m, 1H), 3.41 (s, 2H), 3.01 (s, 4H), 2.86 (s, 4H), 2.45 (s, 3H), 1.61 ( d, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 5-1 and 2-iodoethane.
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 21-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 21-2.
  • Step 4 The preparation method is the same as the compound 1-8, except that the compound 1-7 in the 1-8 process is replaced with the compound 21-3. MS m/z (ESI): 495 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 21-4. Purification by Prep-HPLC gave white solid compound P-21 (6.9 mg, 10%). MS m/z (ESI): 391 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) ⁇ 8.32 (d, 1H), 8.23 (s, 1H), 7.96 (d, 1H), 7.64 ( s, 1H), 7.31 (dd, 1H), 4.24 (q, 2H), 3.48 (s, 2H), 3.11-3.05 (m, 8H), 2.83 (q, 1H), 1.62-1.55 (m, 3H) , 1.41 (t, 3H).
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 in the 3-5 process is replaced with the compound 5-4.
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 22-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 22-2.
  • Step 4 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the process of 1-8 is replaced with the compound 22-3. MS m/z (ESI): 495 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 22-4. Purification by Prep-HPLC gave white solid compound P-22 (180 mg, 45%). MS m/z (ESI): 405 [M+H] + ; 1H NMR (400 MHz, DMSO) ⁇ 9.10 (s, 1H), 8.31-8.11 (m, 2H), 7.93 (d, 1H), 7.39 ( Dd,1H),4.61(t,1H),3.43(s,2H),3.03-2.94(m,3H),2.85-2.75(m,5H),1.62(d,5H),1.24(t,3H) .
  • Step 1 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 3-7.
  • Step 2 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 23-1. Purification by Prep-HPLC gave white solid compound P23 (7 mg, 17%). MS m/z (ESI): 495 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.10 (s, 1H), 8.13 (s, 1H), 7.92 (d, 1H), 7.78 (d) , 1H), 7.36 (dd, 1H), 5.69 (m, 1H), 3.01-2.95 (m, 4H), 2.83-2.80 (m, 4H), 2.77-2.73 (m, 4H), 2.64 (t, 2H) ), 1.49 (d, 6H), 1.24 (t, 3H).
  • Step 1 The preparation method is the same as that of the compound 3-4, except that the compound 3.1 in the 3-4 process is replaced with the compound 24.1. MS m/z (ESI): 151 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 3-4, except that the compound 3-4 in the 3-5 process is replaced with the compound 24-1.
  • Step 3 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 24-2. MS m/z (ESI): 248 [M+H] + .
  • Step 4 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 24-3.
  • Step 5 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 24-4. MS m/z (ESI): 495 [M+H] + .
  • Step 6 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 24-5. Purification by Prep-HPLC gave white solid compound P-24 (70 mg, 6%). MS m/z (ESI): 405 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) 9.17 (s, 1H), 8.13 (s, 1H), 7.95-7.96 (d, 1H), 7.89- 7.91(d,1H), 7.38-7.41(m,2H), 5.78(s,1H), 3.10-3.11(d,4H),2.98-3.01(d,4H),2.73-2.77(t,2H), 2.60-2.64(t,2H), 2.43(s,3H), 1.38-1.40(d,6H).
  • Step 1 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 10-1.
  • Step 2 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 25-1. Purification by Prep-HPLC gave white solid compound P-25 (580 mg, 58%). MS m/z (ESI): 391 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) ⁇ 8.31 (s, 1H), 8.17 (d, 1H), 8.02 (d, 1H), 7.98 ( s, 1H), 7.41 (s, 1H), 7.29 (dd, 1H), 5.91-5.87 (m, 1H), 3.13 - 3.06 (m, 8H), 2.84 - 2.76 (m, 4H), 1.55 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 1-4, except that the compound 1-3 in the 1-4 process is replaced with the compound 5a-3. MS m/z (ESI): 165 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 3-4, except that the compound 3-4 and 2-iodomethane in the 3-5 process are replaced with the compound 26-1 and SEM-Cl. MS m/z (ESI): 295 [M+H] + .
  • Step 3 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 26-2.
  • Step 4 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 26-3. MS m/z (ESI): 346 [M+H] + .
  • Step 5 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 26-4. MS m/z (ESI): 607 [M+H] + .
  • Step 6 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 26-5. Purification by Prep-HPLC gave white solid compound P-25 (15 mg, 24%). MS m/z (ESI): 377 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.02 (s, 2H), 8.44 (s, 1H), 8.02 (s, 1H), 7.90 (d) , 1H), 7.51 (d, 1H), 3.84 (s, 2H), 3.40-3.30 (m, 9H), 1.45-1.38 (m, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 26-1 and sodium difluorochloroacetate. MS m/z (ESI): 215 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 27-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 27-2.
  • Step 4 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the process of 1-8 is replaced with the compound 27-3. MS m/z (ESI): 527 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 27-4. Purification by Prep-HPLC gave white solid compound P27 (15 mg, 22%). MS m/z (ESI): 427 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 11.16 (s, 1H), 9.07 (s, 2H), 8.60 (s, 1H), 8.21-8.02 (m, 2H), 7.94 (d, 1H), 7.80 (d, 1H), 3.89 (s, 2H), 3.57-3.52 (m, 1H), 3.40-3.34 (m, 4H), 3.33-3.28 (m , 4H), 1.53 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 7a and bromomethylcyclopropane.
  • Step 2 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 28-1.
  • Step 3 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 28-2.
  • Step 4 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 28-3. MS m/z (ESI): 503 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 28-4. Purification by Prep-HPLC gave white solid compound P28 (6 mg, 16%). MS m/z (ESI): 403 [M+H] + .
  • Step 1 The preparation method is the same as that of the compound 14-1, except that the compounds 1a and 14.1 in the process of the 14-1 process are replaced with the compound 1a-3 and hydrazine hydrate. MS m/z (ESI): 179 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 3-4, except that the compound 3-4 and 2-iodomethane in the 3-5 process are replaced with the compound 29-1 and SEM-Cl. MS m/z (ESI): 318 [M+H] + .
  • Step 3 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 29-2.
  • Step 4 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 29-3. MS m/z (ESI): 360 [M+H] + .
  • Step 5 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 29-4. MS m/z (ESI): 621 [M+H] + .
  • Step 6 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 29-5. Purification by Prep-HPLC gave white solid compound P-29 (48 mg, 54.5%). MS m / z (ESI): 391 [M + H] +; 1 H NMR (400MHz, CDCl 3) ⁇ 12.76 (s, 1H), 9.47 (s, 1H), 8.75 (s, 2H), 8.19 ( s, 1H), 8.10 (s, 1H), 7.98-7.99 (d, 2H), 7.50-7.52 (d, 1H), 3.82-3.84 (d, 1H), 3.25-3.28 (d, 8H), 2.75- 2.81 (m, 4H), 1.26-1.29 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 1a-2, except that the compound 1a-1 in the 1a-2 process is replaced with the compound 30-1.
  • Step 2 The preparation method is the same as Compound 1a-3 except that Compound 1a-2 in Process 1a-3 is replaced with Compound 30-2. MS m/z (ESI): 184.9 [M+H] + .
  • Step 3 The preparation method is the same as that of the compound 1-4, except that the compound 1-3 in the 1-4 process is replaced with the compound 30-3.
  • Step 4 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 30-4 and methyl iodide.
  • Step 5 The preparation method is the same as that of the compound 1-3, except that the compound 1-2 in the 1-3 process is replaced with the compound 30-5. MS m/z (ESI): 250 [M+H] + .
  • Step 6 The preparation method is the same as that of the compound 2-4, except that the compound 2-3 in the 2-4 process is replaced with the compound 30-6. MS m/z (ESI): 246[M+H] + .
  • Step 7 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the process of 1-8 is replaced with the compound 30-7.
  • Step 8 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 30-8. Purification by Prep-HPLC gave white solid compound P-30 (6.6 mg, 19%). MS m/z (ESI): 407 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) ⁇ 8.21 (d, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7. s, 1H), 7.27 (dd, 1H), 5.15 (s, 2H), 3.89 (s, 3H), 3.62-3.58 (m, 1H), 3.08 (d, 8H), 1.49 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-4, except that the compounds 3-3 and 3.1 in the 3-4 process are replaced with the compounds 6a and 31.1. MS m/z (ESI): 162 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 in the 3-5 process is replaced with the compound 31-1.
  • Step 3 The preparation method is the same as the compound 3-6 except that the compound 3-5 in the 3-6 process is replaced with the compound 31-2.
  • Step 4 The preparation method is the same as the compound 3-7, except that the compound 3-6 in the 3-7 process is replaced with the compound 31-3. MS m/z (ESI): 256 [M+H] + .
  • Step 5 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 31-4. MS m/z (ESI): 517 [M+H] + .
  • Step 6 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 31-5. Purification by Prep-HPLC gave white solid compound P-31 (7 mg, 19%). MS m/z (ESI): 417 [M+H] + .
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 in the 3-5 process is replaced with the compound 31-1. MS m/z (ESI): 177 [M+H] + .
  • Step 2 The preparation method is the same as the compound 3-6 except that the compound 3-5 in the 3-6 process is replaced with the compound 32-1.
  • Step 3 The preparation method is the same as the compound 3-7 except that the compound 3-6 in the 3-7 process is replaced with the compound 32-2.
  • Step 4 The preparation method is the same as that of the compound 1-8, except that the compound 1-7 in the 1-8 process is replaced with the compound 32-3. MS m/z (ESI): 495 [M+H] + .
  • Step 5 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 32-4. Purification by Prep-HPLC gave white solid compound P-32 (10 mg, 10%). MS m/z (ESI): 389 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.00 (s, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 7.92 (d) , 1H), 7.37 (dd, 1H), 3.95 (s, 3H), 3.38 (s, 2H), 3.03-2.93 (m, 4H), 2.86-2.78 (m, 4H), 2.13-2.07 (m, 1H) ), 1.03-0.97 (m, 2H), 0.95-0.91 (m, 2H).
  • Step 1 The preparation method is the same as the compound 1-8 except that the compound 1-7 in the 1-8 process is replaced with the compound 52-1.
  • Step 2 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 52-2. Purification by Prep-HPLC gave white solid compound P-52 (23.54mg, yield 47%). MS m/z (ESI): 416 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.69 (s, 1H), 8.43 (s, 1H), 7.96 (d, 1H), 7.84 (d, 1H), 7.40 (dd, 1H), 6.12-5.96 (m, 1H), 3.10-3.00 (m, 4H), 2.93-2.86 (m, 4H), 2.87-2.79 (m, 4H), 1.42 (d, 6H).
  • Step 1 The preparation method is the same as that of the compound 3-5, except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 55-1 and methyl iodide.
  • Step 2 Compound 55-2 (1.84 g, 10 mmol) in THF (10 mL) EtOAc (EtOAc) 20 mmol), the mixture was allowed to warm to room temperature for 1 h. The reaction mixture was filtered and concentrated to give Compound 55-3.
  • Step 3 The preparation method is the same as the compound 8a-3 except that the compound 8a-2 in the 8a-3 process is replaced with the compound 55-3.
  • Step 4 The preparation method is the same as that of the compound 8a-4, except that the compound 8a-3 in the 8a-4 process is replaced with the compound 55-4.
  • Step 5 The preparation method is the same as that of the compound 3-5 except that the compound 3-4 and 2-iodopropane in the 3-5 process are replaced with the compound 55-5 and methyl iodide.
  • Step 6 The preparation method is the same as Compound 8a except that Compound 8a-4 in Process 8a is replaced by Compound 55-6. MS m/z (ESI): 266 [M+H] + .
  • Step 7 The preparation method is the same as the compound 3-6 except that the compound 3-5 in the 3-6 process is replaced with the compound 55-7. MS m/z (ESI): 384[M+H] + .
  • Step 8 The preparation method is the same as the compound 3-7 except that the compound 3-6 in the 3-7 process is replaced with the compound 55-8. MS m/z (ESI): 330 [M+H] + .
  • Step 9 The preparation method is the same as the compound 1-8, except that the compound 1-7 in the process of 1-8 is replaced with the compound 55-9. MS m/z (ESI): 564 [M+H] + .
  • Step 10 Compound 55-10 (80 mg, 0.14 mmol) in EtOAc (5 mL) EtOAc (EtOAc, EtOAc. 0.56 mmol). The reaction was stirred at room temperature for 1 h and then was taken and purified by LC-MS. The mixture was concentrated under reduced pressure and purified by EtOAc (EtOAc) MS m/z (ESI): 564 [M+H] + .
  • Step 12 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 55-12. Purification by Prep-HPLC gave Compound P-55 (22.7 mg, yield: 92%). MS m/z (ESI): 461 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 8.70 (s, 1H), 8.23 (s, 1H), 7.78 (d, 1H), 7.78 (d) , 1H), 7.58 (s, 1H), 3.99 (dd, 1H), 3.89 (s, 3H), 3.33 - 3.28 (m, 4H), 3.29-3.19 (m, 5H), 2.64 (d, 1H), 2.01(s,3H), 1.43(s,3H), 1.38(d,6H).
  • Step 1 Compound 59-1 (25mg, 0.082mmol) in CH 2 Cl 2 (10mL) at rt was added MCPBA (42mg, 0.246mmol), the mixture was stirred at rt for 30min, LC-MS to follow the reaction. The reaction mixture was quenched with EtOAc EtOAc (EtOAcEtOAcEtOAc. MS m/z (ESI): 337 [M+H] + .
  • Step 2 Compound 59-2 (20 mg, 0.059 mmol) in EtOAc (2 mL)EtOAc. The reaction mixture was concentrated and purified by EtOAc (EtOAc: EtOAc: EtOAc) MS m / z (ESI): 535 [M+H] + .
  • Step 3 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 59-3. Purification by Prep-HPLC gave Compound P-59 (1.7 mg, yield 10%). MS m/z (ESI): 435 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.46 (s, 1H), 8.33 (s, 1H), 7.94 (d, 1H), 7.87 (d) , 1H), 7.38 (dd, 1H), 5.88 (dt, 1H), 4.34 (s, 2H), 3.22 (s, 3H), 3.05-2.95 (m, 4H), 2.88-2.81 (m, 4H), 2.80-2.72 (m, 2H), 2.71-2.59 (m, 2H), 1.38 (d, 6H).
  • Step 2 A solution of compound 65-2 (40 mg, 0.16 mmol) elut elut elut elut elut elut elut elut elut elut elut elut The reaction solution was filtered, concentrated and purified with EtOAc (EtOAc: EtOAc) MS m/z (ESI): 220 [M+H] + .
  • Step 3 Compound 65-3 (800mg, 3.6mmol) in ethanol (2mL) was added Ac 2 O (10mL), the mixture was stirred at 110 °C 2h, LC-MS until the reaction was complete tracking. The reaction mixture was concentrated and purified by EtOAc (EtOAc: EtOAc) MS m/z (ESI): 262 [M+H] + .
  • Step 4 The preparation method is the same as the compound 65-2 except that the compound 65-1 in the process of the 65-2 is replaced with the compound 65-4.
  • Step 5 The preparation method is the same as the compound 65-3 except that the compound 65-2 in the process of the 65-3 is replaced with the compound 65-5. MS m/z (ESI): 277 [M+H] + .
  • Step 7 Compound 65-7 (28mg, 0.09mmol) in toluene (1 mL) at room temperature was added POCl 3 (1mL), the mixture was stirred at 105 °C 3h, LC-MS until the reaction was complete tracking. The reaction mixture was concentrated and purified by EtOAc (EtOAc: EtOAc) MS m/z (ESI): 303 [M+H] + .
  • Step 8 Compound 65-8 (50 mg, 0.16 mmol) eluted eluted eluted eluted eluted The reaction mixture was concentrated and purified by EtOAc (EtOAc: EtOAc:EtOAc) MS m/z (ESI): 266 [M+H] + .
  • Step 9 The preparation method is the same as the compound 1-8 except that the compound 1-7 and the compound 4a in the process of 1-8 are replaced with the compound 65-9 and the compound 65.1.
  • Step 10 The preparation method is the same as the compound P-1 except that the compound 1-8 in the P-1 process is replaced with the compound 65-10. Purification by Prep-HPLC gave white solid compound P-65 (4 mg, 25%). MS m/z (ESI): 409 [M+H] + ; 1 H NMR (400 MHz, DMSO) ⁇ 9.42 (s, 1H), 8.97 (s, 1H), 8.26 (d, 1H), 7.97 (d) , 1H), 7.45 (dd, 1H), 4.75 (dt, 1H), 3.05-2.97 (m, 4H), 2.90-2.77 (m, 4H), 2.58 (s, 3H), 1.51 (d, 6H).
  • CDK1/CCNB1 and CDK9/CCNT were purchased from BPS; CDK2/CCNA1, CDK4/CCND1 and CDK6/CCND1 were purchased from Invitrogen; CDK4/CycD3 and CDK6/CycD3 were purchased from Carna.
  • Adenosine triphosphate (ATP) was purchased from Life tech.
  • the substrate Ulight-4EBP1 and the corresponding detection antibody were purchased from Perkinelmer.
  • the detection system uses Perkinelmer's LANCEUltra system.
  • the test compound was diluted at a gradient of 1:3 and then added to the reaction plate and an appropriate amount of recombinant enzyme was added. Subsequently, a buffer containing a predetermined concentration of ATP/Ulight-4EBP1 premix [50 mM HEPES pH 7.5, 10 mM MgCl 2 , 3 mM MnCl 2 , 1 mM EGTA, 0.01% Tween- 20 , 1 mM TCEP] was added, and the kinase reaction was started at room temperature.
  • a buffer containing a predetermined concentration of ATP/Ulight-4EBP1 premix [50 mM HEPES pH 7.5, 10 mM MgCl 2 , 3 mM MnCl 2 , 1 mM EGTA, 0.01% Tween- 20 , 1 mM TCEP] was added, and the kinase reaction was started at room temperature.
  • the exemplified compounds of the present invention have strong inhibitory activity against CDK4 and CDK6, and have weak inhibitory activity against CDK1 and CDK2, and have selective inhibitory activity against CDK4/6.
  • Comparative Compound 1 D1 the specific structure is shown below, and can be found in WO2012010704 Example I-44
  • Comparative Compound 1 although it has strong inhibitory activity against CDK4 and CDK6, the inhibition of CDK1 and CDK2 is also strong, and CDK4 is not shown. The choice of /6 inhibits activity.
  • Test animals healthy adult male Sprague-Dawley rats (body weight 210-230 g, 12 animals, fasted overnight, fed 4 hours after administration), supplied by Slack Company; preparation of oral solution: Weigh 40.14 mg of compound P-53 In a clean tube, 36.479 mL of 0.5% HPC-H (TCI, E6ZQA) acetate buffer (pH 4.5) was added to the tube and the tube was vortexed for 1-2 minutes. Ultrasound For 20-25 minutes, stir for 20-25 minutes.
  • HPC-H TCI, E6ZQA
  • SD rats were intragastrically administered (10 mg/kg (10 mL/kg)); samples were taken at 4 time points at 0.5, 1, 2, and 4 hours after administration. Only plasma samples were collected continuously, brain tissue and cerebrospinal fluid were Collected at each time point.
  • Blood sample collection Animals were manually controlled and approximately 150 [mu]L of blood/time point was collected through the tail vein into tubes containing K2EDTA. Within 15 minutes, blood samples were placed on wet ice and centrifuged (2000 g, 5 min under 4 °C) to obtain plasma samples.
  • Brain tissue collection Make an incision in the middle of the animal's scalp and then contract the skin. Use a small bone knife and a rongeur to move the skull behind your head. Use a spatula to remove the brain and rinse with cold saline. Place the brain in a spiral tube and store the tube at -70 °C until analysis.
  • Cerebrospinal fluid collection In the case of deep anesthesia of the animal, air is euthanized in the tail vein. Using the occipital bone and the atlas as a symbol, the cerebrospinal fluid was collected by directly piercing the cisterna magna with a butterfly needle. During the collection process, a piece of white paper is placed over the needle as a background to monitor the color change of the sample. In the observation of the color change, the PE tube is quickly closed above the color change and cut over the clamped portion to draw a clean sample into the syringe.
  • Plasma, brain and cerebrospinal fluid samples are temporarily stored in dry ice and then transferred to a cold storage at -80 °C for long-term storage.
  • Glipizide was used as the internal standard in SD rat plasma and brain, and LCMSMS-002 (API-4000, triple quadrupole) was used for testing and analysis. Take 30 ⁇ L of plasma sample and brain tissue sample, add 200 ⁇ L of acetonitrile containing 100 ng/mL internal standard (Glipizide), mix and vortex for 10 min, centrifuge at 5800 rpm for 10 min, then take 2 ⁇ L of the supernatant after centrifugation for LC. - MS/MS analysis.
  • the compound P-53 can cross the blood-brain barrier and is well distributed into the brain, and has good brain permeability.

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Abstract

提供了吡啶胺取代的杂三环化合物、其制法与医药上的用途。具体地，提供了式(I)化合物或其药学上可接受的盐、立体异构体、溶剂化物或前药，及其制备方法和应用。

Description

吡啶胺取代的杂三环化合物、其制法与医药上的用途 技术领域
本发明属于医药技术领域。具体地，本发明特别涉及一种吡啶胺取代的杂三环化合物及其制备方法和作为CDK4/6抑制剂的应用，以及由其制备的药物组合物。
背景技术
CDK是一类丝氨酸/苏氨酸蛋白激酶，只有与周期蛋白结合后才有激活酶性，在细胞周期的启动和各个时期的转换调节中起关键作用。CDK4/6是细胞周期的重要调节蛋白，可磷酸化抑癌基因蛋白Rb，释放E2F转录因子，使细胞顺利通过细胞周期G1/S检测点，细胞周期得以继续。CDK4单基因敲除老鼠存在糖尿病征和细胞缺陷，CDK6单基因敲除老鼠因造血细胞增值缺陷导致轻微的贫血症状，而CDK4和CDK6(CDK4/6)双基因敲除则会使造血前体细胞增殖能力受损，导致双敲除老鼠胚胎晚期的死亡。在肿瘤细胞中，普遍发现CDK4/6-cyclin D/Rb信号通路的超活化。在胞内外各种有丝分裂信号刺激下，cyclin D高表达，调节CDK4/6蛋白与cyclin D的相互作用，促进CDK4/6的定位和激酶活性。激活的CDK4/6通过磷酸化抑制Rb肿瘤抑制蛋白的活性，使Rb-E2F复合物解离，释放游离的E2F入核，调节蛋白转录，启动细胞周期的进行。在上皮细胞恶性肿瘤中常发现CDK4的超活化，而间质细胞肿瘤如肉瘤和血液性癌症中常发现CDK6的超活化。构建乳腺癌荷瘤鼠模型发现，野生型裸鼠全部成瘤，而CDK4敲除裸鼠完全无法成瘤；而用anti-CDK4 siRNA干扰CDK4的表达，则发现裸鼠的肿瘤生长显著受抑制。选择性CDK4/6抑制剂可以诱导细胞G1期阻滞，进而提高造血干/祖细胞对DNA损伤剂如IR的耐受性，有效减少由辐射引起的各种造血毒性，包括骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血等。
近几年各大公司已分别鉴定发现了一系列选择性抑制CDK4和CDK6的抑制剂，用于治疗癌症、心血管障碍及炎症等疾病。如Pfizer的palbociclib、Eli Lilly的Abemaciclib等，此外国内的多家企业也有专利公开，选择性抑制CDK4和CDK6的专利申请包括WO2014183520、WO2015101293、WO2015180642、WO2016014904和WO2016015597等。尽管目前这些小分子CDK抑制剂在临床上具有一定的优势，但也有其自身的缺点，如palbociclib具有较大的中性粒细胞毒性。一般认为，对于CDK4的抑制就可以抑制肿瘤细胞的生长，而CDK6在血液系统高表达，功能为调控造血细胞等的生长，对CDK6的抑制可能会造成血液学方面的毒性，如中性粒细胞减少，红细胞减少等。Palbociclib对CDK4和CDK6都有相同的抑制，酶活性分别是10nm和10nm，其毒性应当和此相关。而Abemaciclib对于CDK4的抑制要强于CDK6的抑制；弱的CDK6抑制剂造成了低的血液学方面的毒性。由于CDK4和CDK6的同源性非常高，有约70％，因此开发选择性的CDK4/6抑制剂，特别是CDK4抑制剂是一个很大的挑战。
此外，晚期肿瘤患者有相当一部分会出现脑转移，这在肺癌、乳腺癌、黑色素瘤中尤为突出，这部分患者运用现有的治疗方法效果很差，主要是由于大部分药物不能进入血脑屏障，因此若能开发具有独特的药代动力学特征，能够有效透过血脑屏障，针对目前临床有重大需求的脑肿瘤或脑转移的肿瘤患者有显著药效的选择性CDK4/6抑制剂，将具有重要的临床意义和广阔的市场前景。为了达到更好的肿瘤治疗效果的目的，更好的满足市场需求，我们希望能开发出新一代的高效低毒的选择性CDK4和CDK6抑制剂。
发明内容
本发明的目的是提供一种结构新颖的可作为选择性CDK4/6抑制剂的化合物。
本发明第一方面提供了一种式(I)所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
Figure PCTCN2017110463-appb-000001
式中，
R1、R3、R4各自独立地为氢、卤素(优选氟、氯、溴)、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)或卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)；
R2为-(CH2)n-Y，其中Y为C3-8环烷基(优选为C3-6环烷基)、3至6元饱和单杂环(优选为4至6元)、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环；n为0、1或2；
Z1、Z2各自独立地为一个键、CRaRb、NRc、O、S或S(O)2，且Z1、Z2不同时为一个键、NRc、O、S或S(O)2；
Ra、Rb各自独立地为氢、卤素(优选氟、氯、溴)、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)；或
Ra、Rb和相连的碳原子共同形成3至6元饱和单杂环、3至6元饱和或部分不饱和单环；
Rc为氢、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C3-8环烷基(优选为C3-6环烷基)、C(O)C1-8烷基(优选为C(O)C1-6烷基，更优选为C(O)C1-3烷基)、C(O)OC1-8烷基(优选为C(O)OC1-6烷基，更优选为C(O)OC1-3烷基)、CONRa1Rb1、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3烷基)、-C(O)CH2CN、-C(O)CH2OH、3至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环；
A环为式(A-1)、式(A-2)、式(A-3)或式(A-4)所示结构：
Figure PCTCN2017110463-appb-000002
其中，R11、R22、R32、R41各自独立地为氢、C1-8烷基、卤代C1-8烷基、C3-8环烷基或3至6元饱和单杂环(优选为4至6元，更优选为5至6元)；
R12、R21、R31、R42各自独立地为氢、卤素、C1-8烷基、卤代C1-8烷基、C3-8环烷基或3至6元饱和单杂环(优选为4至6元，更优选为5至6元)；
所述烷基、烷氧基、环烷基、3至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被1、2或3个选自下组的取代基所取代：CN、乙酰基、羟基、羟甲基、羟乙基、羧基、卤素、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C3-8环烷基(优选为C3-6环烷基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、-C(O)OC1-6烷基、NRa2Rb2、3至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环；
Ra1、Rb1、Ra2、Rb2各自独立地为氢、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)或C1-8烷氧基取代的C1-8烷基(优选为C1-6烷氧基取代的C1-6烷基，更优选为C1-3烷氧基取代的C1-3烷基)。
在另一优选例中，Y为C3-6环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环，所述环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被-(CH2)m-L1取代；L1为CN、乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C3-8环烷基(优选为C3-6环烷基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、NRa2Rb2、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、氮杂环丁烷、氧杂环丁烷、四氢噻吩、四氢吡咯、四氢呋喃、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃；m为0、1或2；Ra2、Rb2如前所定义。
在另一优选例中，m为0或1。
在另一优选例中，所述4至6元饱和单杂环为氮杂环丁烷、氧杂环丁烷、四氢吡咯、四氢呋喃、哌啶、哌嗪、吗啉或四氢吡喃。
在另一优选例中，所述C3-6环烷基为环丁基、环戊基或环己基。
在另一优选例中，所述5至6元单环杂芳基环为噻吩、N-烷基吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、四唑、异噁唑、噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。
在另一优选例中，所述螺杂环为含有1-2个氮或氧原子的双螺杂环。
在另一优选例中，所述桥杂环为含有1-2个氮或氧原子的双环桥杂环。
在另一优选例中，L1中的氮杂环丁烷、氧杂环丁烷、四氢噻吩、四氢吡咯、四氢呋喃、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃为未取代的或被1、2或3个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、卤代C1-3烷氧基、-C(O)OC1-6烷基、NRa3Rb3；其中Ra3、Rb3各自独立地为氢或C1-3烷基。
在另一优选例中，Y为选自下组的基团：环丁基、环戊基、环己基、氮杂环丁烷、四氢吡咯、四氢呋喃、哌啶、哌嗪、吗啉或四氢吡喃，所述基团为未取代或被L1或-CH2-L1取代；L1为CN、乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OCH3、-C(O)OCH2CH3、-C(O)OC(CH3)3、-C(O)OCH(CH3)2、甲基、乙基、正丙基、异丙基、环丙基、环戊基、环己基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、氮杂环丁烷、四氢吡咯、四氢呋喃、哌啶、哌嗪、吗啉、四氢吡喃或NRa2Rb2；Ra2、Rb2各自独 立地为氢、C1-3烷基或C1-3烷氧基取代的C1-3烷基。
在另一优选例中，L1中的氮杂环丁烷、四氢吡咯、四氢呋喃、哌啶、哌嗪、吗啉或四氢吡喃为未取代的或被1、2或3个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、卤代C1-3烷氧基、-C(O)OC1-6烷基、NRa3Rb3；其中Ra3、Rb3各自独立地为氢或C1-3烷基。
在另一优选例中，Rc为氢、-C(O)C1-3烷基、-C(O)OC1-3烷基、-CONRa1Rb1、-SO2C1-3烷基、-C(O)CH2CN、-C(O)CH2OH或-(CH2)p-L2；其中L2为CN、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、NRa1Rb1、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C3-8环烷基(优选为C3-6环烷基)、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环；p为0、1或2；
所述烷基、烷氧基、环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被1个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、NRa2Rb2、氮杂环丁烷、氧杂环丁烷、四氢噻吩、四氢吡咯、四氢呋喃、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃；Ra1、Rb1、Ra2、Rb2如前所定义。
在另一优选例中，p为0或1。
在另一优选例中，所述4至6元饱和单杂环为氮杂环丁烷、氧杂环丁烷、四氢吡咯、四氢呋喃、哌啶、哌嗪、吗啉或四氢吡喃。
在另一优选例中，所述5至6元单环杂芳基环为噻吩、N-烷基吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、四唑、异噁唑、噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。
在另一优选例中，取代基中的氮杂环丁烷、氧杂环丁烷、四氢噻吩、四氢吡咯、四氢呋喃、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃为未取代的或被1、2或3个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、卤代C1-3烷氧基、-C(O)OC1-6烷基、NRa3Rb3；其中Ra3、Rb3各自独立地为氢或C1-3烷基。
在另一优选例中，R11、R22、R32、R41各自独立地为氢或-(CH2)q-L3；其中L3为CN、NRa1Rb1、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C3-8环烷基(优选为C3-6环烷基)、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环；q为0、1或2；
所述烷基、烷氧基、环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被1个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、NRa2Rb2、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃；Ra1、Rb1、Ra2、Rb2如前所定义。
在另一优选例中，q为0或1。
在另一优选例中，所述4至6元饱和单杂环为氮杂环丁烷、氧杂环丁烷、四氢吡咯、四 氢呋喃、哌啶、哌嗪、吗啉或四氢吡喃。
在另一优选例中，所述5至6元单环杂芳基环为噻吩、N-烷基吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、四唑、异噁唑、噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。
在另一优选例中，取代基中的氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃为未取代的或被1、2或3个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、卤代C1-3烷氧基、-C(O)OC1-6烷基、NRa3Rb3；其中Ra3、Rb3各自独立地为氢或C1-3烷基。
在另一优选例中，R12、R21、R31、R42各自独立地为氢、卤素或-(CH2)r-L4；L4为CN、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C3-8环烷基(优选为C3-6环烷基)、NRa1Rb1、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环；r为0、1或2；
所述烷基、烷氧基、环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被1个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、NRa2Rb2、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃；Ra1、Rb1、Ra2、Rb2如前所定义。
在另一优选例中，r为0或1。
在另一优选例中，所述4至6元饱和单杂环为氮杂环丁烷、氧杂环丁烷、四氢吡咯、四氢呋喃、哌啶、哌嗪、吗啉或四氢吡喃。
在另一优选例中，所述5至6元单环杂芳基环为噻吩、N-烷基吡咯、呋喃、噻唑、咪唑、噁唑、吡咯、吡唑、三唑、四唑、异噁唑、噁二唑、噻二唑、吡啶、哒嗪、嘧啶或吡嗪。
在另一优选例中，取代基中的氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃为未取代的或被1、2或3个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、卤代C1-3烷氧基、-C(O)OC1-6烷基、NRa3Rb3；其中Ra3、Rb3各自独立地为氢或C1-3烷基。
在另一优选例中，Ra、Rb各自独立地为氢、氟、氯、C1-3烷基、卤代C1-3烷基；或
Ra、Rb和相连的碳原子共同形成环氧丙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃环、四氢噻吩环、四氢吡咯、哌啶环、四氢吡喃环、环丙基环、环丁基环、环戊基环、环己基环。
在另一优选例中，所述环氧丙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃环、四氢噻吩环、四氢吡咯、哌啶环、四氢吡喃环、环丙基环、环丁基环、环戊基环、环己基环为未取代的或被1、2或3个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、卤代C1-3烷氧基、-C(O)OC1-6烷基、NRa3Rb3；其中Ra3、Rb3各自独立地为氢或C1-3烷基。
在另一优选例中，
Figure PCTCN2017110463-appb-000003
为式(B-1)、式(B-2)、式(B-3)或式(B-4)所示结构：
其中Z、R11、R22、R32、R41、R12、R21、R31、R42如前所定义。
在另一优选例中，Z1为一个键；Z2为CR1aR1b、NRc、O、S或S(O)2；R1a、R1b如Ra、Rb所定义。
在另一优选例中，Z1为CR1aR1b、NRc、O、S或S(O)2；Z2为CR2aR2b(优选为CH2)；R1a、R1b、R2a、R2b如Ra、Rb所定义。
在另一优选例中，Z1为CR1aR1b(优选为CH2)；Z2为CR2aR2b、NRc、O、S或S(O)2；R1a、R1b、R2a、R2b如Ra、Rb所定义。
在另一优选例中，Z1为一个键；Z2为CR2aR2b、NRc、O、S或S(O)2(Z2优选为CR2aR2b，更优选为CH2)；
Figure PCTCN2017110463-appb-000005
为式(B-1)、式(B-2)或式(B-3)所示结构(优选为式(B-2))；R2a、R2b如Ra、Rb所定义。
在另一优选例中，Z1为CR1aR1b、NRc、O、S或S(O)2(Z1优选为CH2或O)；Z2为CR2aR2b(Z2优选为CH2)；
Figure PCTCN2017110463-appb-000006
为式(B-1)、式(B-2)或式(B-4)所示结构；R1a、R1b、R2a、R2b如Ra、Rb所定义。
在另一优选例中，Z1为一个键或O；Z2为CR2aR2b(Z2优选为CH2)；
Figure PCTCN2017110463-appb-000007
为式(B-2)所示结构；R2a、R2b如Ra、Rb所定义。
在另一优选例中，Z1为CR1aR1b(Z1优选为CH2)；Z2为CR2aR2b(Z2优选为CH2)；
Figure PCTCN2017110463-appb-000008
为式(B-1)所示结构；R1a、R1b、R2a、R2b如Ra、Rb所定义。
在另一优选例中，R1、R3、R4各自独立地为氢、卤素、C1-6烷基或卤代C1-6烷基。
在另一优选例中，R1、R3、R4各自独立地为氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、一氯乙基、二氯甲基、1,2－二氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙 基。
在另一优选例中，R1、R3、R4各自独立地为氢。
在另一优选例中，n为0或1。
在另一优选例中，所述化合物选自下表A：
表A
Figure PCTCN2017110463-appb-000009
Figure PCTCN2017110463-appb-000010
在另一优选例中，所述化合物选自下表B：
表B
Figure PCTCN2017110463-appb-000011
Figure PCTCN2017110463-appb-000012
本发明第二方面提供了一种药物组合物，所述药物组合物包括本发明第一方面所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。
本发明第三方面提供了如本发明第一方面所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药、或如本发明第二方面所述药物组合物在制备治疗疾病或病症的药物中的应用，所述疾病或病症选自癌症、异常细胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病、神经变性疾病、由辐射引起的造血毒性疾病，或其组合。
在另一优选例中，所述的癌症选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
在另一优选例中，所述的辐射引起的造血毒性疾病包括但不限于骨髓抑制、嗜中性白血球减少症、白细胞减少症、贫血。
本发明第四方面提供了一种抑制CDK4和/或CDK6活性的方法，其包括给予所需患者治疗有效量的本发明第一方面所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，或如本发明第二方面所述药物组合物。
本发明第五方面提供了一种治疗异常细胞增殖性疾病、感染(例如病毒感染，如疱疹、HIV、真菌感染等)炎性病症(例如类风湿性关节炎、骨关节炎等)、自身免疫性疾病(例如牛皮癣、狼疮、I型糖尿病、糖尿病性肾病、多发性硬化、肾小球性肾炎等)、心血管疾病(例如心肌梗塞、中风、动脉粥样硬化、手术后血管狭窄、再狭窄等)或神经变性疾病(例如阿尔茨海默氏病、帕金森病等)的方法，其包括给予所需患者治疗有效量的本发明第一方面所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，或如本发明第二方面所述药物组合 物，其中所述的异常细胞增殖性疾病可以是癌症。
本发明第六方面提供了一种治疗癌症的方法，其包括给予所需患者治疗有效量的本发明第一方面所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，或如本发明第二方面所述药物组合物，其中所述癌症选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤(例如具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的神经胶质瘤等)、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如非小细胞肺癌、小细胞肺癌、原发或转移性鳞状癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌(例如子宫颈癌、子宫内膜癌等)、头颈肿瘤(例如上颌骨癌、喉癌、咽癌、舌癌、口内癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例如尤因家族性肉瘤、维尔姆斯肉瘤、横纹肌肉瘤、血管肉瘤、胚胎睾丸癌、成神经细胞瘤、视网膜母细胞瘤、肝胚细胞瘤、肾母细胞瘤等)等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，意外地发现了本发明的吡啶胺取代的杂三环结构对CDK4和CDK6具有较高的抑制活性，同时对CDK1和CDK2的抑制活性较弱具有明显的4/6选择性，因此本发明的系列化合物可开发成为选择性CDK4和CDK6抑制剂用于治疗癌症的药物。在此基础上，发明人完成了本发明。
术语定义
如本文所用，“烷基”指直链和支链的饱和的脂族烃基，C1-8烷基为包含1至8个碳原子的烷基，优选为C1-6烷基，更优选为C1-3烷基，定义类似；烷基非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。
如本文所用，“环烷基”指饱和或部分不饱和单环环状烃基，“C3-8环烷基”是指包含3至8个碳原子的环烃基，优选为C3-6环烷基，定义类似。环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛 基等，优选环丙基、环戊基、环己烯基。
如本文所用，“螺环”是指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺环分为双螺环或多螺环，优选为双螺环。更优选为优选为4元/5元、5元/5元或5元/6元双螺环。例如：
Figure PCTCN2017110463-appb-000013
如本文所用，“螺杂环”指单环之间共用一个原子(称螺原子)的多环烃，其中一个或两个环原子选自氮、氧或S(O)n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环的数目将螺杂环分为双螺杂环或多螺杂环，优选双螺杂环。更优选为4元/5元、5元/5元或5元/6元双螺杂环。例
Figure PCTCN2017110463-appb-000014
如：
Figure PCTCN2017110463-appb-000015
如本文所用，“桥环”是指共用两个或两个以上碳原子的多环基团，共用的碳原子称为桥头碳，两个桥头碳之间可以是碳链，也可以是一个键，称为桥。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥环。例如：
Figure PCTCN2017110463-appb-000016
如本文所用，“桥杂环”指共用两个或两个以上原子的多环基团，其中一个或多个环原子选自氮、氧或S(O)n(其中n是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为双环或三环桥杂环。例如：
Figure PCTCN2017110463-appb-000017
如本文所用，“8至10元双环”是指含8至10个环原子的含两个环的桥环，双环可为饱和全碳双环或部分不饱和的全碳双环，8至10元双环的实例包括(但不限于)：
Figure PCTCN2017110463-appb-000018
如本文所用，“8至10元双杂环”是指含8至10个环原子的含两个环的桥杂环，其中1、2、3、4或5个环碳原子被选自氮、氧或硫的杂原子所取代。8至10元双杂环的实例包括(但不限于)四氢喹啉环、四氢异喹啉环、十氢喹啉环等。
如本文所用，“C1-8烷氧基”指-O-(C1-8烷基)，其中烷基的定义如上所述。优选C1-6烷氧基，更优选C1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
如本文所用，“C3-8环烷氧基”指-O-(C3-8环烷基)，其中环烷基的定义如上所述。优选C3-6环烷氧基。非限制性实施例包含环丙氧基、环丁氧基、环戊氧基、环己氧基等。
如本文所用，“C6-10芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，指含有6至10个碳原子的芳基；优选苯基和萘基，更优选苯基。
如本文所用，“一个键”指由其连接的两个基团通过一个共价键连接。
如本文所用，“卤素”指氟、氯、溴或碘。
如本文所用，“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。
例如，“卤代C1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷基的定义如上所述。选为卤代C1-6烷基，更优选为卤代C1-3烷基。卤代C1-8烷基的例子包括(但不限于)一氯甲基、二氯甲基、三氯甲基、一氯乙基、1,2-二氯乙基、三氯乙基、一溴乙基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基等。
又例如，“卤代C1-8烷氧基”指烷氧基被一个或多个(如1、2、3、4或5个)卤素取代，其中烷氧基的定义如上所述。优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基。包括(但不限于)三氟甲氧基、三氟乙氧基、一氟甲氧基、一氟乙氧基、二氟甲氧基、二氟乙氧基等。
又例如，“卤代C3-8环烷基”指环烷基被一个或多个(如1、2、3、4或5个)卤素取代，其中环烷基的定义如上所述。优选为卤代C3-6环烷基。包括(但不限于)三氟环丙基、一氟环丙基、一氟环己基、二氟环丙基、二氟环己基等。
如本文所用，“氘代C1-8烷基”指烷基被一个或多个(如1、2、3、4或5个)氘原子取代，其中烷基的定义如上所述。优选为氘代C1-6烷基，更优选为氘代C1-3烷基。氘代C1-20烷基的例子包括(但不限于)单氘代甲基、单氘代乙基、二氘代甲基、二氘代乙基、三氘代甲基、三氘代乙基等。
如本文所用，“氨基”指NH2，“氰基”指CN，“硝基”指NO2，“苄基”指-CH2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH3，“羟甲基”指-CH2OH，“羟乙基”指-CH2CH2OH，“羟基”指-OH，“硫醇”指SH，“亚环丙基”结构为：
Figure PCTCN2017110463-appb-000019
如本文所用，“杂芳基环”与“杂芳基”可互换使用，是指具有5到10个环原子，优选5或6元单环杂芳基或8至10元双环杂芳基；环阵列中共享6、10或14个π电子；且除碳原子外还具有1到5个杂原子的基团。“杂原子”是指氮、氧或硫。
如本文所用，“3至6元饱和或部分不饱和单环”是指含3至6个环原子的饱和或部分不饱和的全碳单环。单环的实例包括(但不限于)：环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环辛基环等。
如本文所用，“3至6元饱和单杂环”是指3至6元单环中的1、2或3个碳原子被选自氮、氧或S(O)t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳；优选4至6元，更优选5至6元。饱和单杂环的实例包括(但不限于)环氧丙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、吡咯啉、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢吡喃等。
如本文所用，“5至6元单环杂芳基环”是指含5至6个环原子的单杂芳基环，例如包括(但不限于)：噻吩环、N-烷基吡咯环、呋喃环、噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、四唑环、异噁唑环、噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环等。
如本文所用，“8至10元双环杂芳基环”是指含8至10个环原子的双杂芳基环，例如包括(但不限于)：苯并呋喃、苯并噻吩、吲哚、异吲哚、喹啉、异喹啉、吲唑、苯并噻唑、苯并咪唑、喹唑啉、喹喔啉、噌啉、酞嗪。
如本文所用，“取代的”指基团中的一个或多个氢原子，优选为1～5个氢原子彼此独立地被相应数目的取代基取代，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
如本文所用，本文任一基团可以是取代的或未取代的。上述基团为取代时，取代基优选为1至5个以下基团，独立地选自CN、卤素、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤代C1-8烷基(优选为卤代C1-6烷基，更优选为卤代C1-3烷基)、C3-8环烷基(优选为C3-6环烷基)、卤代C1-8烷氧基(优选为卤代C1-6烷氧基，更优选为卤代C1-3烷氧基)、C1-8烷基取代的胺基、胺基、卤代C1-8烷基取代的胺基、4至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环。
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。
本文所述的4至6元饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置， 示例性的单杂环的代表性的取代情况如下所示：
Figure PCTCN2017110463-appb-000020
Figure PCTCN2017110463-appb-000021
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2017110463-appb-000022
表示与其他原子的连接。
如本文所用，“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本发明化合物的量。
如本文所用，“药学可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，最好为哺乳动物，更优选为人，其适合将活性试剂输送到目标靶点而不终止试剂的活性。
如本文所用，“患者”是指一种动物，最好为哺乳动物，更好的为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人类。
如本文所用，“治疗”是指减轻、延缓进展、衰减、预防，或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
制备方法
本发明提供了式(I)化合物的制备方法，本发明中的化合物可以通过多种合成操作制备，这些化合物的示例性制备方法可以包括(但不限于)下文所述的流程。
较佳地，本发明式(I)化合物可以通过以下方案及实施例中所述的示例性方法以及本领域技术人员所用的相关公开文献操作完成。
在具体操作过程中，可以根据需要对方法中的步骤进行扩展或合并。
方案1：
Figure PCTCN2017110463-appb-000023
式(I-1)与式(I-2)通过碳-氮偶联反应得到式(I)化合物。芳胺与芳基卤代物的碳-氮偶联可以在以Pd催化剂、适宜的配体和碱、优选叔丁醇钾或叔丁醇钠和PdO-催化的偶联，例如Buchwald-Hartwig反应，得到最终化合物式(I)。原料式(I-1)和式(I-2)化合物可根据具体结构的不同通过市购，或通过本领域技术人员已知的方法制备得到。
式(I-1)化合物可以通过包括以下步骤的方法制备：
Figure PCTCN2017110463-appb-000024
式(1.1)与式(1.2)化合物在加热条件下反应，得到式(1.3)化合物。式(1.3)化合物与式(1.4)化合物在碱性条件下关环得到式(I-1)化合物。
中间体式(1.1)化合物可以通过两种不同的途径得到。在合成路径的方案1中，式(1.1)化合物可以通过包括如下步骤的方法1制备：
方法1
Figure PCTCN2017110463-appb-000025
式(1a.1)化合物与相应的醇反应得到式(1a.2)化合物，式(1a.2)化合物可以通过卤化剂，如N-卤代琥珀酰亚胺，在合适的溶液如二氯甲烷中反应，得到式(1a.3)化合物，式(1a.3)在碱性条件下与脒反应，得到式(1a.5)化合物。可以对式(1.1)化合物进行修饰，如亲核取代、烷基化反应等。
在合成路径的第二项实施方案中，式(1.1)化合物可以通过包括如下步骤的方法2制备：
方法2
Figure PCTCN2017110463-appb-000026
式(1a.1)化合物与酰化物如酰氯反应成酯，得到式(1b.1)化合物，式(1b.1)化合物在碱 性条件下与式(1b.2)化合物反应，得到式(1b.3)化合物，式(1b.3)化合物用卤化试剂如二氯亚砜、三氯氧磷、五氯化磷、草酰氯等，优选草酰氯，卤化得到式(1b.4)化合物，式(1b.4)与式(1b.5)化合物在碱性条件下发生取代反应得到式(1b.6)化合物，式(1b.6)化合物在酸性条件下脱掉保护基，并关环得到式(1.1)化合物。
以上各步骤中的反应均是本领域技术人员已知的常规反应。如无特殊说明，合成路线中所使用的试剂和原料化合物均可市购得到，或本领域技术人员根据所设计的不同化合物结构参考已知方法制备得到。
与现有技术相比，本发明的主要优点在于：
提供了一系列结构新颖的吡啶胺取代的杂三环化合物，其对CDK4/6具有高选择抑制活性，此外还具有较好的脑通透性，可用作广泛癌症治疗的药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本发明中。
如本文所用，DMB为2,4-二甲氧基苄基，THF为四氢呋喃，EA为乙酸乙酯，PE为石油醚，Ac2O为乙酸酐，NBS为N-溴代琥珀酰亚胺，DCM为二氯甲烷，AIBN为偶氮二异丁腈，Pd(dppf)Cl2为1,1'-双(二苯基磷)二茂铁]二氯化钯，TFA为三氟乙酸，TBSCl为叔丁基二甲基氯硅烷，NCS为N-氯代丁二酰亚胺，DHP为二氢吡喃，LiAlH4为氢化铝锂，PMB为对甲氧基苄基，LiHMDS为二(三甲基硅基)氨基锂，Pd2(dba)3为三(二亚苄基丙酮)二钯，RuPhos为2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯,DMAP为4-二甲氨基吡啶，THP为四氢吡喃，n-BuLi为正丁基锂，TMsOTf为三氟甲磺酸三甲基硅酯，TEBAC为三乙基苄基氯化铵，HATU为2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，DMF为二甲基甲酰胺，DMSO为二甲基亚砜，DIEA为N,N-二异丙基乙胺，BINAP为(2R,3S)-2,2'-双二苯膦基-1,1'-联萘。
如本文所用，室温是指约为20-25℃。
中间体1a的制备
Figure PCTCN2017110463-appb-000027
步骤1:化合物1a-1(10g,89mmol)的二氯甲烷(10mL)溶液加入异丁酰氯(11.2g,106mmol)和三乙胺(18g,178mmol)，混合物在室温搅拌2小时。TLC跟踪至反应结束。反应液加水淬灭，二氯甲烷萃取，有机层干燥浓缩后经combiflash(PE/EA＝5:1)纯化得8g化合物1a-2。MS m/z(ESI):N/A。
步骤2:化合物1a-2(8g,43mmol)的二氯甲烷(100mL)溶液在冰浴加入三氯化铝(11.6g,86mmol)，混合物在室温搅拌2小时。TLC跟踪至反应结束。反应液加盐酸淬灭，二氯甲烷萃取，有机层干燥浓缩后经combiflash(PE/EA＝5:1)纯化得2.5g化合物1a-3。MS m/z(ESI):N/A。
步骤3:化合物1a-3(200mg,1.1mmol)的二氯甲烷(5mL)溶液加入草酰氯(276mg,2.2mmol)，混合物在室温搅拌24小时。反应液浓缩后得化合物1a，直接用于下一步。MS m/z(ESI):N/A。
中间体2a的制备
Figure PCTCN2017110463-appb-000028
化合物2a-1(8.74g,58mmol)的乙醇(100mL)溶液在氩气氛围下冰浴时加入Boc2O(12.7g,58mmol)和三乙胺(7.7mL,58mmol，混合物在室温搅拌下24小时。反应液浓缩后经乙酸乙酯/水体系萃取，有机层干燥浓缩得化合物2a，直接用于下一步。MS m/z(ESI):N/A。
中间体3a的制备
Figure PCTCN2017110463-appb-000029
化合物3a-1(3.8g,23mmol)的乙醇(50mL)溶液加入化合物3a.1(2.67g,23mmol)与碳酸钾(4.8g,35mmol)，混合物在65℃搅拌12小时。反应液过滤后浓缩得化合物3a，直接用于下一步反应。MS m/z(ESI):240[M+H]+。
中间体4a的制备
Figure PCTCN2017110463-appb-000030
化合物4a-1(9.6g,50mmol)，N-Boc哌嗪(9.3g,50mmol)的甲苯(60mL)溶液加入Xantphos(1.4g,2.5mmol)，Pd2(dba)3(2.3g,2.5mmol)和叔丁醇钠(7.2g,75mmol)，混合物在氮气氛围下100℃搅拌过夜。LC-MS跟踪至反应完全。反应液过滤，浓缩，经combiflash(PE/EA＝26％)纯化得13.4g化合物4a。MS m/z(ESI):298[M+H]+。
中间体5a的制备
Figure PCTCN2017110463-appb-000031
步骤1:制备方法同化合物1a-2，不同的是将1a-2制法中的化合物1a-1换成化合物5a-1。MS m/z(ESI):169[M+H]+。
步骤2:化合物5a-2(5g,29.8mmol)的乙腈(50mL)溶液加入三乙胺(4.2g,41.7mmol)和5a.1(1g,11.9mmol)，混合物在室温搅拌2天。LC-MS跟踪至反应结束。反应液加盐酸淬灭，乙酸乙酯萃取，有机层干燥浓缩后经combiflash纯化得2.4g化合物5a-3。MS m/z(ESI): 169[M+H]+。
步骤3:制备方法同化合物1a，不同的是将1a制法中的化合物1a-3换成化合物5a-3。MS m/z(ESI):N/A。
步骤4:化合物5a-4(344mg,1.85mmol)的THF(5mL)溶液在冰浴下加入化合物5a.2(270mg,1.85mmol)和三乙胺(374mg,3.7mmol)，混合物室温搅拌20小时。TLC跟踪至反应结束。反应液浓缩后经combiflash纯化得309mg化合物5a-5。MS m/z(ESI):297[M+H]+。
步骤5:化合物5a-5(309mg,1.04mmol)的盐酸/1,4-二氧六环(4mL)溶液室温搅拌24小时。LC-MS跟踪至反应完全。反应液浓缩，加乙酸乙酯溶解，饱和碳酸氢钠洗涤，有机层干燥浓缩得化合物5a-6，直接用于下一步。MS m/z(ESI):179[M+H]+。
步骤6:化合物5a-6(185mg,1.04mmol)的5a.3(3mL)溶液在105℃搅拌1小时。反应液冷却至室温，浓缩后干燥得化合物5a-7，直接用于下一步反应。MS m/z(ESI):234[M+H]+。
步骤7:化合物5a-7(242mg,1.04mmol)与化合物5a.4(998mg,10.4mmol)的乙醇(4mL)溶液加入乙醇钠(707mg,10.4mmol)，混合物在130℃封管搅拌2天。LC-MS跟踪至反应完全。反应液冷却至室温，浓缩后经combiflash纯化得197mg化合物5a。MS m/z(ESI):230[M+H]+。
中间体6a的制备
Figure PCTCN2017110463-appb-000032
步骤1:制备方法同化合物3-2，不同的是将3-2制法中的化合物3-1换成化合物6a-1。MS m/z(ESI):127[M+H]+。
步骤2:制备方法同化合物3-3，不同的是将3-3制法中的化合物3-2换成化合物6a-2。MS m/z(ESI):205[M+H]+。
中间体7a的制备
Figure PCTCN2017110463-appb-000033
化合物6a(2.5g,12mmol)的DMF(20mL)溶液加入化合物7a.1(1.13g,12mmol)与碳酸钾(4.7g,34.2mmol)，混合物在110℃搅拌2小时。TLC跟踪至反应完全。反应液浓缩后经combiflash(DCM:MeOH＝15:1)纯化得900mg化合物7a。MS m/z(ESI):137[M+H]+。
中间体8a的制备
Figure PCTCN2017110463-appb-000034
步骤1:化合物8a-1(6g,53mmol)的THF(15mL)溶液加入钠氢(2.4g,58mmol)，混合物在60℃搅拌3小时。反应液经冰浴冷却，并逐滴加入碘甲烷(15g,106mmol)，混合物室温搅拌3小时。向体系中加饱和食盐水淬灭反应，减压浓缩去除THF，水相经甲基叔丁基醚萃取，有机层浓缩，combiflash(PE:EA＝25:1)纯化得5.8g化合物8a-2。MS m/z(ESI):127[M+H]+。
步骤2:化合物8a-2(4.8g,38mmol)的THF(40mL)溶液在氩气氛围下于冰浴加入 LiHMDS(40mL)，混合物在冰浴下搅拌2分钟，加入化合物8a.1(4.05g,38mmol)，体系缓慢升至室温。反应液经盐酸溶液淬灭，有机层分别由饱和食盐水和无水硫酸钠干燥后浓缩，combiflash(PE:EA＝25:1)纯化得2g化合物8a-3。MS m/z(ESI):197[M+H]+。
步骤3:化合物8a-3(2g,10mmol)的乙醇(10mL)溶液在室温下加入水合肼(10mL)，混合物在90℃搅拌1小时，减压浓缩，得化合物8a-4，,直接用于下一步反应。MS m/z(ESI):193[M+H]+。
步骤4:化合物8a-4(1.8g,9.3mmol)的乙酸(10mL)溶液在室温下加入三氧化铬(1.8g,18.6mmol)，混合物在60℃搅拌30分钟，减压浓缩，残留物加乙酸乙酯溶解，经水、饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液浓缩，combiflash(PE:EA＝1:1)纯化得0.34g化合物8a。MS m/z(ESI):207[M+H]+。
中间体9a的制备
Figure PCTCN2017110463-appb-000035
步骤1:制备方法同化合物1a-2，不同的是将1a-2制法中的化合物1a-1换成化合物9a-1。MS m/z(ESI):211[M+H]+。
步骤2:制备方法同化合物1a-3，不同的是将1a-3制法中的化合物1a-2换成化合物9a-2。
步骤3:制备方法同化合物8a-4，不同的是将8a-4制法中的化合物8a-3换成化合物9a-3。MS m/z(ESI):207[M+H]+。
步骤4:化合物9a-4(4.12g,20mmol)的四氢呋喃(100mL)溶液加入甲醇(1.21mL,30mmol)，PPh3(6.812g,26mmol)，在冰浴下加入DIAD(5.15mL,26mmol)，混合物室温搅拌过夜。LC-MS跟踪至反应完全。反应液加乙酸乙酯稀释，经饱和食盐水洗涤，有机相干燥后浓缩，经combiflash纯化得化合物9a-5。MS m/z(ESI):221[M+H]+。
步骤5:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物9a-5。MS m/z(ESI):276[M+H]+。步骤6:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物9a-6。MS m/z(ESI):272[M+H]+。
中间体10a的制备
Figure PCTCN2017110463-appb-000036
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物8a和碘乙烷。MS m/z(ESI):235[M+H]+。
步骤2:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物55a-6换成化合物10a-1。MS m/z(ESI):290[M+H]+。
步骤3:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物10a-2。MS m/z(ESI):286[M+H]+。
中间体11a的制备
Figure PCTCN2017110463-appb-000037
步骤1:制备方法同化合物8a-3，不同的是将8a-3制法中的化合物8a-2换成化合物11a-1。MS m/z(ESI):169[M+H]+。
步骤2:制备方法同化合物8a-4，不同的是将8a-4制法中的化合物8a-3换成化合物11a-2。MS m/z(ESI):165[M+H]+。
步骤3:制备方法同化合物8a，不同的是将8a制法中的化合物8a-4换成化合物11a-3。MS m/z(ESI):179[M+H]+。
步骤4:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物11a-4和碘甲烷。MS m/z(ESI):193[M+H]+。
步骤5:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物11a-5。MS m/z(ESI):248[M+H]+。
步骤6:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物11a-6。MS m/z(ESI):244[M+H]+。
中间体12a的制备
Figure PCTCN2017110463-appb-000038
步骤1:制备方法同化合物1a，不同的是将1a制法中的化合物1a-3换成化合物9a-3。MS m/z(ESI):229[M+H]+。
步骤2:制备方法同化合物5a-5，不同的是将5a-5制法中的化合物5a-4和化合物5a.2换成化合物12a-1和化合物2a。MS m/z(ESI):353[M+H]+。
步骤3:制备方法同化合物5a-6，不同的是将5a-6制法中的化合物5a-5换成化合物12a-2。MS m/z(ESI):235[M+H]+。
步骤4:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物12a-3。MS m/z(ESI):290[M+H]+。
步骤5:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物12a-4。MS m/z(ESI):286[M+H]+。
中间体13a的制备
Figure PCTCN2017110463-appb-000039
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物30-4和碘乙烷。MS m/z(ESI):209[M+H]+。
步骤2:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物13a-1。MS m/z(ESI):264[M+H]+。
步骤3:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物13a-2。MS m/z(ESI):260[M+H]+。
中间体14a的制备
Figure PCTCN2017110463-appb-000040
步骤1:制备方法同化合物1-2，不同的是将1-2制法中的化合物1-1换成化合物14a-1。MS m/z(ESI):169[M+H]+。
步骤2：在氩气氛围下，化合物14a-2(1g,5.94mmol)的干燥THF(6mL)溶液在0-5℃时逐滴加入LiAlH4(90mg,2.38mmol)。升温至25℃并搅拌4小时。反应液经冰浴冷却，加乙酸乙酯淬灭，缓慢地倒入冷却的H2SO4(2M)溶液中，得到的溶液经甲基叔丁基醚萃取2次，无水硫酸钠干燥后过滤，减压浓缩得粗产品14a-3直接用于下一步反应。MS m/z(ESI):125[M+H]+。
步骤3：化合物14a-3(736mg,5.94mmol)的甲醇(5mL)溶液在0℃时逐滴加入H2O2(3mL,29.63mmol)，得到的混合物在0℃下加入2％的NaOH(1.6mL)溶液。反应液室温搅拌20h。LC-MS跟踪至反应完全。混合物加水稀释，甲基叔丁基醚萃取，合并有机层，分别用5％硫代硫酸钠和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得无色油状化合物14a-4。MSm/z(ESI):141[M+H]+。
步骤4：化合物14a-4(300mg,2.14mmol)于室温下加入KOH(120mg,2.14mmol)的甲醇(4mL)溶液，反应液室温搅拌2天。LC-MS跟踪至反应完全。混合物冷却后加水稀释，甲基叔丁基醚萃取，合并有机层后经饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得黄色油状化合物14a-5。MS m/z(ESI):155[M+H]+。
步骤5:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物14a-5。MS m/z(ESI):210[M+H]+。
步骤6:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7和化合物1.3换成化合物14a-6和化合物14a.1。MS m/z(ESI):221[M+H]+。
步骤7:制备方法同化合物43-3，不同的是将43-3制法中的化合物43-2换成化合物14a-7。MS m/z(ESI):207[M+H]+。
步骤8:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物14a-8。MS m/z(ESI):262[M+H]+。
步骤9:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物14a-9。MS m/z(ESI):258[M+H]+。
中间体15a的制备
Figure PCTCN2017110463-appb-000041
步骤1：制备方法同化合物8a-3，不同的是将8a-3制法中的化合物8a-2换成化合物15a-1。
步骤2：制备方法同化合物8a-4，不同的是将8a-4制法中的化合物8a-3换成化合物15a-2。MS m/z(ESI):179.2[M+H]+。
步骤3：制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物15a-3和碘甲烷。m/z(ESI):193.3[M+H]+。
步骤4：制备方法同化合物8a，不同的是将8a制法中的化合物8a-4换成化合物15a-4。m/z(ESI):207.3[M+H]+。
步骤5:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物15a-5。MS m/z(ESI):262.2[M+H]+。
步骤6:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物15a-6。MS m/z(ESI):258.2[M+H]+。
中间体16a的制备
Figure PCTCN2017110463-appb-000042
步骤1：制备方法同化合物8a-3，不同的是将8a-3制法中的化合物8a-2与异丁酰氯换成化合物1-2和乙酰氯。m/z(ESI):183[M+H]+。
步骤2：制备方法同化合物8a-4，不同的是将8a-4制法中的化合物8a-3换成化合物16a-1。MS m/z(ESI):179[M+H]+。
步骤3：化合物16a-1(391.6mg,2.2mmol)的乙醇(5mL)在室温下逐滴加入盐酸(36％,2mL)，混合物室温搅拌2h。LC-MS跟踪至反应完全。反应液减压浓缩后经combiflash(volume of PE/EA＝40/60)纯化得黄色油状化合物16a-3(133mg,产率40％)。MS m/z(ESI):151[M+H]+。
步骤4：制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物16a-3和溴代环戊烷。m/z(ESI):219[M+H]+。
步骤5:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物 16a-4。MS m/z(ESI):274[M+H]+。
步骤6:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物16a-5。MS m/z(ESI):270[M+H]+。
中间体17a的制备
Figure PCTCN2017110463-appb-000043
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物9a-4和碘甲烷。MS m/z(ESI):221[M+H]+。
步骤2:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物17a-1。MS m/z(ESI):276[M+H]+。
步骤3:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物17a-2。MS m/z(ESI):272[M+H]+。
中间体18a的制备
Figure PCTCN2017110463-appb-000044
步骤1:制备方法同化合物1a，不同的是将1a制法中的化合物1a-3换成化合物18a-1。MS m/z(ESI):227[M+H]+。
步骤2:制备方法同化合物5a-5，不同的是将5a-5制法中的化合物5a-4换成化合物18a-2。MS m/z(ESI):337[M+H]+。
步骤3:制备方法同化合物5a-6，不同的是将5a-6制法中的化合物5a-5换成化合物18a-3。MS m/z(ESI):219[M+H]+。
步骤4:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物18a-4。MS m/z(ESI):274[M+H]+。
步骤5:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物18a-5。MS m/z(ESI):270[M+H]+。
中间体19a的制备
Figure PCTCN2017110463-appb-000045
步骤1:KOH(14.98g,267.6mmol)的水(3.6mL)与乙醇(67mL)溶液在0℃时加入化合物19a-1(38g,267.6mmol),2min后加入TME,混合物搅拌15min，过滤，滤饼先后用冰乙醇和TME洗涤，干燥得化合物19a-2(46.7g,产率97％)。
步骤2：化合物19a-2(46.7g,259mmol)和1,2-二溴乙烷的DMSO(376mL)溶液室温搅拌2天。混合物加水，石油醚萃取，无水硫酸钠干燥，减压浓缩后经combiflash纯化得化合物 19a-3(26g,产率41％)。MS m/z(ESI):249[M+H]+。
步骤3：化合物19a-3(9g,36.3mmol)的HBr(40mL)溶液加热回流2h。混合物加水，乙酸乙酯萃取，有机层分别经水、饱和碳酸氢钠与饱和食盐水洗涤后，减压浓缩，经combiflash纯化得化合物19a-4(4g,产率58％)。MS m/z(ESI):249[M+H]+。
步骤4：化合物19a-4(1g,5.3mmol)与K2CO3(2.2g,15.8mmol)的乙醇(18mL)溶液加热回流3h。混合物加水，石油醚萃取，有机层经无水硫酸钠干燥后，减压浓缩得化合物19a-5直接用于下一步反应。
步骤5：制备方法同化合物8a-3，不同的是将8a-3制法中的化合物8a-2换成化合物19a-5。
步骤6：制备方法同化合物8a-4，不同的是将8a-4制法中的化合物8a-3换成化合物19a-6。MS m/z(ESI):177[M+H]+。
步骤7：制备方法同化合物8a，不同的是将8a制法中的化合物8a-4换成化合物19a-7。m/z(ESI):191[M+H]+。
步骤8：制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物19a-8和碘甲烷。m/z(ESI):205[M+H]+。
步骤9:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物19a-9。MS m/z(ESI):260[M+H]+。
步骤10:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物19a-10。MS m/z(ESI):256[M+H]+。
中间体20a的制备
Figure PCTCN2017110463-appb-000046
步骤1：制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物20a-1和化合物20a.1。m/z(ESI):345[M+H]+。
步骤2：制备方法同化合物65-3，不同的是将65-3制法中的化合物65-2换成化合物20a-2。m/z(ESI):316[M+H]+。
步骤3：制备方法同化合物65-7，不同的是将65-7制法中的化合物65-6和丙酮换成化合物20a-3和甲醛。m/z(ESI):330[M+H]+。
步骤4：化合物20a-4(1.2g,3.6mmol)的三氟乙酸(10mL)溶液，室温搅拌4h。LC-MS跟踪至反应结束。反应液浓缩得化合物20a-5，直接用于下一步反应。MS m/z(ESI):184[M+H]+。
步骤5：制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物20a-5和化合物20a.2。m/z(ESI):254[M+H]+。
步骤6:化合物20a-6(650mg,2.6mmol)加入三氯氧磷(30mL)，混合物在120℃搅拌2h， 反应液浓缩得化合物20a-7，直接用于下一步反应。m/z(ESI):292[M+H]+。
步骤7：制备方法同化合物8a-4，不同的是将8a-4制法中的化合物8a-3换成化合物20a-7。经combiflash纯化得50mg化合物20a。m/z(ESI):250[M+H]+。
中间体21a的制备
Figure PCTCN2017110463-appb-000047
步骤1:制备方法同化合物3-3，不同的是将3-3制法中的化合物3-2换成化合物55-2。MS m/z(ESI):263[M+H]+。
步骤2:化合物21a-1(2.5g,9.5mmol)中加入化合物21a.1(5mL)，混合物在180℃微波30min。反应液浓缩后经combiflash纯化得化合物21a-2(1g,产率52％)。MS m/z(ESI):209[M+H]+。
步骤3:制备方法同化合物8a，不同的是将8a制法中的化合物8a-4换成化合物21a-2。MS m/z(ESI):223[M+H]+。
步骤4:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4换成化合物21a-3。MS m/z(ESI):265[M+H]+。
步骤5:制备方法同化合物5a-7，不同的是将5a-7制法中的化合物5a-6换成化合物21a-4。MS m/z(ESI):320[M+H]+。
步骤6:制备方法同化合物5a，不同的是将5a制法中的化合物5a-7换成化合物21a-5。MS m/z(ESI):316[M+H]+。
实施例1：N-(5-(哌嗪-1-基)吡啶-2-基)-1-(四氢-2H-吡喃-4-基)-4,5-二氢-1氢-吡唑并[4,3-H]喹唑啉-8-胺(化合物P-1)的制备
Figure PCTCN2017110463-appb-000048
步骤1:化合物1-1(15g,134mmol)的乙醇(260mL)与甲苯(150mL)溶液加入1.1g TsOH，混合物在110℃搅拌过夜。反应液冷却至室温，浓缩后经combiflash(PE/EA＝20％)纯化得17g化合物1-2。MS m/z(ESI):141[M+H]+。
步骤2:化合物1-2(17g,121mmol)加入60mL 1.1，混合物在110℃搅拌2小时。反应 液冷却至室温，浓缩后干燥得化合物1-3，直接用于下一步反应。MS m/z(ESI):196[M+H]+。
步骤3:化合物1-3(20g,103mmol)的乙醇(200mL)溶液加入水合肼(6g,103mmol)，混合物在80℃搅拌过夜。反应液冷却至室温，浓缩后经combiflash(PE/EA＝37％)纯化得8.4g化合物1-4。MS m/z(ESI):137[M+H]+。
步骤4:化合物1-4(500mg,3.67mmol)，化合物1.2(750mg,7.35mmol)，PPh3(1.9g,7.35mmol)的四氢呋喃(15mL)溶液，在冰浴下加入DIAD(1.5g,7.35mmol)，混合物室温搅拌过夜。LC-MS跟踪至反应完全。反应液浓缩后经combiflash(PE/EA＝25％)纯化得200mg化合物1-5。MS m/z(ESI):221[M+H]+。
步骤5:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物1-5。MS m/z(ESI):276[M+H]+。
步骤6:化合物1-6(220mg,0.8mmol)与化合物1.3(800mg,8mmol)的乙醇(8mL)溶液加入乙醇钠(560mg,8mmol)，混合物在130℃搅拌过夜。LC-MS跟踪至反应完全。反应液冷却至室温，浓缩后经combiflash(PE/EA＝26％)纯化得130mg化合物1-7。MS m/z(ESI):273[M+H]+。
步骤7:化合物1-7(130mg,0.48mmol)，4a(150mg,0.48mmol)的1,4-二氧六环(5mL)溶液加入Xantphos(14mg,0.024mmol)，Pd2(dba)3(22mg,0.024mmol)和叔丁醇钠(95mg,0.96mmol)，混合物在氮气氛围下150℃微波反应45分钟。LC-MS跟踪至反应完全。反应液过滤，浓缩，经combiflash(DCM/MeOH＝30％)纯化得90mg化合物1-8。MS m/z(ESI):533[M+H]+。
步骤8：化合物1-8(90mg,0.169mmol)的二氯甲烷(5mL)溶液加入三氟乙酸2mL，混合物室温搅拌30分钟。LC-MS跟踪至反应结束。反应液浓缩，经Prep-HPLC纯化得白色固体化合物P-1(27.3mg,37％)。MS m/z(ESI):433[M+H]+；1H NMR(400MHz,CDCl3)9.92(s,1H),8.73(s,2H),8.36(s,1H),8.02-8.03(d,1H),7.88-7.90(d,1H),7.52-7.55(t,1H),7.44(s,1H),5.67-5.72(m,1H),3.87-3.91(m,2H),3.42-3.47(t,2H),3.24-3.33(t,8H),2.68-2.76(m,4H),1.96-2.06(m,2H),1.81-1.83(d,2H).
实施例2：8-乙基-N-(5-((4-甲基哌嗪-1-基)甲基)吡啶-2-基)-9-异丙基-6,8-二氢-5H-吡唑并[3,4-H]喹啉-2-胺(化合物P-2)的制备
Figure PCTCN2017110463-appb-000049
步骤1:化合物1a(5.5g,27mmol)的THF(100mL)溶液在-35℃加入化合物2a(4.4g,27mmol)和三乙胺(5.5g,54mmol)，混合物室温搅拌24小时。TLC跟踪至反应结束。反应液浓缩后经combiflash(PE:EA＝5:1)纯化得4.6g化合物2-1。MS m/z(ESI):N/A。
步骤2:化合物2-1(4.6g,14.1mmol)的1,4-二氧六环(12mL)溶液加入盐酸/1,4-二氧六环(20mL)，混合物室温搅拌24小时。LC-MS跟踪至反应完全。反应液浓缩，加二氯甲烷溶解，分别用氢氧化钠(1N)和饱和食盐水洗涤，干燥浓缩得化合物2-2。MS m/z(ESI):207[M+H]+。
步骤3:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物2-2。MS m/z(ESI):207[M+H]+。
步骤4:化合物2-3(3.3g,12.6mmol)的乙醇(20mL)溶液加入化合物1.3(12.8g,126mmol)和乙醇钠(9g,126mmol)，混合物在110℃封管搅拌16小时。LC-MS跟踪至反应完全。反应液浓缩后经combiflash(PE:EA＝3:1)纯化得1.7g化合物2-4。MS m/z(ESI):258[M+H]+。
步骤5:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7与4a换成化合物2-4与3a。经Prep-HPLC纯化得白色固体化合物P-2(52mg,67％)。MS m/z(ESI):461[M+H]+；1H NMR(400MHz,DMSO)δ9.24(s,1H),8.22(s,1H),8.11(d,1H),8.08(d,1H),7.60(dd,1H),4.13(q,2H),3.92(dt,1H),3.39(s,2H),2.77(t,2H),2.67(t,2H),2.45-2.15(m,10H),1.38(d,6H),1.32(t,3H),0.94(t,3H).
实施例3：2-乙基-N-(5-((4-甲基哌嗪-1-基)甲基)吡啶-2-基)-1-异丙基-4,5-二氢-1H-咪唑并[4,5-H]喹唑啉-8-胺(化合物P-3)的制备
Figure PCTCN2017110463-appb-000050
步骤1:制备方法同化合物1-2，不同的是将1-2制法中的化合物1-1换成化合物3-1。MS m/z(ESI):N/A。
步骤2:化合物3-2(3g,21mmol)的二氯甲烷(30mL)溶液加入NBS(4.2g,23mmol)，混合物室温搅拌2小时。LC-MS跟踪至反应完全。反应液浓缩后经combiflash(PE:EA＝3:1)纯化得3.5g化合物3-3。MS m/z(ESI):219[M+H]+。
步骤3:化合物3-3(2.5g,11.4mmol)的DMF(20mL)溶液加入化合物3.1(1.25g,11.4mmol)与碳酸钾(5.7g,34.2mmol)，混合物在110℃搅拌2小时。TLC跟踪至反应完全。反应液浓缩后经combiflash(DCM:MeOH＝15:1)纯化得900mg化合物3-4。MS m/z(ESI):N/A。
步骤4:化合物3-4(125mg,0.08mmol)的DMF(10mL)溶液加入钠氢(91mg,0.24mmol)和2-碘丙烷(388mg,0.24mmol)中，混合物在80℃搅拌2小时。LC-MS跟踪至反应完全。反应液加氯化铵淬灭，浓缩后经combiflash(DCM:MeOH＝20:1)纯化得60mg化合物3-5。MS m/z(ESI):207[M+H]+。
步骤5:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物3-5。MS m/z(ESI):262[M+H]+。
步骤6:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物3-6。MS m/z(ESI):258[M+H]+。
步骤7:制备方法同化合物P-2，不同的是将P-2制法中的化合物1-8换成化合物3-7。经Prep-HPLC纯化得白色固体化合物P-3(62mg,62％)。MS m/z(ESI):461[M+H]+。1H NMR(400MHz,DMSO)δ9.42(s,1H),8.18(s,1H),8.12(d,1H),8.02(d,1H),7.61(dd,1H),5.76-5.68(m,1H),3.38(s,2H),2.77(q,4H),2.65(t,2H),2.44-2.18(m,10H),1.50(d,6H),1.24(t,3H),0.94(t,3H).
实施例4：8-乙基-9-异丙基-N-(5-(哌嗪-1-基)吡啶-2-基)-6,8-二氢-5H-吡唑并[3,4-H]喹啉-2-胺(化合物P-4)的制备
Figure PCTCN2017110463-appb-000051
步骤1:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物2-4。MS m/z(ESI):519[M+H]+。
步骤2:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物4-1。得白色固体化合物P-4(1.3g,81％)。MS m/z(ESI):419[M+H]+；1H NMR(400MHz,DMSO)δ8.91(s,1H),8.17(s,1H),7.93(d,1H),7.92(s,1H),7.35(dd,1H),4.12(q,2H),3.89(dt,1H),3.03-2.89(m,4H),2.80(dd,4H),2.78-2.70(m,2H),2.70-2.56(m,2H),1.37(d,6H),1.31(t,3H).
实施例5：
Figure PCTCN2017110463-appb-000052
步骤1:制备方法同化合物3-4，不同的是将3-4制法中的化合物3-3换成化合物6a。MS m/z(ESI):N/A。
步骤2:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4换成化合物5-1。MS m/z(ESI):193[M+H]+。
步骤3:制备方法同化合物3-6，不同的是将3-6制法中的化合物3-5换成化合物5-2。MS m/z(ESI):248[M+H]+。
步骤4:制备方法同化合物3-7，不同的是将3-7制法中的化合物3-6换成化合物5-3。MS m/z(ESI):244[M+H]+。
步骤5:制备方法同化合物P-3，不同的是将P-3制法中的化合物3-7换成化合物5-4。经Prep-HPLC纯化得白色固体化合物P-5(13mg,14％)。MS m/z(ESI):447[M+H]+；1H NMR(400MHz,DMSO)δ9.44(s,1H),8.35-8.33(m,2H),8.15(s,1H),7.67(d,1H),4.66-4.63(m,1H),3.49(s,2H),3.42(s,2H),2.86(q,2H),2.49-2.26(m,10H),1.65(d,6H),1.27(t,3H),0.97(t,3H).
实施例6：
Figure PCTCN2017110463-appb-000053
制备方法同化合物P-3，不同的是将P-3制法中的化合物3-7换成化合物5a。经Prep-HPLC纯化得白色固体化合物P-6(14mg,11.2％)。MS m/z(ESI):433[M+H]+；1H NMR(400MHz,DMSO)δ9.37(s,1H),8.38(s,1H),8.23(d,1H),8.14(s,1H),7.63(d,1H),3.90(s,3H), 3.62(s,2H),3.42(s,2H),3.30-3.25(m,1H),2.40-2.26(m,10H),1.48(d,6H),0.97(t,3H).
实施例7：
Figure PCTCN2017110463-appb-000054
步骤1:制备方法同化合物4a，不同的是将4a制法中的化合物N-Boc哌嗪换成化合物7.1。MS m/z(ESI):226[M+H]+。
步骤2:制备方法同化合物P-6，不同的是将P-6制法中的化合物3a换成化合物7-2。经Prep-HPLC纯化得白色固体化合物P-7(358mg,47％)。MS m/z(ESI):419[M+H]+；1HNMR(400MHz,DMSO)δ9.(s,1H),8.33(s,1H),8.19(d,1H),7.97(s,1H),7.40(d,1H),3.89(s,3H),3.59(s,2H),3.30-3.27(m,1H),3.12-3.09(m,4H),2.54-2.47(m,4H),2.37(q,2H),1.48(d,6H),1.03(t,3H).
实施例8：
Figure PCTCN2017110463-appb-000055
步骤1:制备方法同化合物P-6，不同的是将P-6制法中的化合物3a换成化合物4a。MSm/z(ESI):491[M+H]+。
步骤2:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物8-1。经Prep-HPLC纯化得白色固体化合物P-8(965mg,59％)。MS m/z(ESI):391[M+H]+；1H NMR(400MHz,DMSO)δ9.09(s,1H),8.33(s,1H),8.18(d,1H),7.96(s,1H),7.38(d,1H),3.89(s,3H),3.60(s,2H),3.30-3.25(m,1H),3.05-3.27(m,4H),2.91-2.84(m,4H),1.48(d,6H).
实施例9：1-环戊基-N-(5-(哌嗪-1-基)吡啶-2-基)-4,5-二氢-1H-吡唑并[4,3H]喹唑啉-8-胺(化合物P-9)的制备
Figure PCTCN2017110463-appb-000056
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4与2-碘丙烷换成化合物1-4与9.1。MS m/z(ESI):205[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物9-1。 MS m/z(ESI):260[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物9-2。MS m/z(ESI):256[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物9-3。MS m/z(ESI):517[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物9-4。经Prep-HPLC纯化得白色固体化合物P-9(23mg,3％)。MS m/z(ESI):417[M+H]+；1H NMR(400MHz,CDCl3)9.49(s,1H),8.33(s,1H),7.95-7.96(d,1H),7.84-7.87(d,1H),7.32-7.39(m,2H),6.01-6.09(m,1H),2.97-3.00(t,4H),2.82-2.83(d,4H),2.72-2.77(t,2H),2.66-2.69(t,2H),2.02(s,2H),1.81-1.92(m,4H),1.60-1.61(d,2H).
实施例10：N-(5-((4-甲基哌嗪-1-基)甲基)吡啶-2-基)-1-异丙基-4,5-二氢-1H-吡唑并[4,3H]喹唑啉-8-胺(化合物P-10)的制备
Figure PCTCN2017110463-appb-000057
制备方法同化合物P-3，不同的是将P-3制法中的化合物3-7换成化合物10-1。经Prep-HPLC纯化得白色固体化合物P-10(10mg,11.6％)。MS m/z(ESI):433[M+H]+；1H NMR(400MHz,CDCl3)δ9.77(s,1H),8.39(s,1H),8.14(s,1H),8.02-8.04(d,1H),7.62-7.64(m,1H),7.42(s,1H),5.90-5.97(m,1H),3.40(s,2H),2.77-2.79(d,2H),2.69-2.71(d,2H)2.25-2.31(m,10H),1.39-1.40(d,6H),0.92-0.96(t,3H).
实施例11：
Figure PCTCN2017110463-appb-000058
步骤1:化合物7a(400mg,3mmol)的二氯乙烷(30mL)溶液加入环丙基硼酸(480mg,6mmol)，醋酸铜(560mg,3mmol)，2,2’-联吡啶(440mg,3mmol)和碳酸钾(800mg,6mmol)，混合物在70℃搅拌4小时。LC-MS跟踪至反应完全。反应液浓缩后经combiflash(DCM:MeOH＝20:1)纯化得130mg化合物11-2。MS m/z(ESI):177[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物11-1。MS m/z(ESI):231[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物11-2。MS m/z(ESI):228[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物11-3。MS m/z(ESI):489[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物11-4。经Prep-HPLC纯化得白色固体化合物P-11(13mg,55％)。MS m/z(ESI):389[M+H]+；1H NMR(400MHz,DMSO)δ9.06(s,1H),8.26(d,1H),8.24(s,1H),7.92(d,1H),7.41(dd,1H),3.49-3.39(m,1H),3.38(s,2H),3.02-2.96(m,4H),2.86-2.76(m,4H),2.50(s,3H),1.29-1.15(m,4H).
实施例12：N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-1-异丙基-4,5-二氢-1H-吡唑并[4,3H]喹唑啉-8-胺(化合物P-12)的制备
Figure PCTCN2017110463-appb-000059
制备方法同化合物P-3，不同的是将P-3制法中的化合物3-7与3a换成化合物10-1与7-2。经Prep-HPLC纯化得白色固体化合物P-10(5mg,6％)。MS m/z(ESI):419[M+H]+；1H NMR(400MHz,CDCl3)δ9.44(s,1H),8.33(s,1H),7.96(s,1H),7.88-7.90(d,1H),7.38-7.41(m,2H),5.87-5.94(m,1H),3.08-3.11(d,4H),2.75-2.77(d,2H),2.48-2.50(d,4H),2.34-2.38(m,2H),1.38-1.40(d,6H),0.99-1.02(t,3H).
实施例13：
Figure PCTCN2017110463-appb-000060
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4与2-碘丙烷换成化合物7a与溴戊烷。MS m/z(ESI):205[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物13-1。MS m/z(ESI):260[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物13-2。MS m/z(ESI):256[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物13-3。MS m/z(ESI):517[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物13-4。经Prep-HPLC纯化得白色固体化合物P-13(313mg,64％)。MS m/z(ESI):417[M+H]+；1H NMR(400MHz,DMSO)δ9.08(s,1H),8.24(s,1H),8.00-7.95(m,2H),7.34(dd,1H),4.61-4.55(m,1H),3.41(s,2H),3.00-2.98(m,4H),2.84-2.83(m,4H),2.48-2.47(m,3H),2.25-2.22(m,2H),2.01-1.97(m,5H),1.66-1.64(m,2H).
实施例14：9-异丙基-8-甲基-N-(5-(哌嗪-1-基)吡啶-2-基)-6,8-二氢-5H-吡唑并[3,4-H] 喹啉-2-胺(化合物P-14)的制备
Figure PCTCN2017110463-appb-000061
步骤1:制备方法同化合物2-1，不同的是将2-1制法中的化合物2a换成化合物14.1。MS m/z(ESI):313[M+H]+。
步骤2:制备方法同化合物2-2，不同的是将2-2制法中的化合物2-1换成化合物14-1。MS m/z(ESI):193[M+H]+。
步骤3:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物14-2。MS m/z(ESI):248[M+H]+。
步骤4:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物14-3。MS m/z(ESI):244[M+H]+。
步骤5:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物14-4。MS m/z(ESI):505[M+H]+。
步骤6:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物14-5。经Prep-HPLC纯化得白色固体化合物P-14(280mg,87％)。MS m/z(ESI):405[M+H]+；1H NMR(400MHz,DMSO)δ8.97(s,1H),8.17(s,1H),7.95(d,1H),7.92(d,1H),7.35(dd,1H),3.99(dt,1H),3.81(s,3H),3.06-2.92(m,4H),2.89-2.78(m,4H),2.74(t,2H),2.65(t,2H),1.35(d,6H).
实施例15：
Figure PCTCN2017110463-appb-000062
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4与2-碘丙烷换成化合物7a与碘乙烷。MS m/z(ESI):165[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物15-1。MS m/z(ESI):219[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物15-2。MS m/z(ESI):216[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物15-3。MS m/z(ESI):477[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物15-4。经Prep-HPLC纯化得白色固体化合物P-15(19mg,50％)。MS m/z(ESI):377[M+H]+；1H NMR(400MHz,DMSO)δ9.07(s,1H),8.24(s,1H),8.16(d,1H),7.93(s,1H),7.39(d,1H),4.20(q,2H),3.41(s,2H),3.05(s,4H),2.91(s,4H),2.44(s,3H),1.46(t,3H).
实施例16：
Figure PCTCN2017110463-appb-000063
步骤1:制备方法同化合物1-4，不同的是将1-4制法中的化合物1-3换成化合物5a-3。MS m/z(ESI):165[M+H]+。
步骤2:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4与2-碘丙烷换成化合物16-1与碘甲烷。MS m/z(ESI):179[M+H]+。
步骤3:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物16-2。MS m/z(ESI):234[M+H]+。
步骤4:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物16-3。MS m/z(ESI):230[M+H]+。
步骤5:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物16-4。MS m/z(ESI):491[M+H]+。
步骤6:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物16-5。经Prep-HPLC纯化得白色固体化合物P-16(14mg,23％)。MS m/z(ESI):391[M+H]+；1H NMR(400MHz,DMSO)δ9.04(s,1H),8.30(s,1H),8.22(d,1H),7.95(s,1H),7.38(d,1H),3.81(s,3H),3.71(s,2H),3.09-3.04(m,1H),3.02-3.98(m,4H),2.89-2.81(m,4H),1.41(d,6H).
实施例17：
Figure PCTCN2017110463-appb-000064
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4换成化合物16-1。MS m/z(ESI):207[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物17-1。MS m/z(ESI):262[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物17-2。MS m/z(ESI):258[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物17-3。MS m/z(ESI):519[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物17-4。经Prep-HPLC纯化得白色固体化合物P-15(35mg,50％)。MS m/z(ESI):419[M+H]+；1H NMR(400MHz,DMSO)δ9.10(s,1H),8.30(s,1H),8.25(d,1H),7.99(s,1H),7.41(d,1H),4.55-4.45(m,1H),3.82(s,2H),3.12-3.05(m,5H),2.98-2.93(m,4H),1.47(d,6H),1.41(d,6H).
实施例18：
Figure PCTCN2017110463-appb-000065
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4换成化合物16-1。MS m/z(ESI):193[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物18-1.2。MS m/z(ESI):248[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物18-2。MS m/z(ESI):244[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物18-3。MS m/z(ESI):505[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物18-4。经Prep-HPLC纯化得白色固体化合物P-18(30mg,50％)。MS m/z(ESI):405[M+H]+；1H NMR(400MHz,DMSO)δ9.17(s,1H),8.34(s,1H),8.23(d,1H),7.99(s,1H),7.41(d,1H),4.23(q,2H),3.61(s,2H),3.31-3.27(m,1H),3.13-3.07(m,4H),2.99-2.94(m,4H),1.49(d,6H),1.37(t,3H).
实施例19：
Figure PCTCN2017110463-appb-000066
步骤1:制备方法同化合物13，不同的是将13制法中的化合物1-2换成化合物18-1.1。MS m/z(ESI):248[M+H]+。
步骤2:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物19-1。MS m/z(ESI):244[M+H]+。
步骤3:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物19-2。MS m/z(ESI):505[M+H]+。
步骤4:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物19-3。 经Prep-HPLC纯化得白色固体化合物P-19(8mg,36％)。MS m/z(ESI):405[M+H]+；1H NMR(400MHz,DMSO)δ9.11(s,1H),8.31(s,1H),8.24(d,1H),7.97(s,1H),7.39(d,1H),4.13(q,2H),3.76(s,2H),3.10-3.06(m,1H),3.03-2.97(m,4H),2.89-2.83(m,4H),1.45-1.38(m,9H).
实施例20：
Figure PCTCN2017110463-appb-000067
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-换成化合物7a。MS m/z(ESI):179[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物20-1。MS m/z(ESI):233[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物20-2。MS m/z(ESI):230[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物20-3。MS m/z(ESI):491[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物20-4。经Prep-HPLC纯化得白色固体化合物P-20(7mg,30％)。MS m/z(ESI):391[M+H]+；1H NMR(400MHz,DMSO)δ9.07(s,1H),8.24(s,1H),8.17(d,1H),7.93(s,1H),7.40(d,1H),4.77-4.44(m,1H),3.41(s,2H),3.01(s,4H),2.86(s,4H),2.45(s,3H),1.61(d,6H).
实施例21：
Figure PCTCN2017110463-appb-000068
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4与2-碘丙烷换成化合物5-1与2-碘乙烷。MS m/z(ESI):179[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物21-1。MS m/z(ESI):233[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物21-2。MS m/z(ESI):230[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物21-3。MS m/z(ESI):491[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物21-4。经Prep-HPLC纯化得白色固体化合物P-21(6.9mg,10％)。MS m/z(ESI):391[M+H]+；1H NMR(400MHz,CDCl3)δ8.32(d,1H),8.23(s,1H),7.96(d,1H),7.64(s,1H),7.31(dd,1H),4.24(q,2H),3.48(s,2H),3.11-3.05(m,8H),2.83(q,1H),1.62-1.55(m,3H),1.41(t,3H).
实施例22：
Figure PCTCN2017110463-appb-000069
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4换成化合物5-4。MS m/z(ESI):193[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物22-1。MS m/z(ESI):248[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物22-2。MS m/z(ESI):244[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物22-3。MS m/z(ESI):505[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物22-4。经Prep-HPLC纯化得白色固体化合物P-22(180mg,45％)。MS m/z(ESI):405[M+H]+；1H NMR(400MHz,DMSO)δ9.10(s,1H),8.31-8.11(m,2H),7.93(d,1H),7.39(dd,1H),4.61(t,1H),3.43(s,2H),3.03-2.94(m,3H),2.85-2.75(m,5H),1.62(d,5H),1.24(t,3H).
实施例23：2-乙基-1-异丙基-N-(5-(哌嗪-1-基)吡啶-2-基)-4,5-二氢-1H-咪唑并[4,5-H]喹啉-8-胺(化合物P-23)的制备
Figure PCTCN2017110463-appb-000070
步骤1:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物3-7。MS m/z(ESI):519[M+H]+。
步骤2:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物23-1。经Prep-HPLC纯化得白色固体化合物P-23(7mg,17％)。MS m/z(ESI):419[M+H]+；1H NMR(400MHz,DMSO)δ9.10(s,1H),8.13(s,1H),7.92(d,1H),7.87(d,1H),7.36(dd,1H),5.69(m,1H),3.01-2.95(m,4H),2.83-2.80(m,4H),2.77-2.73(m,4H),2.64(t,2H),1.49(d,6H),1.24(t,3H).
实施例24：1-异丙基-2-甲基-N-(5-(哌嗪-1-基)吡啶-2-基)-4,5-二氢-1H-咪唑并[4,5-H]喹啉-8-胺(化合物P-24)的制备
Figure PCTCN2017110463-appb-000071
步骤1:制备方法同化合物3-4，不同的是将3-4制法中的化合物3.1换成化合物24.1。MS m/z(ESI):151[M+H]+。
步骤2:制备方法同化合物3-4，不同的是将3-5制法中的化合物3-4换成化合物24-1。MS m/z(ESI):193[M+H]+。
步骤3:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物24-2。MS m/z(ESI):248[M+H]+。
步骤4:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物24-3。MS m/z(ESI):244[M+H]+。
步骤5:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物24-4。MS m/z(ESI):505[M+H]+。
步骤6:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物24-5。经Prep-HPLC纯化得白色固体化合物P-24(70mg,6％)。MS m/z(ESI):405[M+H]+；1H NMR(400MHz,CDCl3)9.17(s,1H),8.13(s,1H),7.95-7.96(d,1H),7.89-7.91(d,1H),7.38-7.41(m,2H),5.78(s,1H),3.10-3.11(d,4H),2.98-3.01(d,4H),2.73-2.77(t,2H),2.60-2.64(t,2H),2.43(s,3H),1.38-1.40(d,6H).
实施例25：1-异丙基-N-(5-(哌嗪-1-基)吡啶-2-基)-4,5-二氢-1H-吡唑并[4,3H]喹唑啉-8-胺(化合物P-25)的制备
Figure PCTCN2017110463-appb-000072
步骤1:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物10-1。MS m/z(ESI):491[M+H]+。
步骤2:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物25-1。经Prep-HPLC纯化得白色固体化合物P-25(580mg,58％)。MS m/z(ESI):391[M+H]+；1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.17(d,1H),8.02(d,1H),7.98(s,1H),7.41(s,1H),7.29(dd,1H),5.91-5.87(m,1H),3.13-3.06(m,8H),2.84-2.76(m,4H),1.55(d,6H).
实施例26：9-异丙基-N-(5-(哌嗪-1-基)吡啶-2-基)-6,8-二氢-5H-吡唑并[3,4-H]喹啉-2-胺(化合物P-26)的制备
Figure PCTCN2017110463-appb-000073
步骤1:制备方法同化合物1-4，不同的是将1-4制法中的化合物1-3换成化合物5a-3。MS m/z(ESI):165[M+H]+。
步骤2:制备方法同化合物3-4，不同的是将3-5制法中的化合物3-4与2-碘甲烷换成化合物26-1与SEM-Cl。MS m/z(ESI):295[M+H]+。
步骤3:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物26-2。MS m/z(ESI):350[M+H]+。
步骤4:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物26-3。MS m/z(ESI):346[M+H]+。
步骤5:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物26-4。MS m/z(ESI):607[M+H]+。
步骤6:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物26-5。经Prep-HPLC纯化得白色固体化合物P-25(15mg,24％)。MS m/z(ESI):377[M+H]+；1H NMR(400MHz,DMSO)δ9.02(s,2H),8.44(s,1H),8.02(s,1H),7.90(d,1H),7.51(d,1H),3.84(s,2H),3.40-3.30(m,9H),1.45-1.38(m,6H).
实施例27：8-(二氟甲基)-9-异丙基-N-(5-(哌嗪-1-基)吡啶-2-基)-6,8-二氢-5H-吡唑并[3,4-H]喹啉-2-胺(化合物P-27)的制备
Figure PCTCN2017110463-appb-000074
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4与2-碘丙烷换成化合物26-1与二氟氯乙酸钠。MS m/z(ESI):215[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物27-1。MS m/z(ESI):270[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物27-2。MS m/z(ESI):266[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物27-3。 MS m/z(ESI):527[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物27-4。经Prep-HPLC纯化得白色固体化合物P-27(15mg,22％)。MS m/z(ESI):427[M+H]+；1H NMR(400MHz,DMSO)δ11.16(s,1H),9.07(s,2H),8.60(s,1H),8.21-8.02(m,2H),7.94(d,1H),7.80(d,1H),3.89(s,2H),3.57-3.52(m,1H),3.40-3.34(m,4H),3.33-3.28(m,4H),1.53(d,6H).
实施例28：
Figure PCTCN2017110463-appb-000075
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4与2-碘丙烷换成化合物7a与溴甲基环丙烷。MS m/z(ESI):191[M+H]+。
步骤2:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物28-1。MS m/z(ESI):246[M+H]+。
步骤3:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物28-2。MS m/z(ESI):242[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物28-3。MS m/z(ESI):503[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物28-4。经Prep-HPLC纯化得白色固体化合物P-28(6mg,16％)。MS m/z(ESI):403[M+H]+。1H NMR(400MHz,DMSO)δ9.14(s,1H),8.26(s,1H),8.11(d,1H),7.95(d,1H),7.38(dd,1H),4.07(d,2H),3.43(s,2H),3.05(s,4H),2.92(s,4H),2.50(s,3H),1.44(d,1H),0.49(d,4H).
实施例29：9-异丙基-N-(5-(哌嗪-1-基)吡啶-2-基)-6,8-二氢-5H-吡唑并[3,4-H]喹啉-2-胺(化合物P-29)的制备
Figure PCTCN2017110463-appb-000076
步骤1:制备方法同化合物14-1，不同的是将14-1制法中的化合物1a与14.1换成化合物1a-3与水合肼。MS m/z(ESI):179[M+H]+。
步骤2:制备方法同化合物3-4，不同的是将3-5制法中的化合物3-4与2-碘甲烷换成化合物29-1与SEM-Cl。MS m/z(ESI):309[M+H]+。
步骤3:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物29-2。MS m/z(ESI):364[M+H]+。
步骤4:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物29-3。MS m/z(ESI):360[M+H]+。
步骤5:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物29-4。MS m/z(ESI):621[M+H]+。
步骤6:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物29-5。经Prep-HPLC纯化得白色固体化合物P-29(48mg,54.5％)。MS m/z(ESI):391[M+H]+；1H NMR(400MHz,CDCl3)δ12.76(s,1H),9.47(s,1H),8.75(s,2H),8.19(s,1H),8.10(s,1H),7.98-7.99(d,2H),7.50-7.52(d,1H),3.82-3.84(d,1H),3.25-3.28(d,8H),2.75-2.81(m,4H),1.26-1.29(d,6H).
实施例30：
Figure PCTCN2017110463-appb-000077
步骤1:制备方法同化合物1a-2，不同的是将1a-2制法中的化合物1a-1换成化合物30-1。MS m/z(ESI):185[M+H]+。
步骤2:制备方法同化合物1a-3，不同的是将1a-3制法中的化合物1a-2换成化合物30-2。MS m/z(ESI):184.9[M+H]+。
步骤3:制备方法同化合物1-4，不同的是将1-4制法中的化合物1-3换成化合物30-3。MS m/z(ESI):181[M+H]+。
步骤4:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4与2-碘丙烷换成化合物30-4与碘甲烷。MS m/z(ESI):195[M+H]+。
步骤5:制备方法同化合物1-3，不同的是将1-3制法中的化合物1-2换成化合物30-5。MS m/z(ESI):250[M+H]+。
步骤6:制备方法同化合物2-4，不同的是将2-4制法中的化合物2-3换成化合物30-6。MS m/z(ESI):246[M+H]+。
步骤7:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物30-7。MS m/z(ESI):507[M+H]+。
步骤8:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物30-8。经Prep-HPLC纯化得白色固体化合物P-30(6.6mg,19％)。MS m/z(ESI):407[M+H]+；1H NMR(400MHz,CDCl3)δ8.21(d,1H),8.04(s,1H),7.95(s,1H),7.53(s,1H),7.27(dd,1H), 5.15(s,2H),3.89(s,3H),3.62-3.58(m,1H),3.08(d,8H),1.49(d,6H).
实施例31：
Figure PCTCN2017110463-appb-000078
步骤1:制备方法同化合物3-4，不同的是将3-4制法中的化合物3-3与3.1换成化合物6a与31.1。MS m/z(ESI):163[M+H]+。
步骤2:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4换成化合物31-1。MS m/z(ESI):205[M+H]+。
步骤3:制备方法同化合物3-6，不同的是将3-6制法中的化合物3-5换成化合物31-2。MS m/z(ESI):259[M+H]+。
步骤4:制备方法同化合物3-7，不同的是将3-7制法中的化合物3-6换成化合物31-3。MS m/z(ESI):256[M+H]+。
步骤5:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物31-4。MS m/z(ESI):517[M+H]+。
步骤6:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物31-5。经Prep-HPLC纯化得白色固体化合物P-31(7mg,19％)。MS m/z(ESI):417[M+H]+。1H NMR(400MHz,DMSO)δ9.05(s,1H),8.23(s,1H),8.17(d,1H),7.94(s,1H),7.41(d,1H),4.94-4.84(m,1H),3.39(s,2H),3.08-2.99(m,4H),2.91-2.82(m,4H),2.21-2.15(m,1H),1.65(d,6H),1.00-0.95(m,2H),0.94-0.92(m,2H).
实施例32：
Figure PCTCN2017110463-appb-000079
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4换成化合物31-1。MS m/z(ESI):177[M+H]+。
步骤2:制备方法同化合物3-6，不同的是将3-6制法中的化合物3-5换成化合物32-1。MS m/z(ESI):231[M+H]+。
步骤3:制备方法同化合物3-7，不同的是将3-7制法中的化合物3-6换成化合物32-2。MS m/z(ESI):228[M+H]+。
步骤4:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物32-3。MS m/z(ESI):489[M+H]+。
步骤5:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物32-4。经Prep-HPLC纯化得白色固体化合物P-32(10mg,10％)。MS m/z(ESI):389[M+H]+；1H NMR(400MHz,DMSO)δ9.00(s,1H),8.22(s,1H),8.15(d,1H),7.92(d,1H),7.37(dd,1H),3.95(s,3H),3.38(s,2H),3.03-2.93(m,4H),2.86-2.78(m,4H),2.13-2.07(m,1H),1.03-0.97(m,2H),0.95-0.91(m,2H).
实施例52：1-异丙基-8-(5-(哌嗪-1-基)吡啶-2-基氨基)-4,5-二氢-1H-吡唑并[4,3-H]喹唑啉-3-甲腈(化合物P52)的制备
Figure PCTCN2017110463-appb-000080
步骤1:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物52-1。MS m/z(ESI):516[M+H]+。
步骤2:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物52-2。经Prep-HPLC纯化得白色固体化合物P-52(23.54mg,产率47％)。MS m/z(ESI):416[M+H]+；1HNMR(400MHz,DMSO)δ9.69(s,1H),8.43(s,1H),7.96(d,1H),7.84(d,1H),7.40(dd,1H),6.12-5.96(m,1H),3.10-3.00(m,4H),2.93-2.86(m,4H),2.87-2.79(m,4H),1.42(d,6H).
实施例55：1-(9-异丙基-6,8-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-6,8-二氢-5H-吡唑并[3,4-H]喹唑啉-6-基)乙酮(化合物P-55)的制备
Figure PCTCN2017110463-appb-000081
步骤1:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物55-1和碘甲烷。MS m/z(ESI):185[M+H]+。
步骤2:化合物55-2(1.84g,10mmol)的THF(10mL)溶液在氩气氛围下于-78℃加入LDA(5.5mL,11mmol)，在此温度下搅拌30min后加入TMSCl(2.17g,20mmol)，混合物升至室温反应1h。反应液过滤后浓缩，得到化合物55-3直接用于下一步反应。
步骤3:制备方法同化合物8a-3，不同的是将8a-3制法中的化合物8a-2换成化合物55-3。MS m/z(ESI):255[M+H]+。
步骤4:制备方法同化合物8a-4，不同的是将8a-4制法中的化合物8a-3换成化合物55-4。MS m/z(ESI):251[M+H]+。
步骤5:制备方法同化合物3-5，不同的是将3-5制法中的化合物3-4和2-碘丙烷换成化合物55-5和碘甲烷。MS m/z(ESI):265[M+H]+。
步骤6:制备方法同化合物8a，不同的是将8a制法中的化合物8a-4换成化合物55-6。MS m/z(ESI):279[M+H]+。
步骤7:制备方法同化合物3-6，不同的是将3-6制法中的化合物3-5换成化合物55-7。MS m/z(ESI):334[M+H]+。
步骤8:制备方法同化合物3-7，不同的是将3-7制法中的化合物3-6换成化合物55-8。MS m/z(ESI):330[M+H]+。
步骤9:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7换成化合物55-9。MS m/z(ESI):563[M+H]+。
步骤10:化合物55-10(80mg,0.14mmol)的DMF(5mL)溶液在氩气氛围下于室温加入化合物55.1(17mg,0.17mmol)、HATU(81mg,0.21mmol)和三乙胺(57mg,0.56mmol)。反应液室温搅拌1h，LC-MS跟踪至反应完全。混合物减压浓缩后经Prep-HPLC纯化得化合物55-11(42mg,产率：48％)。MS m/z(ESI):606[M+H]+。
步骤11:化合物55-11(80mg,0.14mmol)的THF(5mL)溶液在氩气氛围下于0℃加入甲基溴化镁，混合物在0℃搅拌30min，LC-MS跟踪至反应完全。反应液加水淬灭，混合物浓缩得化合物55-12，直接用于下一步反应。MS m/z(ESI):561[M+H]+。
步骤12:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物55-12。经Prep-HPLC纯化得化合物P-55(22.7mg,产率92％)。MS m/z(ESI):461[M+H]+；1H NMR(400MHz,DMSO)δ8.70(s,1H),8.23(s,1H),7.98(d,1H),7.87(d,1H),7.58(s,1H),3.99(dd,1H),3.89(s,3H),3.33-3.28(m,4H),3.29-3.19(m,5H),2.64(d,1H),2.01(s,3H),1.43(s,3H),1.38(d,6H).
实施例59：1-异丙基-3-(甲氧基甲基)-N-(5-(哌嗪-1-基)吡啶-2-基)-4,5-二氢-1H-吡唑并[4,3-H]喹唑啉-8-胺(化合物P-59)的制备
Figure PCTCN2017110463-appb-000082
步骤1:化合物59-1(25mg,0.082mmol)的CH2Cl2(10mL)溶液在室温下加入MCPBA(42mg,0.246mmol)，混合物室温搅拌30min，LC-MS跟踪至反应结束。反应液加硫代硫酸钠淬灭，经乙酸乙酯萃取，合并有机层，减压浓缩后经combiflash(PE:EA＝1:2)纯化得化合物59-2(25mg,产率92％)。MS m/z(ESI):337[M+H]+。
步骤2:化合物59-2(20mg,0.059mmol)的甲苯(2mL)溶液加入化合物59.1(33mg,0.119mmol)和NaOtBu(11mg,0.119mmol)，混合物在氩气氛围下于140℃微波20min。反应液浓缩后经combiflash(PE:EA＝1:4)纯化得化合物59-3(20mg,产率64％)。MSm/z(ESI):535[M+H]+。
步骤3:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物59-3。 经Prep-HPLC纯化得化合物P-59(1.7mg,产率10％)。MS m/z(ESI):435[M+H]+；1H NMR(400MHz,DMSO)δ9.46(s,1H),8.33(s,1H),7.94(d,1H),7.87(d,1H),7.38(dd,1H),5.88(dt,1H),4.34(s,2H),3.22(s,3H),3.05-2.95(m,4H),2.88-2.81(m,4H),2.80-2.72(m,2H),2.71-2.59(m,2H),1.38(d,6H).
实施例60：1-(9-异丙基-6,8-二甲基-2-(5-(哌嗪-1-基)吡啶-2-基氨基)-6,8-二氢-5H-吡唑并[3,4-H]喹唑啉-6-基)乙醇(化合物P-60)的制备
Figure PCTCN2017110463-appb-000083
化合物P-55(5mg,0.01mmol)的THF(8mL)与MeOH(2mL)溶液在冰浴下加入NaBH4(1mg,0.026mmol)，混合物室温搅拌30min，LC-MS跟踪至反应完全。反应液加乙醇淬灭，浓缩后经Prep-HPLC纯化得化合物P-60(2.35mg,产率50％)。MS m/z(ESI):463[M+H]+；1H NMR(400MHz,CDCl3)δ8.30(d,1H),8.15(d,1H),7.96(s,1H),7.31(d,1H),4.13(d,1H),4.04-3.93(m,1H),3.88(d,3H),3.35(s,8H),3.04(d,1H),2.63(d,1H),2.49(d,1H),1.45(d,6H),1.21(t,3H),1.14(d,3H).
实施例65：
Figure PCTCN2017110463-appb-000084
步骤1:化合物65-1(100mg,0.48mmol)的DCM(10mL)溶液在0℃加入HNO3(0.3mL)和(CF3CO)2O(3mL)，混合物在0℃搅拌2h,LC-MS跟踪至反应完全。反应液经NaHCO3溶液淬灭，乙酸乙酯萃取，合并有机层，浓缩后经combiflash(EA:PE＝1:1)纯化得化合物65-2(60mg,产率49％)。MS m/z(ESI):250[M+H]+。
步骤2:化合物65-2(40mg,0.16mmol)的醋酸(10mL)溶液在室温下加入Fe(200mg,3.57mmol)，混合物在110℃搅拌1h,LC-MS跟踪至反应完全。反应液过滤，浓缩后经combiflash(EA:PE＝1:1)纯化得化合物65-3(24mg,产率70％)。MS m/z(ESI):220[M+H]+。
步骤3:化合物65-3(800mg,3.6mmol)的乙醇(2mL)溶液加入Ac2O(10mL)，混合物在110℃搅拌2h,LC-MS跟踪至反应完全。反应液浓缩后经combiflash(EA:PE＝1:1)纯化得化合物65-4(700mg,产率73％)。MS m/z(ESI):262[M+H]+。
步骤4:制备方法同化合物65-2，不同的是将65-2制法中的化合物65-1换成化合物65-4。MS m/z(ESI):307[M+H]+。
步骤5:制备方法同化合物65-3，不同的是将65-3制法中的化合物65-2换成化合物65-5。MS m/z(ESI):277[M+H]+。
步骤6:化合物65-6(10mg,0.036mmol)的1,4-二氧六环(10mL)和三氟乙酸(1mL)溶液加入丙酮(1mL)和NaBH(OAc)3(100mg,0.47mmol)，混合物室温搅拌4h,LC-MS跟踪至反应完全。反应液浓缩后经combiflash(PE:EA＝1:4)纯化得化合物65-7(5mg,产率45％)。MS m/z(ESI):319[M+H]+。
步骤7:化合物65-7(28mg,0.09mmol)的甲苯(1mL)溶液在室温下加入POCl3(1mL)，混合物在105℃搅拌3h,LC-MS跟踪至反应完全。反应液浓缩后经combiflash(EA:PE＝1:1)纯化得化合物65-8(10mg,产率38％)。MS m/z(ESI):301[M+H]+。
步骤8:化合物65-8(50mg,0.16mmol)的甲醇(5mL)溶液加入醋酸(1mL)和Zn(54mg,0.83mmol)，混合物室温搅拌20min,LC-MS跟踪至反应完全。反应液浓缩后经combiflash(DCM:MeOH＝20:1)纯化得化合物65-9(40mg,产率90％)。MS m/z(ESI):267[M+H]+。
步骤9:制备方法同化合物1-8，不同的是将1-8制法中的化合物1-7和化合物4a换成化合物65-9和化合物65.1。MS m/z(ESI):509[M+H]+。
步骤10:制备方法同化合物P-1，不同的是将P-1制法中的化合物1-8换成化合物65-10。经Prep-HPLC纯化得白色固体化合物P-65(4mg,25％)。MS m/z(ESI):409[M+H]+；1H NMR(400MHz,DMSO)δ9.42(s,1H),8.97(s,1H),8.26(d,1H),7.97(d,1H),7.45(dd,1H),4.75(dt,1H),3.05-2.97(m,4H),2.90-2.77(m,4H),2.58(s,3H),1.51(d,6H)。
化合物P-35，P-36，P-37和P-40，参照实施例1的类似方法进行制备。
化合物P-33和P-34，参照实施例22的类似方法进行制备。
化合物P-38，P-66，参照实施例2的类似方法进行制备。化合物P-39，参照实施例31的类似方法进行制备。
化合物P-41至化合物P-51，化合物P-53、P-54，P-56至P-58，P-63参照实施例4或实施例6的类似方法进行制备。
化合物P-64，参照化合物65-7的类似方法进行制备。
Figure PCTCN2017110463-appb-000085
Figure PCTCN2017110463-appb-000086
Figure PCTCN2017110463-appb-000087
Figure PCTCN2017110463-appb-000088
Figure PCTCN2017110463-appb-000089
Figure PCTCN2017110463-appb-000090
生物测试
测试例一、体外激酶测试
重组CDK1/CCNB1和CDK9/CCNT购自BPS；CDK2/CCNA1、CDK4/CCND1和CDK6/CCND1购自Invitrogen；CDK4/CycD3和CDK6/CycD3购自Carna。三磷酸腺苷(ATP)购自Life tech。底物Ulight-4EBP1和对应检测抗体购自Perkinelmer。检测体系采用Perkinelmer公司的LANCEUltra系统。
激酶实验中，将待测化合物按1:3的比例进行8个梯度点稀释后，加入反应板中并加适 量的重组酶。随后加入含有预定浓度ATP/Ulight-4EBP1预混物的缓冲液[50mM HEPES pH7.5,10mM MgCl2,3mM MnCl2,1mM EGTA,0.01％ Tween-20,1mM TCEP]，室温下开始激酶反应。反应适当时间后，加入预混有10mM EDTA和检测抗体的检测液，室温反应1小时后，在Tecaninfinite pro上读取荧光值。IC50通过XLfit软件中的四因素模型拟合进行计算。结果如表1和表2和表3。
表1 化合物对CDK4的抑制活性
Figure PCTCN2017110463-appb-000091
表2 化合物对CDK6的抑制活性
Figure PCTCN2017110463-appb-000092
Figure PCTCN2017110463-appb-000093
表3 化合物对CDK1和CDK2的抑制活性
Figure PCTCN2017110463-appb-000094
从表1、表2和表3可以看出，本发明的示例化合物对CDK4和CDK6具有较强的抑制活性，而对CDK1和CDK2的抑制活性弱，具有CDK4/6的选择抑制活性。而对比化合物1(D1，具体结构如下所示，并可参见WO2012010704实施例I-44)虽然对CDK4和CDK6具有较强的抑制活性，但对CDK1和CDK2的抑制也很强，没有显示出CDK4/6的选择抑制活性。
Figure PCTCN2017110463-appb-000095
测试例二、药代动力学和脑分布测试
实验方案：
试验动物：健康成年雄性SD大鼠(体重210-230g，12只，过夜禁食，给药后4小时喂食)，由斯莱克公司提供；口服溶液的制备：称取40.14mg化合物P-53于干净试管中，将36.479mL的0.5％HPC-H(TCI,E6ZQA)的乙酸缓冲液(PH4.5)加入试管中，涡旋试管1-2分钟。超声处 理20-25分钟，搅拌20-25分钟。
给予SD大鼠灌胃给药(10mg/kg(10mL/kg))；在给药后0.5，1，2，4小时共4个时间点采样，只有血浆样品是连续采集，脑组织和脑脊液是在每个时间点采集。
血样采集：手动控制动物，通过尾静脉收集大约150μL的血液/时间点到含K2EDTA的管中。在15分钟内，血液样本被放在湿冰上，离心(2000g,5min under 4℃)，获得血浆样品。
脑组织采集：在动物头皮中间做一个切口，然后收缩皮肤。用小的骨刀和骨钳，把头骨移到脑后。用抹刀去除大脑，用冷盐水冲洗。将大脑放置在螺旋管中，然后将试管储存到-70℃，直到分析。
脑脊液采集：在动物深度麻醉的情况下，在尾静脉注射空气安乐死。以枕骨和寰椎为标志，用蝴蝶针直接刺穿了小脑延髓池来采集脑脊液。在收集的过程中，一张白色的纸作为背景放在针的上方，用来监测样品的颜色变化。在对颜色变化的观察中，在颜色变化上方快速关上PE管，并在夹紧的部位上方剪断，将干净的样品抽进注射器。
样品保存和处理：血浆、大脑和脑脊液样本将暂时保存在干冰中，然后将它们转移到-80℃的冷库中，以长期保存。
分析方法：以SD大鼠血浆和脑为基质，Glipizide为内标，采用LCMSMS-002(API-4000,三重四级杆)进行测试分析。分别取30μL血浆样品和脑组织样品，加入200μL含100ng/mL内标(Glipizide)的乙腈，将其混合涡旋10min，在5800rpm转速下离心10min，然后取2μL离心后的上清液，进行LC-MS/MS分析。取10μL脑脊液样品，加入10μL的甲醇/水(1/1)和60μL含100ng/mL内标(Glipizide)的乙腈，将其混合涡旋5min，然后取2μL上清液进行LC-MS/MS分析。应用LC/MS/MS法测定药物浓度，在大鼠血浆、脑组织内和脑脊液内的药代动力学参数如表4所示：
表4 化合物在大鼠口服给药10mg/kg后的曲线下面积
实施例 化合物P‐53
血浆内AUC(hr*ng/mL) 2620
脑组织内AUC(hr*ng/mL) 4944
脑脊液内AUC(hr*ng/mL) 204
从表4可以看出，化合物P‐53能穿越血脑屏障并且很好地分布到脑中，具有较好的脑通透性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (24)

  1. 一种式(I)所示的化合物，或其药学上可接受的盐、立体异构体、溶剂化物或前药：
    Figure PCTCN2017110463-appb-100001
    式中，
    R1、R3、R4各自独立地为氢、卤素、C1-8烷基或卤代C1-8烷基；
    R2为-(CH2)n-Y，其中Y为C3-8环烷基、3至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环；n为0、1或2；
    Z1、Z2各自独立地为一个键、CRaRb、NRc、O、S或S(O)2，且Z1、Z2不同时为一个键、NRc、O、S或S(O)2；
    Ra、Rb各自独立地为氢、卤素、C1-8烷基、卤代C1-8烷基；或
    Ra、Rb和相连的碳原子共同形成3至6元饱和单杂环、3至6元饱和或部分不饱和单环；
    Rc为氢、C1-8烷基、卤代C1-8烷基、C3-8环烷基、C(O)C1-8烷基、C(O)OC1-8烷基、CONRa1Rb1、-SO2C1-8烷基、-C(O)CH2CN、-C(O)CH2OH、3至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环；
    A环为式(A-1)、式(A-2)、式(A-3)或式(A-4)所示结构：
    Figure PCTCN2017110463-appb-100002
    其中，R11、R22、R32、R41各自独立地为氢、C1-8烷基、卤代C1-8烷基、C3-8环烷基或3至6元饱和单杂环；
    R12、R21、R31、R42各自独立地为氢、卤素、C1-8烷基、卤代C1-8烷基、C3-8环烷基或3至6元饱和单杂环；
    所述烷基、烷氧基、环烷基、3至6元饱和单杂环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被1、2或3个选自下组的取代基所取代：CN、乙酰基、羟基、羟甲基、羟乙基、羧基、卤素、C1-8烷基、C1-8烷氧基、卤代C1-8烷基、C3-8环烷基、卤代C1-8烷氧基、-C(O)OC1-6烷基、NRa2Rb2、3至6元饱和单杂环、 5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环或桥杂环；
    Ra1、Rb1、Ra2、Rb2各自独立地为氢、C1-8烷基或C1-8烷氧基取代的C1-8烷基。
  2. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为C3-6环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环，所述环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被-(CH2)m-L1取代；L1为CN、乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、C1-8烷基、C3-8环烷基、卤代C1-8烷基、NRa2Rb2、C1-8烷氧基、氮杂环丁烷、氧杂环丁烷、四氢噻吩、四氢吡咯、四氢呋喃、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃；m为0、1或2；Ra2、Rb2如权利要求1所定义。
  3. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Y为选自下组的基团：环丁基、环戊基、环己基、氮杂环丁烷、四氢吡咯、四氢呋喃、哌啶、哌嗪、吗啉或四氢吡喃，所述基团为未取代或被L1或-CH2-L1取代；L1为CN、乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OCH3、-C(O)OCH2CH3、-C(O)OC(CH3)3、-C(O)OCH(CH3)2、甲基、乙基、正丙基、异丙基、环丙基、环戊基、环己基、一氟甲基、二氟甲基、三氟甲基、一氟乙基、二氟乙基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙氧基、氮杂环丁烷、四氢吡咯、四氢呋喃、哌啶、哌嗪、吗啉、四氢吡喃或NRa2Rb2；Ra2、Rb2各自独立地为氢、C1-3烷基或C1-3烷氧基取代的C1-3烷基。
  4. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Rc为氢、-C(O)C1-3烷基、-C(O)OC1-3烷基、-CONRa1Rb1、-SO2C1-3烷基、-C(O)CH2CN、-C(O)CH2OH或-(CH2)p-L2；其中L2为CN、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、NRa1Rb1、C1-8烷氧基、卤代C1-8烷基、C3-8环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环；p为0、1或2；
    所述烷基、烷氧基、环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被1个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、NRa2Rb2、氮杂环丁烷、氧杂环丁烷、四氢噻吩、四氢吡咯、四氢呋喃、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃；Ra1、Rb1、Ra2、Rb2如权利要求1所定义。
  5. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R11、R22、R32、R41各自独立地为氢或-(CH2)q-L3；其中L3为CN、NRa1Rb1、C1-8烷基、C1-8烷氧基、卤代C1-8烷基、C3-8环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环；q为0、1或2；
    所述烷基、烷氧基、环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被1个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、NRa2Rb2、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃；Ra1、Rb1、Ra2、Rb2如权利要求1所定义。
  6. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R12、R21、R31、R42各自独立地为氢、卤素或-(CH2)r-L4；L4为CN、C1-8烷基、C1-8烷氧基、卤代C1-8烷基、C3-8环烷基、NRa1Rb1、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环；r为0、1或2；
    所述烷基、烷氧基、环烷基、4至6元饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环或桥杂环为未取代的或被1个选自下组的取代基所取代：乙酰基、羟基、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、C1-3烷基、C1-3烷氧基、卤代C1-3烷基、C3-6环烷基、NRa2Rb2、氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、噁唑烷、哌嗪、二氧戊环、二氧六环、吗啉、硫代吗啉、硫代吗啉-1,1-二氧化物或四氢吡喃；Ra1、Rb1、Ra2、Rb2如权利要求1所定义。
  7. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Ra、Rb各自独立地为氢、氟、氯、C1-3烷基、卤代C1-3烷基；或
    Ra、Rb和相连的碳原子共同形成环氧丙烷、氮杂环丁烷、氧杂环丁烷、四氢呋喃环、四氢噻吩环、四氢吡咯、哌啶环、四氢吡喃环、环丙基环、环丁基环、环戊基环、环己基环。
  8. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，
    Figure PCTCN2017110463-appb-100003
    为式(B-1)、式(B-2)、式(B-3)或式(B-4)所示结构：
    Figure PCTCN2017110463-appb-100004
    其中Z、R11、R22、R32、R41、R12、R21、R31、R42如权利要求1所定义。
  9. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Z1为一个键；Z2为CR1aR1b、NRc、O、S或S(O)2；R1a、R1b如Ra、Rb所定义。
  10. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Z1为CR1aR1b、NRc、O、S或S(O)2；Z2为CR2aR2b；R1a、R1b、R2a、R2b如Ra、Rb所定义。
  11. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Z1为CR1aR1b；Z2为CR2aR2b、NRc、O、S或S(O)2；R1a、R1b、R2a、R2b如Ra、Rb所定义。
  12. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，
    Z1为一个键；Z2为CR2aR2b、NRc、O、S或S(O)2；
    Figure PCTCN2017110463-appb-100005
    为式(B-1)、式(B-2)或式(B-3)所示结构；R2a、R2b如Ra、Rb所定义。
  13. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前 药，其特征在于，Z1为CR1aR1b、NRc、O、S或S(O)2；Z2为CR2aR2b；
    Figure PCTCN2017110463-appb-100006
    为式(B-1)、式(B-2)或式(B-4)所示结构；R1a、R1b、R2a、R2b如Ra、Rb所定义。
  14. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Z1为一个键或O；Z2为CR2aR2b；
    Figure PCTCN2017110463-appb-100007
    为式(B-2)所示结构；R2a、R2b如Ra、Rb所定义。
  15. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，Z1为CR1aR1b；Z2为CR2aR2b；
    Figure PCTCN2017110463-appb-100008
    为式(B-1)所示结构；R1a、R1b、R2a、R2b如Ra、Rb所定义。
  16. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，R1、R3、R4各自独立地为氢、卤素、C1-6烷基或卤代C1-6烷基。
  17. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，n为0或1。
  18. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物选自表A。
  19. 如权利要求1所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，其特征在于，所述化合物选自表B。
  20. 一种药物组合物，所述药物组合物包括权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药；以及药学可接受的载体。
  21. 如权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药、或如权利要求19所述药物组合物在制备治疗疾病或病症的药物中的应用，所述疾病或病症选自癌症、异常细胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病、神经变性疾病、由辐射引起的造血毒性疾病，或其组合。
  22. 一种抑制CDK4和/或CDK6活性的方法，其包括给予所需患者治疗有效量的权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，或如权利要求19所述药物组合物。
  23. 一种治疗异常细胞增殖性疾病、感染、炎性病症、自身免疫性疾病、心血管疾病或神经变性疾病的方法，其包括给予所需患者治疗有效量的权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，或如权利要求19所述药物组合物，其中所述的异常细胞增殖性疾病可以是癌症。
  24. 一种治疗癌症的方法，其包括给予所需患者治疗有效量的权利要求1至18中任一项所述的化合物、或其药学上可接受的盐、立体异构体、溶剂化物或前药，或如权利要求19所述药物组合物，其中所述癌症选自乳腺癌、卵巢癌、前列腺癌、黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉 瘤、脂肪肉瘤、骨软骨瘤、骨瘤、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫癌、头颈肿瘤、多发性骨髓瘤、恶性淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤。
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WO2019206154A1 (zh) * 2018-04-24 2019-10-31 上海海雁医药科技有限公司 Cdk4/6抑制剂及其药学上可接受的盐和多晶型物及其应用
CN111377922A (zh) * 2018-12-29 2020-07-07 武汉光谷通用名药物研究院有限公司 稠合三环类化合物及其用途
WO2020223469A1 (en) * 2019-05-01 2020-11-05 Incyte Corporation N-(1-(methylsulfonyl)piperidin-4-yl)-4,5-di hydro-1h-imidazo[4,5-h]quinazolin-8-amine derivatives and related compounds as cyclin-dependent kinase 2 (cdk2) inhibitors for treating cancer
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CN114685520A (zh) * 2020-12-25 2022-07-01 武汉誉祥医药科技有限公司 三并环化合物及其药物组合物和应用
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
JP2022542711A (ja) * 2019-08-02 2022-10-06 チェンドゥ サイノジェン バイオ－ファーマシューティカル テクノロジー カンパニー リミテッド プロテインキナーゼ阻害剤としての１ｈ－［１，２，３］トリアゾロ［４，５－ｈ］キナゾリン系化合物
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CA3039012A1 (en) 2018-05-17
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