WO2018086589A1 - 1,5,7-三取代的异喹啉衍生物、其制法与医药上的用途 - Google Patents

1,5,7-三取代的异喹啉衍生物、其制法与医药上的用途 Download PDF

Info

Publication number
WO2018086589A1
WO2018086589A1 PCT/CN2017/110459 CN2017110459W WO2018086589A1 WO 2018086589 A1 WO2018086589 A1 WO 2018086589A1 CN 2017110459 W CN2017110459 W CN 2017110459W WO 2018086589 A1 WO2018086589 A1 WO 2018086589A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
group
ring
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2017/110459
Other languages
English (en)
French (fr)
Other versions
WO2018086589A8 (zh
Inventor
周福生
石晓永
王莉肖
许峰
谢婧
卜平
程鹏飞
张志远
蔡南平
兰炯
Original Assignee
上海海雁医药科技有限公司
扬子江药业集团有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海海雁医药科技有限公司, 扬子江药业集团有限公司 filed Critical 上海海雁医药科技有限公司
Priority to CN201780008606.1A priority Critical patent/CN108699002B/zh
Priority to US16/306,331 priority patent/US20200262813A1/en
Publication of WO2018086589A1 publication Critical patent/WO2018086589A1/zh
Publication of WO2018086589A8 publication Critical patent/WO2018086589A8/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the field of medical technology.
  • the invention relates in particular to a 1,5,7-trisubstituted isoquinoline derivative, to a process for its preparation and to the use as an EZH2 inhibitor, and to pharmaceutical compositions prepared therefrom.
  • Histone-lysine-N-methyltransferase EZH2 is involved in DNA methylation and final transcriptional repression; methylation of lysine 27 by catalyzed by cofactor S-adenosyl-L-methionine To histidine H3. This methylation promotes the formation of heterochromatin, which triggers gene silencing.
  • EZH2 is a part of the functional enzyme of PRC2, which maintains the genes regulating development and differentiation through epigenetics, thus ensuring the healthy development of the embryo. Mutation or overexpression of EZH2 is associated with the formation of many cancers. EZH2 controls genes to control tumor development, and inhibition of EZH2 activity slows tumor growth.
  • EZH2 regulates a variety of cancers including breast cancer, prostate cancer, melanoma and bladder cancer.
  • the steroids WO2011140324A1 and WO2012075080A1 disclose steroids as EZH2 inhibitors for the treatment of cancer.
  • PCT application WO2012118812A2 discloses the use of bicyclic heterocyclic compounds as EZH2 inhibitors for the treatment of cancer.
  • the compounds of the invention provide a solution for disease or EZH2-mediated tumor therapy as an EZH2 inhibitor.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • X is NH or O
  • R 1 and R 3 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 C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more Preferred is C 1-3 alkoxy), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or C 3-8 cycloalkoxy (preferably C 3-6 cycloalkoxy) ;
  • halogen preferably fluorine, chlorine, bromine
  • 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 alkyl, more preferably halogenated C 1-3 alkyl
  • C 1-8 alkoxy preferably C 1-6 alkoxy, more
  • R 4 is hydrogen, halogen (preferably fluorine, chlorine, bromine), hydroxyl group, CN, C 1-8 alkyl group (preferably C 1-6 alkyl group, more preferably C 1-3 alkyl group), halogenated C 1 -8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1 A-8 alkoxy group (preferably a C 1-6 alkoxy group, more preferably a C 1-3 alkoxy group), a halogenated C 1-8 alkoxy group (preferably a halogenated C 1-6 alkoxy group, More preferably, it is a halogenated C 1-3 alkoxy group, a C 3-8 cycloalkoxy group (preferably C 3-6 cycloalkoxy group), a C 6-10 aryl group (preferably phenyl group), C (O) C 1-8 alkyl (preferably C(O)
  • Z 1 is N or CR 8 ;
  • Z 2 is N or CR 9 ;
  • Z 3 is N or CR 10 ;
  • R 8 , R 9 and R 10 are each independently hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) ;
  • R 2 is hydrogen, halogen (preferably fluorine, chlorine, bromine), CN, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 2-8 alkynyl (preferably a C 2-6 alkynyl group, more preferably a C 2-3 alkynyl group), a halogenated C 1-8 alkyl group (preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 group) Alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) , C(O)NR a1 R b1 , NR a2 R b2 , NCOR a3 , OR a4 , C 6-10 aryl (preferably phenyl), 4 to 6-membered saturated or unsaturated monoheterocyclic ring, 5 to 6 Monomon
  • R a1 , R b1 , R a2 , R b2 , R a3 , and R a4 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), a 4- to 6-membered saturated monoheterocyclic ring, a 5- to 6-membered monocyclic heteroaryl ring, and a C 6-10 aryl group;
  • R a1 , R b1 and the attached nitrogen atom together form a 5- to 6-membered saturated monoheterocyclic ring;
  • R 5 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) or C 1-8 alkoxy substituted C 1-8 alkyl (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;
  • R 6 is C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 4 To a 6-membered saturated monoheterocyclic ring (preferably azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine or tetrahydropyran, more preferably piperazine Pyridine or tetrahydropyran), spiro, spiro heterocycle, bridged ring, bridged heterocycle;
  • a 6-membered saturated monoheterocyclic ring preferably azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine or te
  • the ring or bridge heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of NR a0 R b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1- 6 alkyl, halogen, acetyl, hydroxy, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1 -6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 al
  • the alkynyl group in R 2 is substituted with a 4 to 6 membered saturated monoheterocyclic ring (preferably piperidine, piperazine, morpholine or tetrahydropyran); said 4 to 6 membered saturated single hetero
  • the ring is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, acetyl Base, hydroxyl group, C 1-3 alkyl group, halogenated C 1-3 alkyl group, C 3-6 cycloalkyl group, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, Piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine,
  • R a1 is hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R b1 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), 4 to 6-membered saturated monoheterocycle (preferably piperidine, piperazine, morpholine or tetrahydropyran), 5 to 6 a monomonocyclic heteroaryl ring (preferably pyridine) or a phenyl group; or R a1 , R b1 and a linked nitrogen atom together form a 4 to 6 membered saturated monoheterocyclic ring (preferably forming piperidine, piperazine, morpholine or tetra Hydropyran ring)
  • the 4- to 6-membered saturated monoheterocyclic ring, 5- to 6-membered monocyclic heteroaryl ring or phenyl group is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , Hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl , azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine , thiomorpholine-1,1-dioxide or tetrahydropyran; R a0 , R b0
  • R a2 is hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R b2 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), 4 to 6-membered saturated monoheterocyclic ring, 5- to 6-membered monocyclic heteroaryl ring, C 6-10 aryl (R b2 Preferably a 5- to 6-membered monocyclic heteroaryl ring, more preferably pyridine);
  • the 4- to 6-membered saturated monoheterocyclic ring, 5- to 6-membered monocyclic heteroaryl ring or aryl group is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , Hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl , azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine , thiomorpholine-1,1-dioxide or tetrahydropyran; R a0 , R b0 are
  • R a3 is a C 1-8 alkyl group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group).
  • R a4 is a C 1-8 alkoxy-substituted C 1-8 alkyl group (preferably a C 1-6 alkoxy-substituted C 1-6 alkyl group, more preferably C 1- 3 alkoxy-substituted C 1-3 alkyl) 5 to 6-membered monocyclic heteroaryl ring (preferably pyridine), C 6-10 aryl group (preferably phenyl);
  • the 5- to 6-membered monocyclic heteroaryl ring or aryl group is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , acetyl group, hydroxyl group, C 1-3 Alkyl, halogenated C 1-3 alkyl, C 3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine Pyrazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl.
  • the aryl group (preferably a phenyl group) in R 2 is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of C 1-8 alkyl groups (preferably C a 1-6 alkyl group, more preferably a C 1-3 alkyl 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), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogen, -O(CH 2 ) n OC 1-8 alkyl or -Y 1 - L 1 ; wherein Y 1 is a bond, CH 2 , NH, O or CON; L 1 is a C 6-10 aryl group (preferably a phenyl group), a 5- to 6-membered monocyclic heteroaryl ring (preferably pyridine), a 4- to 6-membered saturated
  • the aryl group, the 4 to 6 membered saturated monoheterocyclic ring, and the 5 to 6 membered monocyclic heteroaryl ring in L 1 are unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R B0 , hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 ring Alkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thio Morpholine, thiomorpholine-1,1-dioxide or tetrahydropyran; R a0 , R b
  • the 5- to 6-membered monocyclic heteroaryl ring in R 2 is unsubstituted or substituted with 1, 2 or 3 groups selected from the group consisting of halogen, 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 alkyl, more preferably halogen C 1-3 Alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or -Y 2 -L 2 ; wherein Y 2 is a bond, CH 2 or C(O); L 2 is hydrogen, C 3-6 cycloalkyl, 4 to 6-membered saturated monoheterocyclic ring or NR a0 R b0 ; R a0 , R b0 are each independently hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more Preferred is C 1-3 alkyl);
  • the 4- to 6-membered saturated monoheterocyclic ring in L 2 is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C (O)OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl, azetidine, oxetane , tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide Or tetrahydropyran; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl.
  • R 6 is C 1-6 alkyl, CHR a5 R b5 , C 3-6 cycloalkyl, 4 to 6-membered saturated monoheterocyclic ring (preferably azetidine, oxyheterocycle) Butane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine or tetrahydropyran, more preferably piperidine or tetrahydropyran), spiro, spiro heterocycle, bridged ring, bridge Heterocycle; wherein R a5 is hydrogen, methyl or ethyl; R b5 is phenyl, 5- to 6-membered monocyclic heteroaryl ring (preferably pyridine) or 4 to 6-membered saturated monoheterocycle (preferably piperidine) , piperazine, morpholine or tetrahydropyran); the alkyl group,
  • the cycloalkyl group in R 6 is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , halogen, hydroxy, 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) 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 cycloalkane) a 4 to 6 membered saturated monoheterocyclic ring (preferably azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine or
  • the 4- to 6-membered saturated monoheterocyclic ring in R 6 is unsubstituted or substituted with 1, 2 or 3 groups selected from the group consisting of acetyl, C 1-8 alkyl ( Preferred is a C 1-6 alkyl group, more preferably a C 1-3 alkyl group), a C 1-8 alkoxy substituted C 1-8 alkyl group (preferably a C 1-6 alkoxy substituted C 1- 6 alkyl, more preferably C 1-3 alkoxy substituted C 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably - SO 2 C 1-3 alkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 4 to 6-membered saturated monoheterocyclic ring (preferably aze
  • X is NH
  • R 2 is halogen (preferably fluorine, chlorine, bromine), CN, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogen 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) C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy).
  • C 1-8 alkyl preferably C 1-6 alkyl, more preferably C 1-3 alkyl
  • halogen a C 1-8 alkyl group preferably a halogenated C 1-6 alkyl group, more preferably a halogenated C 1-3 alkyl group
  • C 3-8 cycloalkyl group preferably a C 3-6 cycloalkyl group
  • R 2 is a C 2-8 alkynyl group (preferably a C 2-6 alkynyl group, more preferably a C 2-3 alkynyl group); the alkynyl group is a 4 to 6 membered saturated monoheterocyclic ring Substituted (preferably piperidine, piperazine, morpholine or tetrahydropyran);
  • the 4- to 6-membered saturated monoheterocyclic ring is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C(O OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran , tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or Tetrahydropyran; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl.
  • R 2 is C(O)NR a1 R b1 ;
  • R a1 is hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl) ;
  • R b1 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), 4 to 6-membered saturated monoheterocycle (preferably piperidine, piperazine, Morpholine or tetrahydropyran), a 5- to 6-membered monocyclic heteroaryl ring (preferably pyridine) or a phenyl group; or R a1 , R b1 and a linked nitrogen atom together form a 4 to 6-membered saturated monoheterocyclic ring ( Preferably forming a piperidine, piperazine, morpholine or tetrahydropyran ring);
  • the 4- to 6-membered saturated monoheterocyclic ring, 5- to 6-membered monocyclic heteroaryl ring or phenyl group is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , Hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl , azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine , thiomorpholine-1,1-dioxide or tetrahydropyran; R a0 , R b0
  • R 2 is NR a2 R b2 ;
  • R a2 is hydrogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R b2 is Hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), 4 to 6-membered saturated monoheterocyclic, 5- to 6-membered monocyclic heteroaryl ring, C 6-10 aryl (R b2 is preferably a 5- to 6-membered monocyclic heteroaryl ring, more preferably pyridine);
  • the 4- to 6-membered saturated monoheterocyclic ring, 5- to 6-membered monocyclic heteroaryl ring or aryl group is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , Hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl , azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine , thiomorpholine-1,1-dioxide or tetrahydropyran; R a0 , R b0 are
  • R 2 is NCOR a3 ;
  • R a3 is C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl).
  • R 2 is OR a4 ;
  • R a4 is a C 1-8 alkoxy-substituted C 1-8 alkyl group (preferably a C 1-6 alkoxy-substituted C 1-6 alkyl group, More preferably, C 1-3 alkoxy-substituted C 1-3 alkyl), 5- to 6-membered monocyclic heteroaryl ring (preferably pyridine), C 6-10 aryl (preferably phenyl);
  • the 5- to 6-membered monocyclic heteroaryl ring or aryl group is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , acetyl group, hydroxyl group, C 1-3 Alkyl, halogenated C 1-3 alkyl, C 3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine Pyrazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl.
  • R 2 is phenyl; the phenyl group is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of C 1-8 alkyl groups (preferably C 1- a 6 alkyl group, more preferably a C 1-3 alkyl 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), C 1 -8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogen, -O(CH 2 ) n OC 1-8 alkyl or -Y 1 -L 1 Wherein Y 1 is a bond, CH 2 , NH, O or CON; L 1 is a C 6-10 aryl group (preferably a phenyl group), a 5- to 6-membered monocyclic heteroaryl ring (preferably a pyridine), 4 to a 6-membered saturated monoheter
  • the aryl group, a 4 to 6 membered saturated monoheterocyclic ring, and a 5 to 6 membered monocyclic heteroaryl ring are unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , Hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl , azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine , thiomorpholine-1,1-dioxide or tetrahydropyran; R a0 ,
  • R 2 is a structure represented by Formula A:
  • R 1a , R 2a , R 3a , R 4a are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogen C 1- 8- alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy) or halogen; Y 1 , L 1 are as defined above.
  • R 1a , R 3a , and R 4a are hydrogen.
  • R 2 is a 5 to 6 membered monocyclic heteroaryl ring (preferably pyridine, pyrimidine or pyrazole); the 5 to 6 membered monocyclic heteroaryl ring is unsubstituted or 1 , 2 or 3 groups selected from the group consisting of halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), halogenated C 1-8 alkane Base (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or -Y 2 -L 2 ; wherein Y 2 is a bond, CH 2 or C(O); L 2 is hydrogen, C 3-6 cycloalkyl, 4 to 6-membered saturated monoheterocyclic ring or NR a0 R b0 ; each of R a0 , R b0 Independently hydrogen or C 1-8 alkyl (preferably
  • the 4- to 6-membered saturated monoheterocyclic ring is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of NR a0 R b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C(O OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran , tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or Tetrahydropyran; R a0 , R b0 are each independently hydrogen or C 1-3 alkyl.
  • R 2 is a structure represented by formula B or C:
  • R 1b , R 2b , R 3b , R 1c , and R 3c are each independently hydrogen, halogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), Halogenated C 1-8 alkyl (preferably halo C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) ); Y 2 and L 2 are as defined above.
  • R 1b and R 3b are hydrogen.
  • R 1c and R 3c are hydrogen.
  • R 2 is a 4 to 6 membered saturated monoheterocyclic ring (preferably piperidine, piperazine, morpholine or tetrahydropyran); the 4 to 6 membered saturated monoheterocyclic ring is unsubstituted Or by NR a0 R b0 , hydroxymethyl, hydroxyethyl, carboxyl, -C(O)OC 1-6 alkyl, acetyl, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, C 3-6 cycloalkyl, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, oxazolidine, piperazine, dioxolane, dioxane, Morpholine, thiomorpholine, thiomorpholine-1,1-dioxide or tetrahydropyran;
  • R 2 is fluorine, chlorine, bromine, CN, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, or R 2 is as follows:
  • R 5 is hydrogen, methyl, ethyl or methoxy substituted ethyl.
  • R 6 is C 1-6 alkyl or CHR a5 R b5 ; wherein R a5 is hydrogen, methyl or ethyl; R b5 is phenyl, 5- to 6-membered monocyclic heteroaryl ring (preferably pyridine) or a 4 to 6 membered saturated monoheterocyclic ring (preferably piperidine, piperazine, morpholine or tetrahydropyran); the alkyl group, phenyl group is unsubstituted or is 1, 2 or 3 Substituents selected from the group consisting of C 1-3 alkoxy, NR a0 R b0 or a 4- to 6-membered saturated monoheterocyclic ring (preferably piperidine, piperazine, morpholine or tetrahydropyran); A0 and R b0 are each independently hydrogen, methyl or ethyl.
  • R 6 is C 3-6 cycloalkyl (preferably cyclohexyl); the cycloalkyl is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of: NR a0 R b0 , halogen, hydroxy, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6) Alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 4 to 6-membered saturated monoheterocyclic ring (preferably azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole) , piperidine, piperazine
  • R 6 is a structure represented by Formula D:
  • R 1d is hydrogen, halogen or C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl);
  • R 2d is hydrogen, NR a0 R b0 , halogen, hydroxy, 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), 4 to 6 membered saturated monoheterocyclic ring (preferably azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, morpholine or tetrahydrogen) Pyran);
  • R a0 , R b0 are each independently hydrogen, acetyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkane
  • R 6 is a 4 to 6 membered saturated monoheterocyclic ring (preferably azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, piperazine, ???
  • a tetrahydropyran more preferably piperidine or tetrahydropyran
  • the 4 to 6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 groups selected from the group consisting of: Acetyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 1-8 alkoxy substituted C 1-8 alkyl (preferably C 1 a -6 alkoxy-substituted C 1-6 alkyl group, more preferably a C 1-3 alkoxy-substituted C 1-3 alkyl group, a -SO 2 C 1-8 alkyl group (preferably -SO 2 C) a 1-6 alkyl group, more preferably a -SO 2 C 1-3 alkyl 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
  • R 6 is a tetrahydropyran or a structure represented by Formula E:
  • R 1e , R 2e , R 3e , R 4e are each independently hydrogen or methyl;
  • R 0e is hydrogen, acetyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1 -3 alkyl), C 1-8 alkoxy substituted C 1-8 alkyl (preferably C 1-6 alkoxy substituted C 1-6 alkyl, more preferably C 1-3 alkoxy Substituted C 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl), halogenated C 1 -8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), 4 to a 6-membered saturated monoheterocyclic ring (preferably azetidine, oxetane, tetrahydro
  • R 6 is a spiro ring, a spiro heterocycle, a bridged ring, or a bridged heterocyclic ring.
  • R 6 is a double spiro heterocycle containing 1-2 nitrogen or oxygen atoms.
  • R 6 is a bicyclic bridged heterocyclic ring containing 1-2 nitrogen or oxygen atoms.
  • R 6 is as follows:
  • R 1 is hydrogen or halogen (preferably fluorine, chlorine, bromine).
  • R 3 is hydrogen or halogen (preferably fluorine, chlorine, bromine).
  • R 4 is hydroxy, C 1-3 alkyl (preferably methyl or ethyl) or C 1-3 alkoxy (preferably methoxy).
  • Z 1 is N;
  • Z 2 is CR 9 ;
  • Z 3 is CR 10 ;
  • R 9 and R 10 are each independently hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkane A group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group), preferably R 9 and R 10 are hydrogen.
  • Z 1 is N; Z 2 and Z 3 are CH; X is NH; R 1 is hydrogen; R 3 is hydrogen or fluorine; and R 2 , R 4 , R 5 , R 6 are as specified in the specification. definition.
  • R 10 is hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkyl (preferably C 1- 6 alkyl, more preferably C 1-3 alkyl), preferably R 10 is hydrogen.
  • Z 1 and Z 2 are N; Z 3 is CH; X is NH; R 1 and R 3 are hydrogen; and R 2 , R 4 , R 5 and R 6 are as defined in the specification.
  • Z 1 is N;
  • Z 2 is CR 9 ;
  • Z 3 is N;
  • R 9 is hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkyl (preferably C 1- 6 alkyl, more preferably C 1-3 alkyl), preferably R 9 is hydrogen.
  • Z 1 and Z 3 are N; Z 2 is CH; X is NH; R 1 and R 3 are hydrogen; and R 2 , R 4 , R 5 and R 6 are as defined in the specification.
  • Z 1 is CR 8 ;
  • Z 2 is N;
  • Z 3 is CR 10 ;
  • R 8 and R 10 are each independently hydrogen, halogen (preferably fluorine, chlorine, bromine), C 1-8 alkane A group (preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group), preferably R 8 and R 10 are hydrogen.
  • Z 2 is N; Z 1 and Z 3 are CH; X is NH; R 1 and R 3 are hydrogen; and R 2 , R 4 , R 5 and R 6 are as defined in the specification.
  • the compound is selected from the following table A
  • 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, solvate, stereoisomer or prodrug thereof; A pharmaceutically acceptable carrier.
  • a third aspect of the invention provides the compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, solvated Use of a substance, stereoisomer or prodrug or a pharmaceutical composition according to the second aspect of the invention for the preparation of an EZH2 inhibitor.
  • a fourth aspect of the invention provides the compound of the first aspect of the invention, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, or the pharmaceutical composition of the second aspect of the invention Application of EZH2-mediated diseases or conditions.
  • a fifth aspect of the invention provides a method of treating a disease or condition mediated by EZH2 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, or a solvent thereof A compound, a stereoisomer or a prodrug, or a pharmaceutical composition according to the second aspect of the invention.
  • a sixth aspect of the invention provides a method of treating a disease or condition mediated by EZH2 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, or a solvent thereof a compound, a stereoisomer or a prodrug, and another therapeutically active agent.
  • the disease or condition mediated by EZH2 is selected from the group consisting of cancer, pulmonary hypertension, myelofibrosis, human immunodeficiency virus (HIV) disease, graft versus host disease (GVHD), Weaver syndrome, Psoriasis vulgaris or liver fibrosis.
  • HIV human immunodeficiency virus
  • GVHD graft versus host disease
  • Weaver syndrome Psoriasis vulgaris or liver fibrosis.
  • the disease or condition mediated by EZH2 is cancer.
  • the cancer mediated by EZH2 includes, but is not limited to, thyroid cancer, cardiac sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract tumor, liver cancer, mantle cell lymphoma, osteosarcoma, nervous system sarcoma, Gynecological cancer, hematological tumor, adrenal neuroblastoma, skin cancer, astrocytic tumor, breast cancer, colorectal cancer, endometrial cancer, head and neck cancer, oral cancer.
  • 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 or 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 1,1,1-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, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-e
  • 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 C 3-6 Cycloalkyl, definitionally similar; non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl
  • the group, the cycloheptatrienyl group, the cyclooctyl group and the like are 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 Such as:
  • 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, examples of which include ( But 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.
  • bicyclic heterocycles include, but are not limited to, tetrahydroquinoline rings, tetrahydroisoquinoline rings, decahydroquinoline rings, 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, most 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.
  • halo C 1-8 alkoxy include, but are not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethane. Oxyl 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. Examples of halogenated C 3-8 cycloalkyl groups 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 1-8 alkyl groups include, but are not limited to, monodeuterated methyl, monodeuterated ethyl, dideuterated methyl, diterpene ethyl, triterpene methyl, triterpenoid B 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.
  • 3- to 6-membered saturated or partially unsaturated monocyclic rings include, but are not limited to, cyclopropyl ring, cyclobutyl ring, cyclopentyl ring, cyclopentenyl ring, cyclohexyl ring, cyclohexenyl ring, ring.
  • 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.
  • 3- to 6-membered saturated monoheterocycles include, but are not limited to, propylene oxide, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, piperidine, pyrroline, oxazole Alkane, 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 above groups 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- to
  • EZH2 inhibitor refers to an agent (in the present invention, a compound of formula (I)) capable of inhibiting the increase in the expression of histone lysine N-methyltransferase EZH2, which is PRC2
  • the catalytic functional subunit is responsible for the Lys27 methylation of a specific histone H3 (H3K27) and is indispensable for stem cell self-renewal.
  • a disease or condition mediated by EZH2 refers to an abnormal episode formed in a patient due to abnormal expression of the histone lysine N-methyltransferase EZH2 resulting in an abnormal epigenetic modification.
  • 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.
  • Step 1 in the presence of a base system, a reaction site or group (such as NH, OH, etc.) having a nucleophilic property in the compound of the formula (I-1) is substituted with a compound of the formula (I-2), A compound of formula (I-3) is produced.
  • a reaction site or group such as NH, OH, etc.
  • Suitable base systems include potassium carbonate present in DMSO, potassium carbonate present in DMF, and the like.
  • Step 2 Reduction of the nitro group in the formula (I-2) to an amino group gives the compound of the formula (I-4), and the reduction method can be referred to a conventional method in the art.
  • Step 3 Reductive amination of an aldehyde or ketone of R 5 and R 6 with a compound of formula (I-4) affords a compound of formula (I).
  • the reductive amination conditions are toluene reflux, water removal plus reducing agent reduction, or reduction in a catalytic system formed by acid-metal hydride.
  • the acid includes Lewis acid or Bronsted acid such as acetic acid, trifluoroacetic acid, titanium tetrachloride, and a solvent. It can be changed between dichloromethane, 1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, methanol, diethyl ether, acetonitrile, etc.
  • Suitable reducing agents include sodium triacetoxyborohydride, Sodium cyanoborohydride, sodium borohydride, and the like.
  • the reaction temperature is from room temperature to 70 °C.
  • R 2 in the compound of formula (I) may be modified by methods known to those skilled in the art, such as hydrogenation or metal reduction, or alkylation, ether formation, ester formation, amide formation, carboxylic acid formation, and the like.
  • the arylation with arylboronic acid can be carried out in the presence of a Pd catalyst, a suitable ligand and a base, preferably a carbonate, a phosphate of sodium, potassium or cesium, or an organic base such as triethylamine. DIPEA and so on.
  • the solvent can be varied between toluene, 1,4-dioxane, DMF, acetonitrile, alcohol, etc., and in some cases even water and other solvents.
  • Conventional catalysts such as Pd (PPh 3) 4 or Pd (OAc) 2, to promote a more complex type reaction with PdCl 2 PdO catalyst precursor and the ligand is more effective.
  • the preferred starting material is formula (I-2-A):
  • the compound of the formula (I-2-A) can be produced by the method (A) comprising the following steps:
  • the compound of the formula (I-2-1) is cyclized with DMF-DMA to obtain a compound of the formula (I-2-2), and the compound of the formula (I-2-2) is reacted with an ammonia-methanol solution to obtain the formula (I-2-3).
  • the compound, a compound of the formula (I-2-3), is halogenated with SOX 2 , SO 2 X 2 , POX 3 or PX 5 , more preferably POCl 3 which is preferably chlorine or bromine to give a compound of the formula (I-2-4).
  • the compound of the formula (I-2-A) can be obtained by modifying the compound (I-2-4) by a method conventional in the art.
  • Reduction of the compound of the formula (I-1-1) by a suitable reduction method gives the compound of the formula (I-1-A).
  • Suitable reduction methods include reduction with borane in tetrahydrofuran and reduction with lithium aluminum hydride in an anhydrous inert solvent including methyl t-butyl ether, tetrahydrofuran, and the like.
  • the intermediate compound of formula (I-1-1) can be obtained by two different routes.
  • the compound of formula (I-1-1) can be prepared by Process 1 comprising the following steps:
  • the compound of the formula (1.1) is reacted with malononitrile, and after ring opening, the ring is reclosed to obtain a compound of the formula (1.2), and the compound of the formula (1.2) is reacted with an acid to obtain a compound of the formula (1.3), and the compound of the formula (1.3) is preferably used.
  • suitable bases include alkali metal hydroxides, preferably sodium hydroxide, potassium hydroxide; alkali metal alkoxides, preferably sodium alkoxide.
  • the compound of formula (I-1-1) can be prepared by Process 2 comprising the following steps:
  • the compound of formula (1.5) and formula (1.6) is subjected to ring closure under basic conditions to give a compound of formula (I-1-1).
  • Suitable basic systems include potassium t-butoxide present in DMSO, potassium carbonate present in DMSO. Potassium carbonate or the like present in DMF.
  • a series of novel 1,5,7-trisubstituted isoquinoline derivatives are provided which have high inhibitory activity against EZH2 and are useful as drugs for treating tumors.
  • 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 1 A mixture of compound 2a-1 (500 mg, 1.82 mmol), DMF-DMA (575 mg, 5.47 mmol) and 5 mL of DMF was stirred overnight at 110 ° C under nitrogen atmosphere. LC-MS was followed until the reaction was complete. The reaction mixture was cooled, concentrated, and purified by silica gel column chromatography. MS m/z (ESI): N/A.
  • Step 2 Compound 2a-2 (130mg, 0.481mmol) was added NH 3 ⁇ MeOH (3mL, 7M ) , and the mixture in sealed tube was stirred overnight at 60 deg.] C. LC-MS was followed until the reaction was complete. The mixture was cooled and filtered, and the filter cake was evaporated to dryness to give the compound (yel. MS m/z (ESI): 266 [M+H] + .
  • Step 3 Compound 2a-3 (80 mg, 0.297 mmol) was added 2 mL of phosphorus oxychloride, and the mixture was stirred at 100 ° C for 2 hours. LC-MS was followed until the reaction was complete. The mixture was cooled, poured into ice water, adjusted to pH 8 with aqueous ammonia, extracted with ethyl acetate and dried and concentrated to yield 100% white solid compound 2a-4. MS m/z (ESI): 289 [M+H] + .
  • Step 4 Compound 2a-4 (100 mg, 0.347 mmol), 1a (98 mg, 0.522 mmol) and potassium carbonate (240 mg, 1.74 mmol) were added to 5 mL of DMF, and the mixture was stirred at 70 ° C overnight under argon. LC-MS was followed until the reaction was complete. The mixture was cooled, poured into water and filtered to give 150 mg of red solid compound 2a. MS m/z (ESI): 405.1 [M+H] + .
  • Step 1 A solution of compound 3a-1 (2 g, 9.3 mmol). LC-MS was followed until the reaction was complete. The reaction mixture was cooled, poured into water, and then evaporated. MS m/z (ESI): 226 [M+H] + .
  • Step 2 The preparation method is the same as the compound 2a-3 except that the compound 2a-2 in the 2a-3 process is replaced with the compound 3a-2. This gave 900 mg of a yellow solid compound 3a-3 crude product. MS m/z (ESI): 225 [M+H] + .
  • Step 3 The preparation method is the same as the compound 2a-4 except that the compound 2a-3 in the 2a-4 process is replaced with the compound 3a-3. Purification by combiflash gave white solid compound 3a-4 (1.8 g, 72%). MS m/z (ESI): 288.9 [M+H] + .
  • Step 4 The preparation method is the same as that of the compound 2a except that the compound 2a-4 in the process of 2a is replaced with the compound 3a-4. 700 mg of red solid compound 3a-5 was obtained. MS m/z (ESI): 359 [M+H] + .
  • Step 5 A solution of compound 3a-5 (700 mg, 1.96 mmol) and sodium bicarbonate (246 mg, 2.93 mmol) in ethanol (100 mL) was stirred at 80 ° C and sodium thiosulfate (1.7 g, 9.78 mmol) (15 mL) solution, the mixture was stirred at 80 ° C for 1 hour. LC-MS was followed until the reaction was complete. The reaction solution was cooled to room temperature, and a hydrochloric acid solution (300 mL, 37%) was added and the mixture was heated to 60 ° C and stirred for 1 hour. After cooling to room temperature, the mixture was adjusted to pH 8 with sodium hydroxide (4N), ethyl acetate was evaporated, and the organic layer was evaporated. MS m/z (ESI): 329 [M+H] + .
  • Step 1 A solution of compound 6a.1 (500 mg, 2.45 mmol) in EtOAc (5 mL, 12 N). Water was added to the reaction mixture, and the cake was filtered, and washed with water to give 560 mg of Compound Compound 6a. MS m/z (ESI): 248 [MH] + .
  • Step 2 A solution of compound 6a.2 (560 mg, 2.25 mmol) in DMF (5 mL). LC-MS was followed until the reaction was complete. The reaction mixture was extracted with EtOAc EtOAc (EtOAc)EtOAc. MS m/z (ESI): 262 [MH] + .
  • Step 3 The preparation method was the same as the compound 2a-2 except that the compound 2a-1 in the 2a-2 process was replaced with the compound 6a.3, and the mixture was stirred at 110 ° C for 4 hours.
  • Step 4 The preparation method is the same as the compound 2a-3 except that the compound 2a-2 in the 2a-3 process is replaced with the compound 6a.4. MS m/z (ESI): 259 [M+H] + .
  • Step 5 The preparation method is the same as the compound 2a-4 except that the compound 2a-3 in the 2a-4 process is replaced with the compound 6a.5. MS m/z (ESI): 277 [M+H] + .
  • Step 6 The preparation method was the same as the compound 2a except that the compound 2a-4 in the 2a process was replaced with the compound 6a.6, and the mixture was stirred at 70 ° C for 5 hours. MS m/z (ESI): 393 [M+H] + .
  • Step 7 The preparation method was the same as that of the compound 3a except that the compound 3a-5 in the process of 3a was replaced with the compound 6a.7, and the mixture was stirred at 80 ° C overnight.
  • Step 1 Compound 4a (500 mg, 1.34 mmol), compound 7a.1 (624 mg, 4.02 mmol), EtOAc EtOAc EtOAc EtOAc Sodium triacetoxyborohydride (852 mg, 4.02 mmol) was added portion wise and stirred at rt overnight. LC-MS was followed until the reaction was complete. The reaction solution was poured into water, and the mixture was adjusted to pH 8 with sodium hydrogen carbonate solution, extracted with dichloromethane, dried and concentrated to give the compound 7a-1. MS m / z (ESI): 512.2 [M + H] +.
  • Step 2 The preparation method is the same as the compound 7a-1 except that the compounds 4a and 7a.1 in the 7a-1 process are replaced with the compound 7a-1 and acetaldehyde. Purification by combiflash gave solid compound 7a (400 mg, 58%). MS m/z (ESI): 542.3 [M+H] + .
  • Step 2 To a solution of compound 9a-1 (286 mg, 0.88 mmol) and 2-iodopropane (249 mg, 1.47 mmol) in DMF (5 mL) 3 hours. LC-MS was followed until the reaction was complete. The reaction solution was poured into water, extracted with ethyl acetate, and then evaporated and evaporated. MS m/z (ESI): 298 [M+H] + .
  • Step 1 A solution of compound 2a-4 (5 g, 6.9 mmol) in EtOAc (EtOAc) (EtOAc) LC-MS was followed until the reaction was complete. The reaction mixture was cooled to room temperature. After filtered, the filtrate was evaporated to ethylamine. MS m/z (ESI): 257 [M+H] + .
  • Step 3 The preparation method is the same as that of the compound 7a, except that the compound 7a-1 and the acetaldehyde in the process of the 7a process are replaced with the compound 11a-2 and the tetrahydropyrone.
  • Step 4 The preparation method is the same as that of the compound 7a, except that the compound 7a-1 in the process of 7a is replaced with the compound 11a-3.
  • Step 5 The preparation method is the same as the compound 2a-4 except that the compound 2a-3 in the 2a-4 process is replaced by the compound 11a-4.
  • Step 6 The preparation method is the same as the compound 2a except that the compound 2a-4 in the process of 2a is replaced with the compound 11a-5.
  • the preparation method is the same as that of the compound 10a, except that the compound z-6 in the process of 10a is replaced with the compound 21-1.
  • Step 1 A solution of the compound malononitrile (12 g, 181.7 mmol) in dry tetrahydrofuran (225 mL) was stirred for 1 hour in ice-cooled, sodium hydrogen (4.8 g, 199.8 mmol) was added in portions and stirred for 2 hours, and compound 13a was added dropwise. -1 (16.8 g, 199.8 mmol), the mixture was slowly warmed to room temperature for 1 hour. The reaction mixture was quenched with aq. EtOAc (EtOAc)EtOAc. MS m/z (ESI): 151 [M+H] + .
  • Step 2 A mixture of compound 13a-2 (28 g, 181.7 mmol), EtOAc (2. The reaction solution was filtered, and the solid residue was crystallized from methanol to yield 25 g of Compound 13a-3. MS m/z (ESI): 151 [M+H] + .
  • Step 3 The preparation method is the same as the compound 2a-4 except that the compound 2a-3 in the 2a-4 process is replaced with the compound 13a-3.
  • Step 4 A mixture of compound 13a-4 (300 mg, 1.78 mmol), sodium methoxide (481 mg, 8.9 mmol) and methanol (15 mL). LC-MS was followed until the reaction was complete. The solvent was removed by concentration, the residue was taken and water was applied to EtOAc. MS m/z (ESI): 495 [M+H] + .
  • Step 5 The preparation method is the same as Compound 1a except that Compound 1a-1 in Process 1a is replaced by Compound 13a-5. MS m/z (ESI): 152 [M+H] + .
  • Step 6 The preparation method is the same as Compound 2a except that Compound 2a-4 in Process 2a is replaced by Compound 13a-6. MS m/z (ESI): 152 [M+H] + .
  • Step 7 The preparation method is the same as the compound 11a-1 except that the compound 2a-4 in the 11a-1 process is replaced with the compound 13a-7.
  • Step 1 The preparation method was the same as the compound z-225 except that the compound z-156 in the z-225 process was replaced with the compound 14a-1.
  • Step 2 The preparation method is the same as that of the compound 9a-1 except that the compound 6a in the 9a-1 process is replaced with the compound 14a-2.
  • the preparation method is the same as that of the compound 1a, and the compound 1a-1 in the method of preparation 1a is replaced with the compound z-6.
  • Step 1 Compound 38a-1 (10.36 g, 70 mmol), benzyl chloride (10.58 g, 84 mmol) LC-MS was followed until the reaction was complete. The reaction solution was cooled and filtered, and the filtrate was concentrated and purified by combiflash to yield 4 g of Compound 38a-2. MS m/z (ESI): 239 [M+H] + .
  • Step 2 The preparation method is the same as Compound 1a except that Compound 1a-1 in Process 1a is replaced by Compound 38a-2. MS m/z (ESI): 243 [M+H] + .
  • Step 1 To a solution of the compound propyl amide (420 mg, 5 mmol) in EtOAc (10 mL) EtOAc (EtOAc (EtOAc) Stir at room temperature for 3 hours. LC-MS was followed until the reaction was complete. Saturated ammonium chloride solution and water were added to the reaction mixture, and a solid was precipitated, filtered, and the filter cake was washed with water and dried under reduced pressure to give 520 mg of Compound 39a-2. MS m/z (ESI): 162 [M+H] + .
  • Step 2 The preparation method is the same as the compound 38a-2 except that the compound 38a-1 in the 38a-2 process is replaced with the compound 39a-2.
  • Step 3 The preparation method is the same as Compound 1a except that Compound 1a-1 in Process 1a is replaced by Compound 39a-3. MS m/z (ESI): 257 [M+H] + .
  • Step 1 Compound 40a-1 (120 g, 0.74 mol), magnesium chloride (63.5 g, 0.67 mol) and triethylamine (187 mL, 1.33 mol) in acetonitrile (250 mL), slowly added dropwise acetyl chloride below 20 °C (52.3 g, 0.67 mol), the mixture was stirred at room temperature overnight. A hydrochloric acid solution was added to the reaction mixture to adjust the pH to 1-2, ethyl acetate was evaporated, and the organic layer was dried and concentrated to give compound 40a-2. MS m/z (ESI): 203 [M+H] + .
  • Step 2 A solution of compound 40a-2 (154 g, 0.59 mol) in acetic acid (500 mL). The reaction solution was concentrated to 200 mL, added with 200 mL of ethanol, stirred, and filtered to give Compound 40a-3. MS m/z (ESI): 171 [M+H] + .
  • Step 3 A solution of sodium hydroxide (1 g, 25.6 mmol) in water (18 mL) EtOAc (EtOAc, EtOAc. After an hour, it was heated to 80 ° C and stirred for 3 hours. The reaction solution was filtered, and the cake was dried under reduced pressure to give Compound 40a-4. MS m/z (ESI): 185 [M+H] + .
  • Step 4 Compound 40a-4 (20 g, 108 mmol) in EtOAc (EtOAc: EtOAc. 40a.1 (20.34 g, 130 mmol), the mixture was stirred at room temperature for 16 h. The reaction solution was extracted with ethyl acetate/water, and then dried and concentrated, and then purified to afford compound 40a-5. MS m/z (ESI): 305.1 [M+H] + .
  • Step 5 The preparation method is the same as Compound 1a except that Compound 1a-1 in Process 1a is replaced by Compound 40a-5.
  • Step 6 The preparation method is the same as the compound 29b-2 except that the compound 29b-1 in the process of the 29b-2 process is replaced with the compound 40a-6.
  • Step 1 The preparation method is the same as Compound 38a-2 except that Compound 38a-1 in Process 38a-2 is replaced by Compound 41a-1. MS m/z (ESI): 239 [M+H] + .
  • Step 2 A solution of compound 41a-2 (300 mL, EtOAc. LC-MS was followed until the reaction was complete. The reaction was quenched with methanol, and the mixture was concentrated and purified by combiflash to yield 100 mg of white solid compound 41a-3. MS m/z (ESI): 242 [M+H] + .
  • Step 3 A solution of compound 41a-3 (60 mg, EtOAc. LC-MS was followed until the reaction was complete. The system was quenched with water and extracted with ethyl acetate. MS m/z (ESI): N/A.
  • Step 1 Compound 1b-1 (1 g, 4 mmol) in EtOAc (20 mL). LC-MS was followed until the reaction was complete. The reaction solution was cooled, poured into 200 mL of water, extracted with ethyl acetate, and concentrated to give 1.1 g of Compound 1b-2 crude product. MS m/z (ESI): 495 [M+H] + .
  • Step 2 Compound DMF (20mL) 1b-2 ( 1g, 3.92mmol) was added a solution of the compound Pd (dppf) Cl 2 (144mg , 0.19mmol), compound 1b.2 (1.2g, 3.33mmol) and potassium acetate ( 570 mg, 5.8 mmol), and the mixture was stirred at 80 ° C under argon overnight. The reaction mixture was concentrated and purified by combiflash to afford compound 1b (400 mg, 31%). MS m / z (ESI): 304 [M + H] +.
  • the intermediate compound is represented by the formulae (A) and (B), and the substituent R is shown in the following table.
  • the preparation method is the same as that of the compound 1b, except that the compounds 1b-2 and 1b.2 in the process of the 1b process are replaced with the compounds 27b-1 and 27b.1.
  • Step 1 The preparation method was the same as that of the compound 11a-3 except that the compound 11a-2 in the 11a-3 process was replaced with the compound 28b-1. MS m/z (ESI): 27.21. [M+H] + .
  • Step 2 The preparation method is the same as the compound z-9 except that the compound 9-2 in the z-9 process is replaced with the compound 28b-2.
  • Step 1 Compound 29b-1 (500 mg, 2.48 mmol) in dichloromethane (30 mL) EtOAc (EtOAc) hour. The reaction solution was diluted with methylene chloride, washed with 1M aqueous hydrochloric acid and sodium hydrogen carbonate, and then cooled to room temperature. The organic layer was dried and concentrated to give 650 mg of white solid compound 29b-2. MS m/z (ESI): 2221. [M+H] + .
  • Step 2 A mixture of compound 29b-2 (528 mg, 2 mmol), compound 29b.1 (427 mg, 2.2 mmol), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc A sodium bicarbonate solution was added to the mixture, concentrated, and purified by combiflash to yield 150 mg of Compound 29b-3. MS m/z (ESI): 378 [M+H] + .
  • Step 3 The preparation method is the same as the compound z-8 except that the compound 8-1 in the z-8 process is replaced with the compound 29b-3.
  • Step 4 The preparation method was the same as the compound z-226 except that the compound z-201 in the z-226 process was replaced with the compound 29b-4. MS m/z (ESI): 292 [M+H] + .
  • Step 1 The preparation method was the same as that of the compound 9a except that the compound 9a-1 and 2-iodopropane in the process of the process 9a were replaced with the compound 30b-1 and N-methylpiperazine. MS m/z (ESI): 240 [M+H] + .
  • Step 2 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 30b-2.
  • Step 3 a solution of compound 30b-3 (700 mg, 3.35 mmol) in water (50 mL) EtOAc (EtOAc) Cuprous bromide (960 mg, 6.69 mmol) was continued for 1 hour. LC-MS was followed until the reaction was complete. The reaction mixture was poured into water, and the mixture was evaporated to EtOAc EtOAc EtOAc. MS m/z (ESI): 275 [M+H] + .
  • Step 4 The preparation method is the same as that of the compound 1b, except that the compound 1b-2 in the 1b process is replaced with the compound 30b-4.
  • Step 1 A solution of compound 31b-1 (500 mg, 2.9 mmol) in carbonic acid (6 mL) was added NBS (540 mg, 3 mmol) and benzoyl peroxide (49 mg, 0.2 mmol) under argon. Stir at °C for 36 hours. The reaction solution was concentrated and purified by combiflash to yield 160 mg of Compound 31b-2. MS m/z (ESI): 275 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 9a, except that the compound 9a-1 and 2-iodopropane in the process of Process 9a are replaced with the compound 31b-1 and morpholine.
  • the preparation method is the same as that of the compound 9a, except that the compound 9a-1 and 2-iodopropane in the process of the process 9a are replaced with the compounds 32b-1 and 32b.1.
  • Step 1 Compound 35b-1 (7.8 g, 50 mmol) in dichlorohexane (150 mL) EtOAc. Sodium hydroxide (20 mL, 10%) was added to the reaction mixture, and the organic layer was dried and concentrated to give 10 g of Compound 35b-2. MS m/z (ESI): 228 [M+H] + .
  • Step 2 A solution of compound 35b-2 (10 g, 44 mmol. The reaction solution was cooled to room temperature, adjusted to pH 8 with potassium carbonate, and ethyl acetate was evaporated. MS m/z (ESI): 184 [M+H] + .
  • Step 1 The preparation method is the same as the compound 35b-2 except that the morpholine in the 35b-2 process is replaced with the compound 36b.1. MS m/z (ESI): 230 [M+H] + .
  • Step 2 The preparation method is the same as the compound 35b, except that the compound 35b-2 in the 35b process is replaced with the compound 36b-2.
  • Step 1 Compound 35b-1 (1 g, 6.98 mmol), triethylamine (1.41 g, 13.97 mmol), DMAP (128 mg, 1.05 mmol) in dichloroethane (30 mL) Acetic anhydride (2.2 g, 10.48 mmol) was stirred at room temperature overnight. The reaction solution was poured into water, extracted with dichloromethane, and the organic layer was washed with 1M hydrochloric acid and water, and then dried and concentrated to give 1.3 g of Compound 37b-1. MS m/z (ESI): 240 [M+H] + .
  • Step 3 The preparation method is the same as the compound 35b except that the compound 35b-2 in the 35b process is replaced with the compound 37b-2.
  • Step 1 Compound 3a-4 (1 g, 4.35 mmol) in tetrahydrofuran (20 mL), water (4 mL), EtOAc (EtOAc (EtOAc) hour. LC-MS was followed until the reaction was complete. The reaction solution was filtered cold, and the filtrate was concentrated to give Compound 38b-1. MS m/z (ESI): 213 [M+H] + .
  • Step 2 To a solution of compound 38b-1 (220 mg, 1 mmol) in EtOAc (30 mL) EtOAc (EtOAc, EtOAc, EtOAc Stir at room temperature for 6 hours. LC-MS was followed until the reaction was complete. The reaction solution was concentrated and purified by combiflash to give compound 38b-2. MS m/z (ESI): 275.9 [M+H] + .
  • Step 3 The preparation method is the same as Compound 2a except that Compound 2a-4 in Process 2a is replaced by Compound 38b-2. MS m/z (ESI): 392 [M+H] + .
  • Step 1 The preparation method is the same as the compound 35b-2 except that the morpholine in the 35b-2 process is replaced with the compound 39b.1. MS m/z (ESI): 228 [M+H] + .
  • Step 2 The preparation method is the same as the compound 35b, except that the compound 35b-2 in the 35b process is replaced with the compound 39b-1.
  • Step 1 The preparation method is the same as the compound 35b-2 except that the morpholine in the 35b-2 process is replaced with the compound 41b.1. MS m/z (ESI): 197 [M+H] + .
  • Step 2 The preparation method is the same as the compound 35b except that the compound 35b-2 in the 35b process is replaced with the compound 41b-1.
  • Step 1 A solution of compound 42b-1 (20 g, 110.4 mmol) and DCMMeOH (21.8 g, 110.4 mmol) The reaction liquid was cooled, poured into ice water, and the solid was precipitated, filtered, and the filter cake was dried under reduced pressure to give 32 g of solid compound 42b-2.
  • Step 2 A solution of compound 42b-2 (32 g, 148.4 mmol) in MeOH (150 mL) LC-MS was followed until the reaction was complete. 5 g of potassium carbonate in water (10 mL) was slowly added to the reaction mixture, concentrated, and extracted with ethyl acetate/water. MS m/z (ESI): 230.6 [M+H] + .
  • Step 3 The preparation method is the same as the compound 2a-2 except that the compound 2a-1 in the 2a-2 process is replaced with the compound 42b-3. MS m/z (ESI): 226.7 [M+H] + .
  • Step 4 The preparation method is the same as the compound 2a-3 except that the compound 2a-2 in the 2a-3 process is replaced with the compound 42b-4. MS m/z (ESI): 224.9 [M+H] + .
  • Step 1 The preparation method is the same as the compound 31b-2 except that the compound 31b-1 in the process of the 31b-2 process is replaced with the compound 43b-1.
  • Step 2 The preparation method is the same as that of the compound 9a, except that the compound 9a-1 and 2-iodopropane in the process of the process 9a are replaced with the compound 43b-2 and morpholine.
  • the preparation method is the same as that of the compound 9a, except that the compound 9a-1 and 2-iodopropane in the process of Process 9a are replaced with the compounds 43b-2 and 14a.
  • the preparation method is the same as that of the compound 31b-2, except that the compound 9a-1 in the process of the 31b-2 process is replaced with the compound 45b-1.
  • Step 1 A solution of compound 46b-1 (500 mg, 2.49 mmol) in THF (10 mL) EtOAc. LC-MS was followed until the reaction was complete. The reaction mixture was poured into ice water, extracted with ethyl acetate. MS m/z (ESI): 204 [M+H] + .
  • the preparation method is the same as that of the compound 46b, except that the compound 46b-2 in the method of the method 46b is replaced with the compound 47b-1.
  • the preparation method is the same as that of the compound 46b, except that the compound 46b-2 and N-methylpiperazine in the process of the method 46b are replaced with the compound 47b-1 and dimethylamine.
  • the preparation method is the same as that of the compound 9a, except that the compound 9a-1 and 2-iodopropane in the process of the process 9a are replaced with the compound 49b-1 and N-methylpiperazine.
  • the preparation method is the same as that of the compound 46b, except that the N-methylpiperazine in the process of the method 46b is replaced with morpholine. MS m/z (ESI): 275 [M+H] + .
  • the preparation method is the same as that of the compound 50b, except that the compound 50b-1 in the 50b process is replaced with N-methylpiperazine. MS m/z (ESI): 285 [M+H] + .
  • Step 1 Compound 2a (200 mg, 0.496 mmol), Compound 1b (225 mg, 0.744 mmol), Pd (dppf) Cl 2 (1,8 mg, 0.025 mmol), sodium carbonate (105 mg, 0.992 mmol), 1,4- A mixture of oxyhexacyclohexane (4 mL) and 0.4 mL of water was stirred at 100 ° C for 30 minutes under an argon atmosphere. LC-MS was followed until the reaction was complete. The reaction liquid was cooled, poured into water, and filtered to give 200 mg of a red solid compound 1-1. MS m/z (ESI): 500.3 [M+H] + .
  • Step 2 A solution of compound 1-1 (200 mg, 0.4 mmol) elute LC-MS was followed until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated to give 150 mg of Compound Compound 1-2. MS m/z (ESI): N/A.
  • Step 3 Compound 1-2 (130 mg, 0.277 mmol), compound 1.1 (138 mg, 1.38 mmol), and a solution of acetic acid (0.5 mL) in dichloromethane (20 mL), stirred at room temperature for 30 min.
  • Sodium borohydride (586 mg, 2.77 mmol) was stirred at room temperature for 7 h.
  • LC-MS was followed until the reaction was complete.
  • the reaction solution was poured into water, and the mixture was adjusted to pH 8 with sodium bicarbonate solution, extracted with dichloromethane, and then dried and evaporated.
  • Step 4 Compound 1-3 (200 mg, 0.361 mmol), acetaldehyde (159 mg, 3.61 mmol), and 0.5 mL of dichloromethane (20 mL) Sodium (766 mg, 3.61 mmol) was stirred at room temperature overnight. LC-MS was followed until the reaction was complete. The reaction mixture was poured into water, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated MS m/z (ESI): 582.4 [M+H] + .
  • the preparation method is the same as that of the compound z-1, except that the compound 1-3 and acetaldehyde in the z-1 process are replaced with the compound 4a and the tetrahydropyrone. Purification by Prep-HPLC gave white solid compound z-2 (57 mg, 31%). MS m/z (ESI): 457.2 [M+H] + .
  • Step 1 The preparation method is the same as the compound z-1 except that the compound 1-3 and acetaldehyde in the z-1 process are replaced with the compound 3a and the tetrahydropyrone. Purification by Prep-TLC gave yellow solid compound 4-1 (40 mg, 10.6%). MS m/z (ESI): 437 [M+H] + .
  • Step 2 The preparation method is the same as the compound z-1 except that the compound 1-3 in the z-1 process is replaced by the compound 4-1, and toluene is used as a solvent. Purification by Prep-HPLC gave white solid compound z-4 (3.5 mg, 10%). MS m/z (ESI): 441 [M+H] + .
  • Step 1 The preparation method was the same as that of the compound z-7, except that the compound 7.1 in the z-7 process was replaced with the compound 2b, and the reaction was carried out for 15 minutes under microwave. 82 mg of the compound 8-1 was obtained as a yellow oil. MS m/z (ESI): 681.4 [M+H] + .
  • Step 2 A solution of compound 8-1 (82 mg, 0.12 mmol) in dichloromethane (6 mL). LC-MS was followed until the end of the reaction. The reaction mixture was concentrated and purified with EtOAcjjjjj MS m/z (ESI): N/A.
  • Step 1 The preparation method was the same as that of the compound 4-1 except that the compound 3a and the tetrahydropyrone in the 4-1 process were replaced with the compounds 9-1 and 9.1. MS m/z (ESI): 628[M+H] + .
  • Step 2 The preparation method is the same as the compound z-4, except that the compound 4-1 in the z-4 process is replaced with the compound 9-1.
  • Step 3 A solution of compound 9-2 (180 mg, 0.275 mmol) in dichloromethane (10 mL) LC-MS was followed until the end of the reaction. The reaction mixture was concentrated to give purified white crystals (yield: MS m/z (ESI): 466 [M+H] + .
  • Step 1 The preparation method is the same as the compound z-7, except that the compound 7.1 in the z-7 process is replaced by the compound 10.1, and acetonitrile is used as a solvent.
  • Compound 10-1 (66 mg, 72%) was purified by combiflash. MS m/z (ESI): 447.4 [M+H] + .
  • Step 2 Compound 10-1 (66 mg, 0.188 mmol), EtOAc (EtOAc) LC-MS was followed until the end of the reaction. The reaction mixture was filtered, and the filtrate was evaporated. MS m/z (ESI): 449.3 [M+H] + .
  • Step 1 The preparation method is the same as the compound z-7, except that the compound 7.1 in the z-7 process is replaced by the compound 11.1, and acetonitrile is used as a solvent. Purification by combiflash gave compound 11-1 (70 mg, 79%). MS m/z (ESI): 433.4 [M+H] + .
  • Step 2 The preparation method was the same as the compound z-10 except that the compound 10-1 in the z-10 process was replaced with the compound 11-1. Purification by Prep-HPLC gave white solid compound z-11 (20 mg, 28.4%). MS m/z (ESI): 435.3 [M+H] + .
  • Step 1 Compound 1c (100 mg, 0.32 mmol) in 1,4-dioxane (10 mL) was added THF (70 mg, 0.64 mmol) and trifluoroacetic acid (110 mg, 0.96 mmol) After stirring for 1 hour, sodium triacetoxyborohydride (210 mg, 0.96 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated to give the title compound (yel. MS m/z (ESI): 397 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 12-1 except that the compound 1c and the tetrahydropyrone in the 12-1 process are replaced with the compound 12-1 and acetaldehyde. Purification by Prep-HPLC gave white solid compound z-12 (0.85 mg, 1%). MS m/z (ESI): 425.3 [M+H] + .
  • Step 1 The preparation method was the same as that of the compound 4-1 except that the compound 3a and the tetrahydropyrone in the 4-1 method were replaced with the compounds 6a and 13.1. MS m/z (ESI): 546 [M+H]+.
  • Step 2 The preparation method is the same as the compound z-4, except that the compound 4-1 in the z-4 process is replaced with the compound 13-1.
  • Step 3 The preparation method is the same as the compound z-8, except that the compound 17-1 in the z-8 process is replaced with the compound 13-2. Purification by HPTLC gave white solid compound z-13 (100 mg, 67.2%). MS m/z (ESI): 474 [M+H] + .
  • Step 1 The preparation method was the same as the compound z-7 except that the compound 7.1 in the z-7 process was replaced with the compound 7b, and the compound 14-1 (80 mg, 70%) was purified by combiflash. MS m/z (ESI): 557.4 [M+H] + .
  • Step 2 Compound 14-1 (80 mg, 0.144 mmol). LC-MS was followed until the end of the reaction. The reaction mixture was concentrated. EtOAc mjjjjjjjj MS m/z (ESI): 473.3 [M+H] + .
  • Step 2 The preparation method is the same as that of the compound 15-1 except that the compound 4a and 15.1 in the 15-1 process are replaced with the compound 15-1 and the compound acetaldehyde. Purification by silica gel column chromatography (dichloromethanol /methanol: MS m/z (ESI): 526.0 [M+H] + .
  • Step 1 The preparation method is the same as the compound z-1 except that the compound 1-3 and acetaldehyde in the z-1 process are replaced with the compound 6a and the tetrahydropyrone.
  • Step 2 The preparation method is the same as the compound z-1 except that the compound 1-3 in the z-1 process is replaced with the compound 16-1. Purification by Prep-HPLC gave white solid compound z-16 (9.6 mg, 4%). MS m/z (ESI): 475.3 [M+H] + .
  • Example 17 3-((5-((1R,4R)-4-(Dimethylamino)cyclohexyl)(ethyl)amino)-7-(6-(1-methylpiperidin-4) Of pyridyl-3-yl)-ylamino)methyl)-4,6-lutidine-2(1H)-one (compound z-17)
  • Step 1 The preparation was carried out in the same manner as the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process were replaced with the compounds 22b and 27b.
  • Step 2 A solution of compound 17-1 (30 mg, EtOAc) (EtOAc) LC-MS was followed until the end of the reaction. The reaction mixture was filtered, and then filtered and evaporated, mjjjj MS m/z (ESI): 622.5 [M+H] + .
  • Example 18 1-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylamino)-5-(methyl(tetrahydro-2H-pyridyl) Of m--4-yl)amino)isoquinoline-7-carboxamide (compound z-18)
  • Step 1 Toluene sodium hypochlorite solution (201 mg) was added dropwise to a solution of compound z-18 (245 mg, 0.54 mmol) and sodium hydroxide (108 mg, 2.7 mmol) in 1,4-dioxane (5 mL) and water (5 mL) , 2.7 mmol), and the mixture was stirred at 80 ° C for 3 hours. LC-MS was followed until the end of the reaction. The pH of the reaction mixture was adjusted to 7-8 with 4N aqueous hydrochloric acid, and the solvent was evaporated. The residue was purified from methylene chloride/water. MS m/z (ESI): 422 [M+H] + .
  • Step 2 A solution of compound 19-1 (105 mg, 0.25 mmol) and triethylamine (101 mg, 1 mmol) in dichloromethane (5 mL). Stir for 3 hours. LC-MS was followed until the end of the reaction. The reaction was quenched with EtOAc (EtOAc)EtOAc. MS m/z (ESI): 464.3 [M+H] + .
  • Step 1 The preparation method is the same as the compound z-6, except that the compound z-3 in the z-6 process is replaced with the compound 12a.
  • Step 2 A mixture of compound 21-1 (70 mg, 0.148 mmol), EtOAc (4 mL, 1M) LC-MS was followed until the end of the reaction. The reaction mixture was poured into water, and the mixture was evaporated to EtOAc. EtOAc (EtOAc m. 1.4%). MS m/z (ESI): 491.4 [M+H] + .
  • the structures of the compounds Z-23 to Z-194 and Z-195 to Z-215 are those in the formula (I) when X is NH; Z 1 is N; Z 2 and Z 3 are CH; and R 1 and R 3 are hydrogen;
  • R 2 , R 4 , and NR 5 R 6 are as shown in the following table:
  • Example 194 4-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylamino)-8-(ethyl(tetrahydro-2H-pyridyl) Preparation of m--4-yl)amino)quinoline-6-carbonitrile (compound z-194)
  • Step 1 Compound 194-1 (2.1g, 10mmol) in CH (OEt) 3 (20mL) was added Compound 194.1 (2.1g, 15mmol), the mixture was stirred at 80 deg.] C 1 hour.
  • the LC-MS was traced to completion of the reaction, and the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with n-hexane to afford compound 194-2.
  • Step 2 A solution of compound 194-2 (1.85 g, 5 mmol) in diphenyl ether (15 mL) LC-MS was traced to completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was dried and concentrated, and then purified by combiflash to obtain compound 194-3. MS m/z (ESI): 266 [MH] + .
  • Step 3 The preparation method is the same as the compound 2a-4 except that the compound 2a-3 in the process of the compound 2a-4 is replaced with the compound 194-3.
  • Step 4 The preparation method is the same as the compound 2a except that the compound 2a-4 in the process of the compound 2a is replaced with the compound 194-4.
  • Step 5 The preparation method is the same as the compound 11a-1 except that the compound 2a-4 in the process of the compound 11a-1 is replaced with the compound 194-5.
  • Step 6 The preparation method is the same as the compound 11a-3 except that the compound 11a-2 in the process of the compound 11a-3 is replaced with the compound 194-6. MS m/z (ESI): 495 [M+H] + .
  • Step 7 The preparation method is the same as the compound 11a-4 except that the compound 11a-3 in the process of the compound 11a-4 is replaced with the compound 194-7.
  • Step 8 The preparation method is the same as the compound z-7, except that the compound z-3 and 7.1 in the process of the compound z-7 are replaced with the compound 194-8 and sodium cyanoborohydride.
  • Example 206 3-((5-(Ethyl(4-isopropylcyclohexyl)amino)-7-(2-methoxyethoxy)isoquinolin-1-ylamino) Preparation of methyl)-4,6-dimethyl-2(1H)-one (compound z-206)
  • Step 1 The preparation method is the same as that of the compound 1b, except that the compound 1b-2 in the 1b process is replaced with the compound 2a-4.
  • Step 2 Compound 206-1 (1g, 2.99mmol) in acetone (20mL) was added dropwise H 3 K 5 O 18 S 4 (2.02g, 3.29mmol) in water (4mL) solution, the mixture was stirred at room temperature for 15 minutes. LC-MS was followed until the reaction was complete. The system was quenched with ammonium chloride solution, extracted with dichloromethane, and then dried and evaporated. MS m/z (ESI): 223 [M+H] + .
  • Step 3 The preparation method is the same as that of the compound 2a except that the compound 2a-4 and 1a in the process of 2a are replaced with the compound 206-2 and 2-bromoethyl methyl ether. MS m/z (ESI): 283.1 [M+H] + .
  • Step 4 The preparation method is the same as Compound 2a except that Compound 2a-4 in Process 2a is replaced by Compound 206-3. MS m/z (ESI): 399.3 [M+H] + .
  • Step 5 The preparation method is the same as Compound 3a except that Compound 3a-5 in Process 3a is replaced by Compound 206-4. MS m/z (ESI): 369.3 [M+H] + .
  • Step 6 The preparation method is the same as the compound 15-1 except that the compound 4a in the 15-1 process is replaced with the compound 206-5.
  • Step 7 The preparation method is the same as the compound z-15 except that the compound 15-1 in the z-15 process is replaced with the compound 206-6. Purification by Prep-HPLC gave solid compound z-206 (38 mg, 18%). MS m/z (ESI): 522.4 [M+H] + .
  • Example 216 4-((5-((4-(Dimethylamino)cyclohexyl)(ethyl)amino)-7-(6-(4-methylpiperazin-1-yl)pyridine-3 Of -yl)isoquinolin-1-ylamino)methyl)-1,5-dimethyl-1H-pyrazole-3-(2H)-one (compound z-216)
  • Step 1 Compound 2a-4 (100 mg, 0.34 mmol) in EtOAc (2 mL). Water was added to the reaction mixture, filtered, and the filter cake was washed with water and dried under reduced pressure at a temperature below 50 ° C to obtain Compound 216-1. MS m/z (ESI): 418[M+H] + .
  • Step 2 Compound 216-1 (3 g, 7.1 mmol) m.
  • the reaction mixture was concentrated to give Compound 216-2.
  • Step 3 Compound 216-2 (470 mg, 1.7 mmol) in EtOAc (10 mL). LC-MS was followed until the reaction was complete. The reaction solution was extracted with a dichloromethane/water system, the organic layer was dried and concentrated, and then purified by combiflash to afford compound 216-3. MS m/z (ESI): 512 [M+H] + .
  • Step 4 The preparation method is the same as that of the compound 11a-1 except that the compound 2a-4 in the 11a-1 process is replaced with the compound 216-3.
  • Step 5 The preparation method is the same as the compound 15-1 except that the compound 4a in the 15-1 process is replaced with the compound 216-4. MS m/z (ESI): 607 [M+H] + .
  • Step 6 The preparation method is the same as the compound z-15 except that the compound 15-1 in the z-15 process is replaced with the compound 216-5.
  • Step 7 The preparation method is the same as the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process are replaced by the compounds 216-6 and 5b.
  • Example 217 1-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylamino)-7-(6-(4-methylpiperazine) Preparation of -1-yl)pyridin-3-yl)isoquinoline-5-carbonitrile (compound z-217)
  • Step 1 The preparation method was the same as that of the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process were replaced with the compounds 2a and 5b.
  • Step 2 The preparation method is the same as the compound 11a-1 except that the compound 2a-4 in the 11a-1 process is replaced with the compound 217-1.
  • Step 3 The preparation method is the same as the compound 30b-4 except that the compound 30b-3 in the 30b-4 process is replaced with the compound 217-2.
  • Step 4 The preparation method is the same as the compound z-6, except that the compound z-3 in the z-6 process is replaced with the compound 217-3. Purification by Prep-HPLC gave white solid compound z-217 (3 mg, 3.4%). MS m/z (ESI): 495 [M+H] + .
  • Example 218 3-((5-((4-(Dimethylamino)cyclohexyl)(ethyl)amino)-6-fluoro-7-(6-(4-methylpiperazin-1-yl) Preparation of pyridin-3-yl)isoquinolin-1-ylamino)methyl)-4,6-dimethyl-2(1H)-one (compound z-218)
  • Step 1 The preparation method is the same as that of the compound 15-1, except that the compound 4a in the 15-1 process is replaced with the compound 11a-2.
  • Step 2 The preparation method is the same as the compound z-15 except that the compound 15-1 in the z-15 process is replaced with the compound 218-1.
  • Step 3 The preparation method is the same as that of the compound 2a, except that the compounds 2a-4 and 1a in the process of 2a are replaced with the compounds 218-2 and 38a.
  • Step 4 The preparation method is the same as the compound z-8 except that the compound 8-1 in the z-8 process is replaced with the compound 218-3. MS m/z (ESI): 544 [M+H] + .
  • Step 5 The preparation method is the same as the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process are replaced by the compounds 218-4 and 5b. Purification by Prep-HPLC gave white solid compound z-218 (1 mg, 3.4%). MS m/z (ESI): 641.5 [M+H] + .
  • Example 219 3-((5-((4-(Dimethylamino)cyclohexyl)(ethyl)amino)-3-methoxy-7-(6-(4-methylpiperazine-1) Of pyridyl-3-yl)isoquinolin-1-ylamino)methyl)-4,6-dimethyl-2(1H)-one (compound z-219)
  • Step 1 The preparation method is the same as that of the compound 15-1, except that the compound 4a in the 15-1 process is replaced with the compound 6c.
  • Step 2 The preparation method is the same as the compound z-15 except that the compound 15-1 in the z-15 process is replaced with the compound 219-1.
  • Step 3 The preparation method is the same as the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process are replaced by the compounds 219-2 and 5b. Purification by Prep-HPLC gave white solid compound z-219 (400 mg, 97%). MS m/z (ESI): 653.5 [M+H] + .
  • Example 220 3-((5-(Ethyl(2-methylpiperidin-4-yl)amino)-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl Preparation of isoquinolin-1-ylamino)methyl)-4,6-lutidine-2(1H)-one (compound z-220)
  • Step 1 The preparation method is the same as that of the compound 15-1, except that the compound 15.1 in the 15-1 process is replaced with the compound 40b. MS m/z (ESI): 692 [M+H] + .
  • Step 2 The preparation method is the same as the compound z-15 except that the compound 15-1 in the z-15 process is replaced with the compound 220-1.
  • Step 3 The preparation method is the same as the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process are replaced by the compounds 220-2 and 5b.
  • Step 4 Compound 220-3 (20 mg, 0.025 mmol) in dichloromethane (10 mL). LC-MS was followed until the end of the reaction. The reaction mixture was concentrated and purified with EtOAc EtOAc EtOAc MS m/z (ESI): 495 [M+H] + .
  • Step 1 A solution of compound 3d (100 mg, 1.1 mmol) and EtOAc (EtOAc, EtOAc (EtOAc) LC-MS was followed until the reaction was complete. The reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, and then purified by combiflash to obtain 300 mg of solid compound 221-1. MS m/z (ESI): 595.4 [M+H] + .
  • Step 1 Compound 22-1 (46 g, 407 mmol), EtOAc (EtOAc (EtOAc) After that, it was stirred to room temperature and stirred for 16 hours. The solid in the system was pulverized, washed with ethyl acetate several times, and dried under reduced pressure to give Compound 222-2. MS m/z (ESI): 160 [M+H] + .
  • Step 2 Compound 222.1 (25.4 g, 277 mmol). The reaction solution was concentrated and purified by combiflash to give 28 g of Compound 222-3. MS m/z (ESI): 271 [M+H] + .
  • Step 3 Compound 222-3 (13 g, 48 mmol) in diphenyl ether (100 mL). The reaction mixture was purified by combiflash to give compound 222-4. MS m/z (ESI): 225 [M+H] + .
  • Step 4 Compound 222-4 (1.1 g, 4.91 mmol) and triethylamine (2 g, 19.64 mmol) in dichloromethane (30 mL) g, 12.28 mmol), the mixture was stirred at 30 ° C for 4 hours. LC-MS was followed until the reaction was complete. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. MS m/z (ESI): 357 [M+H] + .
  • Step 5 Compound 222-5 (4 g, 2.8 mmol), 222.2 (478 mg, 3.4 mmol), Xantphos (162 mg, 0.28 mmol), Pd 2 (dba) 3 (258 mg, 0.28 mmol), sodium tert-butoxide (444 mg, A solution of 4.64 mmol) in toluene (6 mL) was then reacted in a microwave at 100 °C for 12 min. LC-MS was followed until the reaction was complete. The reaction solution was filtered, concentrated and purified by EtOAc EtOAc EtOAc MS m/z (ESI): 495 [M+H] + .
  • Step 6 A solution of compound 222-6 (1.07 g, 3.07 mmol) elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut elut A solution of DMF (5 mL) was added and the mixture was stirred at room temperature for 3 hr. LC-MS was followed until the reaction was complete. The reaction solution was poured into water, extracted with dichloromethane, and then dried and evaporated. MS m/z (ESI): 377 [M+H] + .
  • Step 7 The preparation method is the same as the compound 222-6, except that the compounds 222-5 and 222.2 in the 222-6 process are replaced by the compounds 222-7 and 1a. Purification by Prep-HPLC gave white solid compound z-222 (2.9mg, 1%). MS m/z (ESI): 495 [M+H] + .
  • Example 223 3-((5-((4-(Dimethylamino)cyclohexyl)(ethyl)amino)-4-fluoro-7-(6-(4-methylpiperazin-1-yl) Preparation of pyridin-3-yl)isoquinolin-1-ylamino)methyl)-4,6-dimethyl-2(1H)-one (compound z-223)
  • Step 1 The preparation method is the same as that of the compound 11a-2, except that the compound 11a-1 in the 11a-2 process is replaced with the compound 2a-3. MS m/z (ESI): 285 [MH] + .
  • Step 2 The preparation method is the same as the compound 2a-4 except that the compound 2a-3 in the 2a-4 process is replaced with the compound 223-1.
  • Step 3 The preparation method is the same as Compound 2a except that Compound 2a-4 in Process 2a is replaced by Compound 223-2. MS m/z (ESI): 421 [M+H] + .
  • Step 4 The preparation method is the same as Compound 3a except that Compound 3a-5 in Process 3a is replaced by Compound 223-3. MS m/z (ESI): 391 [M+H] + .
  • Step 5 The preparation method is the same as the compound z-4, except that the compound 4-1 in the z-4 process is replaced with the compound 223-4.
  • Step 6 The preparation method is the same as the compound z-15 except that the compound 15-1 in the z-15 process is replaced with the compound 223-5. MS m/z (ESI): 544 [M+H] + .
  • Step 7 The preparation method was the same as the compound z-7 except that the compounds z-3 and 7.1 in the z-7 process were replaced with the compounds 223-6 and 5b. Purification by Prep-HPLC gave white solid compound z-223 (0.5 mg, 22%). MS m/z (ESI): 564 [M+H] + .
  • Example 224 3-((5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-6-fluoro-7-(6-(4-methylpiperazin-1-yl)) Preparation of pyridin-3-yl)isoquinolin-1-ylamino)methyl)-4,6-dimethyl-2(1H)-one (compound z-224)
  • Example 225 N-(4-((1-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylamino)-7-(6- Preparation of (4-methylpiperazin-1-yl)pyridin-3-yl)isoquinolin-5-yl)(ethyl)amino)cyclohexyl)acetamide (compound z-225)
  • Example 227 1-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylamino)-5-((1R,4R)-4- Preparation of (Dimethylamino)cyclohexyl)(ethyl)amino)isoquinoline-7-carboxamide (Compound z-227)
  • Step 1 The preparation method was the same as the compound z-6 except that the compound z-3 in the z-6 process was replaced with the compound z-15. MS m/z (ESI): 473.3 [M+H] + .
  • Step 2 A mixture of compound 227-1 (70 mg, 0.148 mmol) and sodium hydroxide (4 mL, 1M) LC-MS was followed until the end of the reaction. The reaction mixture was poured into water, the mixture was adjusted to pH 3, ethyl acetate was evaporated and evaporated, evaporated, evaporated, evaporated. . MS m/z (ESI): 491.4 [M+H] + .
  • Example 228 3-((5-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-7-((1-methylpiperidin-4-ylamino)methyl)isoquine Preparation of phenyl-1-ylamino)methyl)-4,6-dimethyl-2(1H)-one (compound z-228)
  • Step 1 The preparation method is the same as the compound 1a except that the compound 1a-1 in the process of Process 1a is replaced with the compound z-6. MS m/z (ESI): 436.3 [M+H] + .
  • Step 2 The preparation method is the same as the compound z-2 except that the compound 4a and the tetrahydropyrone in the z-2 process are replaced with the compound 228-1 and the compound 228.1. Purification by Prep-HPLC gave white solid compound z-228 (3.6 g, 1.6%). MS m/z (ESI): 533.4 [M+H] + .
  • Example 231 3-((5-((1S,4S)-4-(Dimethylamino)cyclohexyl)(ethyl)amino)-6-fluoro-7-(6-(4-methyl) Preparation of piperazin-1-yl)pyridin-3-yl)isoquinolin-1-ylamino)methyl)-4,6-dimethyl-2(1H)-one (compound z-231)
  • Step 1 The preparation method is the same as the compound 218-3 except that the compound 218-2 in the 218-3 process is replaced with the compound 42a.
  • Step 2 The preparation method is the same as the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process are replaced with the compounds 231-1 and 5b.
  • Step 3 The preparation method is the same as the compound z-8 except that the compound 8-1 in the z-8 process is replaced with the compound 231-2. Purification by Prep-HPLC gave white solid compound z-231 (0.7 mg, 1%). MS m/z (ESI): 641.4 [M+H] + .
  • Example 232 3-((5-((1R,4R)-4-(Dimethylamino)cyclohexyl)(ethyl)amino)-6-fluoro-7-(6-(4-methyl) Preparation of piperazin-1-yl)pyridin-3-yl)isoquinolin-1-ylamino)methyl)-4,6-dimethyl-2(1H)-one (compound z-232)
  • Step 1 The preparation method is the same as the compound 218-3 except that the compound 218-2 in the 218-3 process is replaced with the compound 43a.
  • Step 2 The preparation method is the same as the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process are replaced by the compounds 232-1 and 5b.
  • Step 3 The preparation method is the same as the compound z-8 except that the compound 8-1 in the z-8 process is replaced with the compound 232-2. Purification by Prep-HPLC gave white solid compound z-232 (23 mg, 24%). MS m/z (ESI): 641.4 [M+H] + .
  • Example 233 3-((7-Chloro-5-((1S,4S)-4-(dimethylamino)cyclohexyl)(ethyl)amino)isoquinolin-1-yloxy) A Of 4,6-lutidine-2(1H)-one (compound z-233)
  • Example 234 3-((7-chloro-5-((1R,4R)-4-(dimethylamino)cyclohexyl)(ethyl)amino)isoquinolin-1-yloxy) A Of 4,6-lutidine-2(1H)-one (compound z-234)
  • Step 1 Compound 42b (277 mg, 1.233 mmol), Compound 41a (300 mg, 1.263 mmol), EtOAc (EtOAc, EtOAc, EtOAc, EtOAc LC-MS was followed until the reaction was complete. The reaction solution was concentrated and purified by combiflash to yield 450 mg of Compound 233-1. MS m/z (ESI): 449.9 [M+H] + .
  • Step 2 The preparation method is the same as the compound 38b-1 except that the compound 3a-4 in the 38b-1 process is replaced with the compound 233-1.
  • Step 3 The preparation method is the same as the compound 15-1 except that the compound 4a in the 15-1 process is replaced with the compound 233-2.
  • Step 4 The preparation method is the same as the compound z-15 except that the compound 15-1 in the z-15 process is replaced with the compound 233-3. MS m/z (ESI): 573 [M+H] + .
  • Step 5 The preparation method is the same as the compound z-8 except that the compound 8-1 in the z-8 process is replaced with the compound 233-4.
  • the solid compound z-233 (2.2 mg, 1.4%) and z-234 (4.5 mg, 3%) were purified by Prep-HPLC. MS m/z (ESI): 483 [M+H] + .
  • Step 1 The preparation method was the same as the compound z-7, except that the compounds z-3 and 7.1 in the z-7 process were replaced with the compounds 31a and 235.1. MS m/z (ESI): 564 [M+H] + .
  • Step 2 The preparation method was the same as the compound z-10 except that the compound 10-1 in the z-10 process was replaced with the compound 235-1.
  • Step 3 The preparation method is the same as the compound z-8 except that the compound 8-1 in the z-8 process is replaced with the compound 235-2. Purification by Prep-HPLC gave white solid compound z-235 (1.3 mg, 1.8%). MS m/z (ESI): 448 [M+H] + .
  • Recombinant PRC2 (EZH2-Y641F) was purchased from Active Motif, S-methylthioadenosine (SAM) and L-polylysine (PLL) were purchased from Sigma-Aldrich, H3(1-50)K27me1 polypeptide. Purchased from Cisbio.
  • the detection system uses Perkinelmer's LANCEUltra system. In the enzyme activity experiment, the test compound was diluted at a gradient of 1:3, and then added to the reaction plate and 100 ng of the recombinase was added.
  • the cell lines used, Pfeiffer (CRL-2632), suDHL-6 (CRL-2959), and suDHL-10 (CRL-2963) were purchased from the American Type Culture Collection (ATCC). All cell lines were cultured in RPMI-1640 medium (Gbico) containing 10% fetal bovine serum (Gibco). The cultured cells were collected by centrifugation and the cell density was measured on a CounterStar counter. The appropriate number of cells were then seeded in 96-well plates and incubated overnight. The test compound was diluted at 8 gradient points in a ratio of 1:3 and added to the corresponding wells.

Landscapes

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

Abstract

提供了1,5,7-三取代的异喹啉衍生物、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

1,5,7-三取代的异喹啉衍生物、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1,5,7-三取代的异喹啉衍生物及其制备方法和作为EZH2抑制剂的应用，以及由其制备的药物组合物。
背景技术
组蛋白-赖氨酸-N-甲基转移酶EZH2参与DNA的甲基化和最终的转录抑制；通过辅因子S-腺苷-L-甲硫氨酸催化赖氨酸27位的甲基转移至组氨酸H3。这种甲基化促进异染色质的形成，从而引发基因沉默。EZH2是PRC2功能酶的部分，是通过表观遗传学维持控制调节发育和分化的基因，从而保证胚胎健康发育。EZH2的突变或过表达与许多癌症的形成相关。EZH2控制基因控制肿瘤发展，抑制EZH2的活性会减慢肿瘤的生长速度。作为靶向抑制剂，EZH2能调控多种癌症包括，乳腺癌，前列腺癌，黑色素瘤和膀胱癌。PCT申请WO2011140324A1和WO2012075080A1披露了吲哚类化合物作为EZH2抑制剂用于治疗癌症。PCT申请WO2012118812A2公开了双环杂环化合物作为EZH2抑制剂用于癌症的治疗。
因此，抑制EZH2活性将有效降低细胞增殖和侵袭，从而为EZH2介导的疾病或病症提供有益的治疗。本发明化合物作为EZH2抑制剂为疾病或由EZH2介导的肿瘤治疗提供解决方案。
发明内容
本发明的目的是提供一类结构新颖的可作为EZH2抑制剂的化合物。
本发明提供了一种式(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 PCTCN2017110459-appb-000001
式中，X为NH或O；
R1、R3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)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、C3-8环烷基(优选为C3-6环烷基)或C3-8环烷氧基(优选为C3-6环烷氧基)；
R4为氢、卤素(优选氟、氯、溴)、羟基、CN、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)、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烷氧基(优选为卤代C1-6 烷氧基，更优选为卤代C1-3烷氧基)、C3-8环烷氧基(优选为C3-6环烷氧基)、C6-10芳基(优选苯基)、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)；
Z1为N或CR8；Z2为N或CR9；Z3为N或CR10；
R8、R9、R10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)；
R2为氢、卤素(优选氟、氯、溴)、CN、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、C2-8炔基(优选为C2-6炔基，更优选为C2-3炔基)、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)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、C(O)NRa1Rb1、NRa2Rb2、NCORa3、ORa4、C6-10芳基(优选苯基)、4至6元饱和或不饱和单杂环、5至6元单环杂芳基环；
Ra1、Rb1、Ra2、Rb2、Ra3、Ra4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)、4至6元饱和单杂环、5至6元单环杂芳基环、C6-10芳基；
或Ra1、Rb1和相连的氮原子共同形成5至6元饱和单杂环；
R5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)；
R6为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)、4至6元饱和单杂环(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃，更优选为哌啶或四氢吡喃)、螺环、螺杂环、桥环、桥杂环；
所述烷基、环烷基、烷氧基、炔基、芳基、4至6元饱和或不饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环、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：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、卤素、乙酰基、羟基、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)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3烷基)、C6-10芳基、4至6元饱和单杂环、5至6元单环杂芳基、O(CH2)nOC1-8烷基或-Y-L取代；其中Y为一个键、CH2、NH、O、CON或C(O)；L为C6-10芳基、5至6元单环杂芳基环、4至6元饱和单杂环或NRa0Rb0；Ra0、Rb0各自独立地为氢、乙酰基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、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，R2中的炔基被4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)取代；所述4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，Ra1为氢或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；Rb1为氢、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)、5至6元单环杂芳基环(优选为吡啶)或苯基；或Ra1、Rb1和相连的氮原子共同形成 4至6元饱和单杂环(优选形成哌啶、哌嗪、吗啉或四氢吡喃环)；
所述4至6元饱和单杂环、5至6元单环杂芳基环或苯基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，Ra2为氢或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；Rb2为氢、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、4至6元饱和单杂环、5至6元单环杂芳基环、C6-10芳基(Rb2优选为5至6元单环杂芳基环，更优选为吡啶)；
所述4至6元饱和单杂环、5至6元单环杂芳基环或芳基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，Ra3为C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)。
在另一优选例中，Ra4为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)、5至6元单环杂芳基环(优选为吡啶)、C6-10芳基(优选为苯基)；
所述5至6元单环杂芳基环或芳基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2中的芳基(优选为苯基)为未取代的或被1、2或3个选自下组的基团取代：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)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤素、-O(CH2)nOC1-8烷基或-Y1-L1；其中Y1为一个键、CH2、NH、O或CON；L1为C6-10芳基(优选苯基)、5至6元单环杂芳基环(优选为吡啶)、4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)或NRa0Rb0；Ra0、Rb0各自独立地为氢或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；
L1中的芳基、4至6元饱和单杂环、5至6元单环杂芳基环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2中的5至6元单环杂芳基环为未取代的或被1、2或3个选自下组的基团取代：卤素、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)或-Y2-L2；其中Y2为一个键、CH2或C(O)；L2为氢、C3-6环烷基、4至6元饱和单杂环或NRa0Rb0；Ra0、Rb0各自独立地为氢或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；
L2中的4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、 羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R6为C1-6烷基、CHRa5Rb5、C3-6环烷基、4至6元饱和单杂环(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃，更优选为哌啶或四氢吡喃)、螺环、螺杂环、桥环、桥杂环；其中Ra5为氢、甲基或乙基；Rb5为苯基、5至6元单环杂芳基环(优选为吡啶)或4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)；所述烷基、苯基为未取代的或被1、2或3个选自下组的基团取代：C1-3烷氧基、NRa0Rb0或4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)；Ra0、Rb0各自独立地为氢、甲基或乙基。
在另一优选例中，R6中的环烷基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、卤素、羟基、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(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃)；Ra0、Rb0各自独立地为氢、乙酰基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、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)；所述4至6元饱和单杂环为未取代的或被C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)取代。
在另一优选例中，R6中的4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：乙酰基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、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)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3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)、4至6元饱和单杂环(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃)；所述乙酰基为未取代的或被CN或羟基取代。
在另一优选例中，X为NH。
在另一优选例中，R2为卤素(优选氟、氯、溴)、CN、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)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)。
在另一优选例中，R2为C2-8炔基(优选为C2-6炔基，更优选为C2-3炔基)；所述炔基被4至6元饱和单杂环取代(优选为哌啶、哌嗪、吗啉或四氢吡喃)；
所述4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2为C(O)NRa1Rb1；Ra1为氢或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；Rb1为氢、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、4至6元饱和单杂环(优选为 哌啶、哌嗪、吗啉或四氢吡喃)、5至6元单环杂芳基环(优选为吡啶)或苯基；或Ra1、Rb1和相连的氮原子共同形成4至6元饱和单杂环(优选形成哌啶、哌嗪、吗啉或四氢吡喃环)；
所述4至6元饱和单杂环、5至6元单环杂芳基环或苯基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2为NRa2Rb2；Ra2为氢或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；Rb2为氢、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、4至6元饱和单杂环、5至6元单环杂芳基环、C6-10芳基(Rb2优选为5至6元单环杂芳基环，更优选为吡啶)；
所述4至6元饱和单杂环、5至6元单环杂芳基环或芳基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2为NCORa3；Ra3为C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)。
在另一优选例中，R2为ORa4；Ra4为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)、5至6元单环杂芳基环(优选为吡啶)、C6-10芳基(优选为苯基)；
所述5至6元单环杂芳基环或芳基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2为苯基；所述苯基为未取代的或被1、2或3个选自下组的基团取代：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)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)、卤素、-O(CH2)nOC1-8烷基或-Y1-L1；其中Y1为一个键、CH2、NH、O或CON；L1为C6-10芳基(优选苯基)、5至6元单环杂芳基环(优选为吡啶)、4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)或NRa0Rb0；Ra0、Rb0各自独立地为氢或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；
所述芳基、4至6元饱和单杂环、5至6元单环杂芳基环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2为式A所示结构：
Figure PCTCN2017110459-appb-000002
其中R1a、R2a、R3a、R4a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)、 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)、C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)或卤素；Y1、L1如上所定义。
在另一优选例中，R1a、R3a、R4a为氢。
在另一优选例中，R2为5至6元单环杂芳基环(优选为吡啶、嘧啶或吡唑)；所述5至6元单环杂芳基环为未取代的或被1、2或3个选自下组的基团取代：卤素、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)或-Y2-L2；其中Y2为一个键、CH2或C(O)；L2为氢、C3-6环烷基、4至6元饱和单杂环或NRa0Rb0；Ra0、Rb0各自独立地为氢或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；
所述4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2为式B或C所示结构：
Figure PCTCN2017110459-appb-000003
其中R1b、R2b、R3b、R1c、R3c各自独立地为氢、卤素、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)；Y2、L2如上所定义。
在另一优选例中，R1b、R3b为氢。
在另一优选例中，R1c、R3c为氢。
在另一优选例中，R2为4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)；所述4至6元饱和单杂环为未取代的或被NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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取代；Ra0、Rb0各自独立地为氢或C1-3烷基。
在另一优选例中，R2为氟、氯、溴、CN、甲基、乙基、正丙基、异丙基、环丙基、甲氧基、乙氧基、三氟甲基，或R2为如下结构：
Figure PCTCN2017110459-appb-000004
Figure PCTCN2017110459-appb-000005
在另一优选例中，R5为氢、甲基、乙基或甲氧基取代的乙基。
在另一优选例中，R6为C1-6烷基或CHRa5Rb5；其中Ra5为氢、甲基或乙基；Rb5为苯基、5至6元单环杂芳基环(优选为吡啶)或4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)；所述烷基、苯基为未取代的或被1、2或3个选自下组的基团取代：C1-3烷氧基、NRa0Rb0或4至6元饱和单杂环(优选为哌啶、哌嗪、吗啉或四氢吡喃)；Ra0、Rb0各自独立地为氢、甲基或乙基。
在另一优选例中，R6为C3-6环烷基(优选为环己基)；所述环烷基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、卤素、羟基、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(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃)；Ra0、Rb0各自独立地为氢、乙酰基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、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)；所述4至6元饱和单杂环为未取代的或被C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)取代。
在另一优选例中，R6为式D所示的结构：
Figure PCTCN2017110459-appb-000006
其中R1d为氢、卤素或C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)；R2d为氢、NRa0Rb0、卤素、羟基、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)、4至6元饱和单杂环(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃)；Ra0、Rb0各自独立地为氢、乙酰基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、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)；所述4至6元饱和单杂环为未取代的或被C1-8烷氧基(优选为C1-6烷氧基，更优选为C1-3烷氧基)取代。
在另一优选例中，R6为4至6元饱和单杂环(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃，更优选为哌啶或四氢吡喃)；所述4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：乙酰基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、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)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3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)、4至6元饱和单杂环(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃)；所述乙酰基为未取代的或被CN或羟基取代。
在另一优选例中，R6为四氢吡喃或式E所示的结构：
Figure PCTCN2017110459-appb-000007
其中R1e、R2e、R3e、R4e各自独立地为氢或甲基；R0e为氢、乙酰基、C1-8烷基(优选为C1-6烷基，更优选为C1-3烷基)、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)、-SO2C1-8烷基(优选为-SO2C1-6烷基，更优选为-SO2C1-3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)、4至6元饱和单杂环(优选为氮杂环丁烷、氧杂环丁烷、四氢呋喃、四氢噻吩、四氢吡咯、哌啶、哌嗪、吗啉或四氢吡喃)；所述乙酰基为未取代的或被CN或羟基取代。
在另一优选例中，R6为螺环、螺杂环、桥环、桥杂环。
在另一优选例中，R6为含有1-2个氮或氧原子的双螺杂环。
在另一优选例中，R6为含有1-2个氮或氧原子的双环桥杂环。
在另一优选例中，R6为如下结构：
Figure PCTCN2017110459-appb-000008
Figure PCTCN2017110459-appb-000009
在另一优选例中，R1为氢或卤素(优选氟、氯、溴)。
在另一优选例中，R3为氢或卤素(优选氟、氯、溴)。
在另一优选例中，R4为羟基、C1-3烷基(优选为甲基或乙基)或C1-3烷氧基(优选为甲氧基)。
在另一优选例中，Z1为N；Z2为CR9；Z3为CR10；R9、R10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)，优选地R9、R10为氢。
在另一优选例中，Z1为N；Z2、Z3为CH；X为NH；R1为氢；R3为氢或氟；R2、R4、R5、R6如说明书所定义。
在另一优选例中，Z1为N；Z2为N；Z3为CR10；R10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)，优选地R10为氢。
在另一优选例中，Z1、Z2为N；Z3为CH；X为NH；R1、R3为氢；R2、R4、R5、R6如说明书所定义。
在另一优选例中，Z1为N；Z2为CR9；Z3为N；R9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)，优选地R9为氢。
在另一优选例中，Z1、Z3为N；Z2为CH；X为NH；R1、R3为氢；R2、R4、R5、R6如说明书所定义。
在另一优选例中，Z1为CR8；Z2为N；Z3为CR10；R8、R10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)，优选地R8、R10为氢。
在另一优选例中，Z2为N；Z1、Z3为CH；X为NH；R1、R3为氢；R2、R4、R5、R6如说明书所定义。
在另一优选例中，所述化合物选自下表A
表A：
Figure PCTCN2017110459-appb-000010
Figure PCTCN2017110459-appb-000011
Figure PCTCN2017110459-appb-000012
Figure PCTCN2017110459-appb-000013
Figure PCTCN2017110459-appb-000014
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、溶剂化物、立体异构体或前药；以及药学可接受的载体。
本发明第三方面提供了本发明第一方面所述的化合物、或其药学上可接受的盐、溶剂化 物、立体异构体或前药或本发明第二方面所述药物组合物在制备EZH2抑制剂的应用。
本发明第四方面提供了本发明第一方面所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药或本发明第二方面所述药物组合物在制备由EZH2介导的疾病或病症的应用。
本发明第五方面提供了一种治疗由EZH2介导的疾病或病症的方法，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、溶剂化物、立体异构体或前药，或本发明第二方面所述药物组合物。
本发明第六方面提供了一种治疗由EZH2介导的疾病或病症的方法，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、溶剂化物、立体异构体或前药，以及另一种治疗活性试剂。
在另一优选例中，由EZH2介导的疾病或病症选自：癌症、肺动脉高压、骨髓纤维化、人类免疫缺陷病毒(HIV)疾病、移植物抗宿主病(GVHD)、韦弗综合征、寻常性银屑病或肝纤维化。
在另一优选例中，由EZH2介导的疾病或病症为癌症。
在另一优选例中，由EZH2介导的癌症包括但不是限于，甲状腺癌、心脏肉瘤、肺癌、胃肠道癌、泌尿生殖道肿瘤、肝癌、套细胞淋巴瘤、骨肉瘤，神经系统肉瘤、妇科癌、血液系统肿瘤、肾上腺神经母细胞瘤、皮肤癌、星形细胞肿瘤、乳腺癌、大肠癌、子宫内膜癌，头颈部癌、口腔癌。
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，意外地发现了这类1,5,7-三取代异喹啉衍生物对EZH2Y641F等酶以及SU-DHL-6和SU-DHL-10等细胞具有较高的抑制活性。因此该系列化合物有望开发成为用于治疗肿瘤的药物。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，可优选为C1-6烷基或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，可优选为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 PCTCN2017110459-appb-000015
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 PCTCN2017110459-appb-000016
如：
Figure PCTCN2017110459-appb-000017
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 PCTCN2017110459-appb-000018
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 PCTCN2017110459-appb-000019
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，双环的实例包括(但不限于)：
Figure PCTCN2017110459-appb-000020
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。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，最优选苯基。
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。卤代C1-8烷氧基的例子包括(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。卤代C3-8环烷基的例子包括(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C1-8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 PCTCN2017110459-appb-000021
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。3至6元饱和或部分不饱和单环的实例包括(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。3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，上述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(其中，sub表示取代基)：
Figure PCTCN2017110459-appb-000022
Figure PCTCN2017110459-appb-000023
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2017110459-appb-000024
表示与其他原子的连接。
如本文所用，“EZH2抑制剂”是指一种能够抑制组蛋白赖氨酸N-甲基转移酶EZH2表达增加的试剂(本发明中是指一种式(I)化合物)，其为PRC2的催化功能亚单位，是负责特定组蛋白H3(H3K27)的Lys27甲基化和对干细胞自我更新不可缺少的。
如本文所用，“由EZH2介导的疾病或病症”是指由于组蛋白赖氨酸N-甲基转移酶EZH2的异常表达而导致异常的表观遗传修饰，从而在患者中形成的异常情况。
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。
Figure PCTCN2017110459-appb-000025
步骤1：在碱体系的存在下，式(I-1)化合物中所具有的亲核性质的反应位点或基团(如NH,OH等)与式(I-2)化合物发生取代反应，生成式(I-3)化合物，合适的碱体系包括存在于DMSO的碳酸钾、存在于DMF的碳酸钾等。
步骤2：将式(I-2)中的硝基还原成氨基得到式(I-4)化合物，还原方法可参考本领域常规方法。
步骤3：通过R5与R6的醛或酮与式(I-4)化合物进行还原胺化得到式(I)化合物。还原胺化条件为甲苯回流除水加还原剂还原，或者在酸-金属氢化物形成的催化体系中还原，酸包括醋酸、三氟乙酸、四氯化钛等路易斯酸或布朗斯特酸，溶剂可以在二氯甲烷、1,2-二氯乙烷、1,4-二氧六环、四氢呋喃、甲醇、乙醚、乙腈等溶剂之间改变，合适的还原剂包括三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钠等。反应温度为室温至70℃。
可以对式(I)化合物中的R2采用本领域技术人员已知的方法进行修饰，如氢化或金属还原，或烷基化、醚形成、酯形成、酰胺形成、羧酸形成等。用芳基硼酸进行的芳基化可以在Pd催化剂、适宜的配体和碱，优选钠、钾或铯的碳酸盐、磷酸盐的存在下进行，也可以使用有机碱，如三乙胺，DIPEA等。溶剂可以在甲苯，1,4-二氧六环，DMF，乙腈、醇等，在一些情况下甚至是水以及其他溶剂之间改变。常用催化剂如Pd(PPh3)4或Pd(OAc)2、PdO催化剂的PdCl2型前体与更有效的配体一起促进更复杂的反应。
原料、包括式(I-2)和式(I-1)化合物或是本领域技术人员已知的，或他们可以通过已知方法制备。
优选的原料是式(I-2-A):
Figure PCTCN2017110459-appb-000026
式(I-2-A)化合物可以通过包括如下步骤的方法(A)制备：
方法(A)
Figure PCTCN2017110459-appb-000027
式(I-2-1)化合物与DMF-DMA成环得到式(I-2-2)化合物，式(I-2-2)化合物与氨-甲醇溶液反应得到式(I-2-3)化合物，式(I-2-3)化合物与优选氯或溴的SOX2、SO2X2、POX3或PX5、更 优选POCl3进行卤化，得到式(I-2-4)化合物。可以对(I-2-4)化合物用本领域常规的方法进行修饰得到式(I-2-A)化合物。
在制备式(I)化合物的另一方面，优选的原料是式(I-1-A):
Figure PCTCN2017110459-appb-000028
式(I-1-A)化合物可以通过如下步骤制备：
Figure PCTCN2017110459-appb-000029
将式(I-1-1)化合物通过合适的还原方法还原得到式(I-1-A)化合物。合适的还原方法包括：用硼烷在四氢呋喃溶液中进行还原、用氢化锂铝在无水的惰性溶剂中进行还原，惰性溶剂包括：甲基叔丁基醚、四氢呋喃等。
中间体式(I-1-1)化合物可以通过两种不同的途径得到。在合成路径的第一项实施方案中，式(I-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 PCTCN2017110459-appb-000030
使式(1.1)化合物与丙二腈反应，开环后重新关环得到式(1.2)化合物，使式(1.2)化合物与酸反应，得到式(1.3)化合物，使式(1.3)化合物与优选氯或溴的SOX2、SO2X2、POX3或PX5、更优选POCl3进行卤化，得到式(1.4)化合物，使式(1.4)化合物在碱性条件下与醇反应，得到式(I-1-1)化合物，适宜的碱包括碱金属氢氧化物,优选氢氧化钠、氢氧化钾；碱金属醇盐，优选醇钠。
在合成路径的第二项实施方案中，式(I-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 PCTCN2017110459-appb-000031
使式(1.5)与式(1.6)化合物在碱性条件下关环得到式(I-1-1)化合物，合适的碱性体系包括存在于DMSO的叔丁醇钾、存在于DMSO的碳酸钾、存在于DMF的碳酸钾等。
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1,5,7-三取代的异喹啉衍生物，其对EZH2具有高抑制活性，可用作治疗肿瘤的药物。
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 PCTCN2017110459-appb-000032
化合物1a-1(22.5g,152mmol)的四氢呋喃(500mL)溶液在冰浴下缓慢加入四氢铝锂(11.5g,0.3mol)，混合物室温搅拌过夜。分别向体系加15mL水，30mL氢氧化钠溶液(15％)，过滤，浓缩滤液得110g白色固体化合物1a。MS m/z(ESI):N/A。
中间体2a的制备
Figure PCTCN2017110459-appb-000033
步骤1：化合物2a-1(500mg,1.82mmol)，DMF-DMA(575mg,5.47mmol)和5mLDMF的混合物在氮气氛围下于110℃搅拌过夜。LC-MS跟踪至反应完全。反应液冷却后浓缩后经硅胶柱色谱纯化得白色固体化合物2a-2(130mg,26％)。MS m/z(ESI):N/A。
步骤2：化合物2a-2(130mg,0.481mmol)中加入NH3·MeOH(3mL,7M)，混合物在60℃封管搅拌过夜。LC-MS跟踪至反应完全。混合物冷却后过滤，滤饼经减压蒸馏得80mg黄色固体化合物2a-3。MS m/z(ESI):268[M+H]+。
步骤3：化合物2a-3(80mg,0.297mmol)中加入三氯氧磷2mL，混合物在100℃搅拌2小时。LC-MS跟踪至反应完全。混合物冷却后倒入冰水中，用氨水调pH至8，乙酸乙酯萃取后干燥，浓缩得100mg白色固体化合物2a-4。MS m/z(ESI):289[M+H]+。
步骤4：5mL DMF中加入化合物2a-4(100mg,0.347mmol)，1a(98mg,0.522mmol)和碳酸钾(240mg,1.74mmol)，混合物在氩气氛围下于70℃搅拌过夜。LC-MS跟踪至反应完全。混合 物冷却后倒入水中，过滤后得150mg红色固体化合物2a。MS m/z(ESI):405.1[M+H]+。
中间体3a的制备
Figure PCTCN2017110459-appb-000034
步骤1：化合物3a-1(2g,9.3mmol)与化合物3a.1(3.1g,27.9mmol)的DMF(20mL)溶液在110℃搅拌过夜。LC-MS跟踪至反应完全。反应液冷却后倒入水中，乙酸乙酯萃取，干燥浓缩后经combiflash纯化得黄色固体化合物3a-2(1.3g,66.3％)。MS m/z(ESI):226[M+H]+。
步骤2：制备方法同化合物2a-3，不同的是将2a-3制法中的化合物2a-2换成化合物3a-2。得900mg黄色固体化合物3a-3粗产品。MS m/z(ESI):225[M+H]+。
步骤3：制备方法同化合物2a-4，不同的是将2a-4制法中的化合物2a-3换成化合物3a-3。经combiflash纯化得白色固体化合物3a-4(1.8g,72％)。MS m/z(ESI):288.9[M+H]+。
步骤4：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4换成化合物3a-4。得700mg红色固体化合物3a-5。MS m/z(ESI):359[M+H]+。
步骤5：化合物3a-5(700mg,1.96mmol)和碳酸氢钠(246mg,2.93mmol)的乙醇(100mL)溶液在80℃搅拌并逐滴加入硫代硫酸钠(1.7g,9.78mmol)的水(15mL)溶液，混合物在80℃搅拌1小时。LC-MS跟踪至反应完全。反应液冷却至室温，加入盐酸溶液(300mL,37％)并加热至60℃搅拌1小时。冷却至室温，加氢氧化钠(4N)调pH至8，乙酸乙酯萃取，分离有机层，干燥浓缩后得600mg黄色固体化合物3a。MS m/z(ESI):329[M+H]+。
中间体4a的制备
Figure PCTCN2017110459-appb-000035
化合物2a(150mg,0.372mmol)和碳酸氢钠(39mg,0.465mmol)的乙醇(5mL)溶液在80℃搅拌并逐滴加入硫代硫酸钠(324mg,1.86mmol)的水(0.5mL)溶液。滴加完成后，浓缩反应液，残留物加水(100mL)溶解后过滤，收集滤饼得100mg淡黄色固体化合物4a。MS m/z(ESI):375.1[M+H]+。
中间体5a的制备
Figure PCTCN2017110459-appb-000036
化合物3-溴丙炔(1.64g,13.8mmol)的THF(10mL)溶液中加入碳酸钾(3.17g,23mmol)和吗啡啉(1g,11.5mmol)，混合物在70℃搅拌6小时。反应液经乙酸乙酯/水体系萃取，有机层干燥浓缩，combiflash(EA/PE＝1:2)纯化得化合物5a(450mg,31％)。MS m/z(ESI):N/A。
中间体6a的制备
Figure PCTCN2017110459-appb-000037
步骤1：化合物6a.1(500mg,2.45mmol)的硫酸(5mL,12N)溶液在冰浴下加入硝酸(0.5mL,12N)，混合物在室温搅拌2小时。向反应液中加水，过滤取滤饼，经水洗涤干燥后得560mg固体化合物6a.2。MS m/z(ESI):248[M-H]+。
步骤2：化合物6a.2(560mg,2.25mmol)的DMF(5mL)溶液加入碘甲烷(639mg,4.5mmol)和碳酸钾(931mg,6.75mmol)，混合物在60℃搅拌5小时。LC-MS跟踪至反应完全。反应液经乙酸乙酯/水萃取，浓缩有机层，经combiflash(EA/PE＝10:1)纯化得化合物6a.3(530mg,89％)。MS m/z(ESI):262[M-H]+。
步骤3：制备方法同化合物2a-2，不同的是将2a-2制法中的化合物2a-1换成化合物6a.3，混合物在110℃搅拌4小时。MS m/z(ESI):N/A。
步骤4：制备方法同化合物2a-3，不同的是将2a-3制法中的化合物2a-2换成化合物6a.4。MS m/z(ESI):259[M+H]+。
步骤5：制备方法同化合物2a-4，不同的是将2a-4制法中的化合物2a-3换成化合物6a.5。MS m/z(ESI):277[M+H]+。
步骤6：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4换成化合物6a.6，混合物在70℃搅拌5小时。MS m/z(ESI):393[M+H]+。
步骤7：制备方法同化合物3a，不同的是将3a制法中的化合物3a-5换成化合物6a.7，混合物在80℃搅拌过夜。MS m/z(ESI):363[M+H]+。
中间体7a的制备
Figure PCTCN2017110459-appb-000038
步骤1：化合物4a(500mg,1.34mmol)，化合物7a.1(624mg,4.02mmol)，与三氟乙酸7.5mL的1,4-二氧六环(75mL)溶液室温搅拌2小时，冰浴下分批加入三乙酰氧基硼氢化钠(852mg,4.02mmol)，再室温搅拌过夜。LC-MS跟踪至反应完全。反应液倒入水中，用碳酸氢钠溶液调pH至8，二氯甲烷萃取后干燥，浓缩得700mg化合物7a-1。MS m/z(ESI):512.2[M+H]+。
步骤2：制备方法同化合物7a-1，不同的是将7a-1制法中的化合物4a与7a.1换成化合物7a-1与乙醛。经combiflash纯化得固体化合物7a(400mg,58％)。MS m/z(ESI):542.3[M+H]+。
中间体8a的制备
Figure PCTCN2017110459-appb-000039
化合物8a.1(1.02g,7.43mmol)和碳酸钾(2.65g,14.86mmol)的乙腈(20mL)溶液在50℃搅拌2小时，反应液过滤后浓缩。残留物中加甲醇50mL和8a-1(550mg,2.97mmol)，冰浴下分批加入三乙酰氧基硼氢化钠(1.89g,8.92mmol)，混合物室温搅拌过夜。LC-MS跟踪至反应完全。反应液倒入水中，调pH至1，乙酸乙酯萃取除杂，水层调pH至7，再经乙酸乙酯萃取，合并有机层，干燥浓缩得600mg化合物8a。MS m/z(ESI):272.1[M+H]+。
中间体9a的制备
Figure PCTCN2017110459-appb-000040
步骤1：化合物6a(410mg,1.15mmol)的二氯甲烷(4mL)溶液加入盐酸/1,4-二氧六环(4mL,4M)，混合物室温搅拌过夜。LC-MS跟踪至反应完全。反应液浓缩得336mg白色固体化合物9a-1。MS m/z(ESI):258[M+H]+。
步骤2：化合物9a-1(286mg,0.88mmol)和2-碘丙烷(249mg,1.47mmol)的DMF(5mL)溶液中加入碳酸钾(338mg,2.44mmol)，混合物在氩气氛围下60℃搅拌3小时。LC-MS跟踪至反应完全。反应液倒入水中，乙酸乙酯萃取，有机层干燥浓缩得220mg化合物9a。MS m/z(ESI):298[M+H]+。
中间体10a的制备
Figure PCTCN2017110459-appb-000041
化合物z-6(700mg,1.65mmol)的乙醇(30mL)溶液中加入氢氧化钠(30mL,1N)，混合物在100℃搅拌20小时。LC-MS跟踪至反应完全。反应液浓缩去除乙醇后加盐酸溶液(2M)中和，乙酸乙酯萃取，有机层干燥，浓缩得250mg黄色化合物10a。MS m/z(ESI):451.3[M+H]+。
中间体11a的制备
Figure PCTCN2017110459-appb-000042
步骤1：化合物2a-4(5g,6.99mmol)的乙酸(20mL)溶液加热至75℃，缓慢加入铁粉(1.96g,34.96mmol)，混合物75℃搅拌1小时。LC-MS跟踪至反应完全。反应液冷却至室温，过滤后滤液倒入水中，乙酸乙酯萃取浓缩后经combiflash纯化得黄色固体化合物11a-1(1.2g,67％)。 MS m/z(ESI):257[M+H]+。
步骤2：化合物11a-1(1.2g,4.67mmol)的乙腈(200mL)溶液中加入selectfluor(1.5g,4.2mmol)，混合物室温搅拌过夜。LC-MS跟踪至反应完全。反应液倒入水中，乙酸乙酯萃取浓缩后经combiflash纯化得黄色固体化合物11a-2(260mg,20％)。MS m/z(ESI):275[M+H]+。
步骤3：制备方法同化合物7a，不同的是将7a制法中的化合物7a-1与乙醛换成化合物11a-2与四氢吡喃酮。MS m/z(ESI):341[M+H]+。
步骤4：制备方法同化合物7a，不同的是将7a制法中的化合物7a-1换成化合物11a-3。MS m/z(ESI):368[M+H]+。
步骤5：制备方法同化合物2a-4，不同的是将2a-4制法中的化合物2a-3换成化合物11a-4。MS m/z(ESI):387[M+H]+。
步骤6：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4换成化合物11a-5。MS m/z(ESI):503[M+H]+。
中间体12a的制备
Figure PCTCN2017110459-appb-000043
制备方法同化合物10a，不同的是将10a制法中的化合物z-6换成化合物21-1。MS m/z(ESI):492.4[M+H]+。
中间体13a的制备
Figure PCTCN2017110459-appb-000044
步骤1：化合物丙二腈(12g,181.7mmol)的干燥四氢呋喃(225mL)溶液在冰浴下搅拌1小时，分批加入钠氢(4.8g,199.8mmol)并搅拌2小时，逐滴加入化合物13a-1(16.8g,199.8mmol)，混合物缓慢升至室温反应1小时。反应液中加盐酸溶液淬灭，乙酸乙酯萃取，有机层干燥浓缩后得黄色固体化合物13a-2，直接用于下一步。MS m/z(ESI):151[M+H]+。
步骤2：化合物13a-2(28g,181.7mmol)，盐酸(23.2g,4M,636.4mmol)和水(160mL)的混合物搅拌回流5小时。反应液过滤，固体残留物经甲醇重结晶得25g化合物13a-3。MS m/z(ESI):151[M+H]+。
步骤3：制备方法同化合物2a-4，不同的是将2a-4制法中的化合物2a-3换成化合物13a-3。MS m/z(ESI):169[M+H]+。
步骤4：化合物13a-4(300mg,1.78mmol)，甲醇钠(481mg,8.9mmol)和甲醇(15mL)的混合物在100℃微波16小时。LC-MS跟踪至反应完全。浓缩去除溶剂，残留物加水并调pH至7，过滤得225mg固体化合物13a-5。MS m/z(ESI):419[M+H]+。
步骤5：制备方法同化合物1a，不同的是将1a制法中的化合物1a-1换成化合物13a-5。MS m/z(ESI):152[M+H]+。
步骤6：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4换成化合物13a-6。MS m/z(ESI):152[M+H]+。
步骤7：制备方法同化合物11a-1，不同的是将11a-1制法中的化合物2a-4换成化合物13a-7。MS m/z(ESI):389[M+H]+。
中间体14a的制备
Figure PCTCN2017110459-appb-000045
步骤1：制备方法同化合物z-225，不同的是将z-225制法中的化合物z-156换成化合物14a-1。MS m/z(ESI):159[M+H]+。
步骤2：制备方法同化合物9a-1，不同的是将9a-1制法中的化合物6a换成化合物14a-2。MS m/z(ESI):115[M+H]+。
中间体15a的制备
Figure PCTCN2017110459-appb-000046
制备方法同化合物1a，不同的将1a制法中的化合物1a-1换成化合物z-6。MS m/z(ESI):436[M+H]+。
中间体16a至37a的制备
通用步骤：化合物16a至37a是以异喹啉类醛酮化合物为原料，按照中间体7a的类似方法进行制备。其结构为式(I)中当X为NH；Z1为N；Z2、Z3为CH；R1、R3为氢时；R2、R4、NR5R6为下表所示结构：
Figure PCTCN2017110459-appb-000047
Figure PCTCN2017110459-appb-000048
Figure PCTCN2017110459-appb-000049
中间体38a的制备
Figure PCTCN2017110459-appb-000050
步骤1：化合物38a-1(10.36g,70mmol)，苄氯(10.58g,84mmol)和氧化银(19.5g,84mmol)的甲苯(260mL)溶液在105℃搅拌过夜。LC-MS跟踪至反应完全。反应液冷却后过滤，滤液浓缩后经combiflash纯化得4g化合物38a-2。MS m/z(ESI):239[M+H]+。
步骤2：制备方法同化合物1a，不同的是将1a制法中的化合物1a-1换成化合物38a-2。MS m/z(ESI):243[M+H]+。
中间体39a的制备
Figure PCTCN2017110459-appb-000051
步骤1：化合物丙酰胺(420mg,5mmol)的DMSO(10mL)溶液中加入叔丁醇钾(560mg,5.25mmol)并于室温搅拌30分钟，冰浴下加入化合物39a-1(480mg,5mmol)后于室温搅拌3小时。LC-MS跟踪至反应完全。反应液中加入饱和氯化铵溶液和水，有固体析出，过滤，滤饼用水洗涤，减压干燥得520mg化合物39a-2。MS m/z(ESI):163[M+H]+。
步骤2：制备方法同化合物38a-2，不同的是将38a-2制法中的化合物38a-1换成化合物39a-2。MS m/z(ESI):253[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-1换成化合物39a-3。MS m/z(ESI):257[M+H]+。
中间体40a的制备
Figure PCTCN2017110459-appb-000052
步骤1：化合物40a-1(120g,0.74mol)，氯化镁(63.5g,0.67mol)和三乙胺(187mL,1.33mol)的乙腈(250mL)溶液，在低于20℃下缓慢滴加乙酰氯(52.3g,0.67mol)，混合物室温搅拌过夜。反应液中加盐酸溶液调pH至1-2，乙酸乙酯萃取，有机层干燥，浓缩得化合物40a-2并直接用于下一步。MS m/z(ESI):203[M+H]+。
步骤2：化合物40a-2(154g,0.59mol)的乙酸(500mL)溶液缓慢加入水合肼(36g,0.59mol)，混合物加热至100℃搅拌3小时。反应液浓缩至200mL，加200mL乙醇后搅拌，过滤得化合物40a-3。MS m/z(ESI):171[M+H]+。
步骤3：氢氧化钠(1g,25.6mmol)的水(18mL)溶液在冰浴下加入化合物40a-3(2g,12.8mol)和硫酸二甲酯(3.22g,25.6mmol)，混合物室温搅拌1小时后加热至80℃搅拌3小时。反应液过滤，滤饼减压干燥得化合物40a-4。MS m/z(ESI):185[M+H]+。
步骤4：化合物40a-4(20g,108mmol)的DMF(260mL)溶液，在氩气氛围下冰浴中缓慢加入钠氢(6.5g,130mmol)，并在冰浴下搅拌1小时，再加入化合物40a.1(20.34g,130mmol)，混合物室温搅拌16小时。反应液经乙酸乙酯/水体系萃取，有机层干燥，浓缩，combiflash纯化得化合物40a-5。MS m/z(ESI):305.1[M+H]+。
步骤5：制备方法同化合物1a，不同的是将1a制法中的化合物1a-1换成化合物40a-5。MS m/z(ESI):N/A。
步骤6：制备方法同化合物29b-2，不同的是将29b-2制法中的化合物29b-1换成化合物40a-6。MS m/z(ESI):N/A。
中间体41a的制备
Figure PCTCN2017110459-appb-000053
步骤1：制备方法同化合物38a-2，不同的是将38a-2制法中的化合物38a-1换成化合物41a-1。MS m/z(ESI):239[M+H]+。
步骤2：化合物41a-2(300mg,1.26mmol)的二氯甲烷(10mL)溶液在冰浴下加入DIBAL-H(2mL,3mmol)，混合物室温搅拌过夜。LC-MS跟踪至反应完全。甲醇淬灭反应，体系浓缩后经combiflash纯化得100mg白色固体化合物41a-3。MS m/z(ESI):242[M+H]+。
步骤3：化合物41a-3(60mg,0.249mmol)的甲醇(5mL)溶液在冰浴下加入硼氢化钠(5mg,0.124mmol)，混合物室温搅拌2小时。LC-MS跟踪至反应完全。体系加水淬灭，乙酸乙酯萃取，有机层干燥浓缩得化合物41a，直接用于下一步反应。MS m/z(ESI):N/A。
中间体42a与43a的制备
Figure PCTCN2017110459-appb-000054
手性拆分得化合物42a与43a。MS m/z(ESI):428[M+H]+。
中间体1b的制备
Figure PCTCN2017110459-appb-000055
步骤1：化合物1b-1(1g,4mmol)的乙腈(20mL)溶液中加入化合物1b.1(3.5mL)，混合物在氩气氛围下加热回流4小时。LC-MS跟踪至反应完全。反应液冷却后倒入200mL水中，乙酸乙酯萃取后合并，浓缩后得1.1g化合物1b-2粗产品。MS m/z(ESI):255[M+H]+。
步骤2：化合物1b-2(1g,3.92mmol)的DMF(20mL)溶液中加入化合物Pd(dppf)Cl2(144mg,0.19mmol)，化合物1b.2(1.2g,3.33mmol)和醋酸钾(570mg,5.8mmol)，混合物在氩气氛围下80℃搅拌过夜。反应液浓缩后经combiflash纯化得化合物1b(400mg,31％)。MS m/z(ESI):304[M+H]+。
Figure PCTCN2017110459-appb-000056
或硼酸或硼酸酯中间体
中间体化合物如式(A)与(B)所示，取代基R如下表所示。
通用步骤：化合物2b至25b是溴化物为原料，按照中间体1b的类似方法进行制备。
Figure PCTCN2017110459-appb-000057
Figure PCTCN2017110459-appb-000058
中间体27b的制备
Figure PCTCN2017110459-appb-000059
制备方法同化合物1b，不同的是将1b制法中的化合物1b-2与1b.2换成化合物27b-1与27b.1。MS m/z(ESI):255.1[M+H]+。
中间体28b的制备
Figure PCTCN2017110459-appb-000060
步骤1：制备方法同化合物11a-3，不同的是将11a-3制法中的化合物11a-2换成化合物28b-1。MS m/z(ESI):271.2[M+H]+。
步骤2：制备方法同化合物z-9，不同的是将z-9制法中的化合物9-2换成化合物28b-2。MS m/z(ESI):171.2[M+H]+。
中间体29b的制备
Figure PCTCN2017110459-appb-000061
步骤1：化合物29b-1(500mg,2.48mmol)的二氯甲烷(30mL)溶液加入三乙胺(500mg,4.97mmol)，冰浴下搅拌并加入MsCl(340mg,2.98mmol)，混合物室温搅拌20小时。反应液加二氯甲烷稀释，分别用1M的盐酸和碳酸氢钠溶液洗涤，冷却至室温，有机层干燥，浓缩得650mg白色固体化合物29b-2。MS m/z(ESI):224.1[M+H]+。
步骤2：化合物29b-2(528mg,2mmol)，化合物29b.1(427mg,2.2mmol)，碳酸铯(847mg,2.6mmol)和DMF(5mL)的混合物在氩气氛围下于100℃搅拌过夜。向混合物中加碳酸氢钠溶液，浓缩，combiflash纯化得150mg化合物29b-3。MS m/z(ESI):378[M+H]+。
步骤3：制备方法同化合物z-8，不同的是将z-8制法中的化合物8-1换成化合物29b-3。MS m/z(ESI):278[M+H]+。
步骤4：制备方法同化合物z-226，不同的是将z-226制法中的化合物z-201换成化合物29b-4。MS m/z(ESI):292[M+H]+。
中间体30b的制备
Figure PCTCN2017110459-appb-000062
步骤1：制备方法同化合物9a，不同的是将9a制法中的化合物9a-1与2-碘丙烷换成化合物30b-1与N-甲基哌嗪。MS m/z(ESI):240[M+H]+。
步骤2：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30b-2。MS m/z(ESI):210[M+H]+。
步骤3：化合物30b-3(700mg,3.35mmol)的水(50mL)溶液在冰浴下加氢溴酸5mL和亚硝酸叔丁酯(517mg,5.02mmol)，搅拌30分钟后，冰浴下加入溴化亚铜(960mg,6.69mmol)，继续反应1小时。LC-MS跟踪至反应完全。反应液倒入水中，用饱和碳酸氢钠溶液调pH至8，乙酸乙酯萃取，有机层干燥浓缩，经combiflash纯化得410mg化合物30b-4。MS m/z(ESI):275[M+H]+。
步骤4：制备方法同化合物1b，不同的是将1b制法中的化合物1b-2换成化合物30b-4。MS m/z(ESI):321[M+H]+。
中间体31b的制备
Figure PCTCN2017110459-appb-000063
步骤1：化合物31b-1(500mg,2.9mmol)的四氯化碳(6mL)溶液在氩气氛围下加NBS(540mg,3mmol)和过氧化苯甲酰(49mg,0.2mmol)，混合物在80℃搅拌36小时。反应液浓缩，经combiflash纯化得160mg化合物31b-2。MS m/z(ESI):275[M+H]+。
步骤2：制备方法同化合物9a，不同的是将9a制法中的化合物9a-1与2-碘丙烷换成化合物31b-1与吗啉。MS m/z(ESI):258[M+H]+。
中间体32b的制备
Figure PCTCN2017110459-appb-000064
制备方法同化合物9a，不同的是将9a制法中的化合物9a-1与2-碘丙烷换成化合物32b-1与32b.1。MS m/z(ESI):158[M+H]+。
中间体33b的制备
Figure PCTCN2017110459-appb-000065
化合物33b-1(1g,4mmol)，DIPEA(1g,8mmol)，HATU(2.45g,6.45mmol)的DMF(25mL)溶液搅拌1小时后，加入2-氨基吡啶(450mg,4.8mmol)并搅拌过夜。LC-MS跟踪至反应完全。反应液倒入水中，乙酸乙酯萃取，有机层干燥浓缩，得1.1g化合物33b。MS m/z(ESI):325[M+H]+。
中间体34b的制备
Figure PCTCN2017110459-appb-000066
化合物34b-1(3g,25mmol)的盐酸(30mL,1M)溶液室温搅拌过夜。反应液经二氯甲烷萃取，有机层干燥浓缩，得1.1g化合物34b，直接用于下一步反应。MS m/z(ESI):N/A。
中间体35b的制备
Figure PCTCN2017110459-appb-000067
步骤1：化合物35b-1(7.8g,50mmol)的二氯乙烷(150mL)溶液加入吗啉(4.4g,50mmol)和三乙酰氧基硼氢化钠(21g,100mmol)，混合物室温搅拌过夜。反应液中加入氢氧化钠(20mL,10％)，有机层干燥浓缩，得10g化合物35b-2。MS m/z(ESI):228[M+H]+。
步骤2：化合物35b-2(10g,44mmol)的盐酸(100mL,6M)溶液在50℃搅拌过夜。反应液冷却至室温，用碳酸钾调pH至8，乙酸乙酯萃取，有机层干燥浓缩，得10g化合物35b并直接用于下一步反应。MS m/z(ESI):184[M+H]+。
中间体36b的制备
Figure PCTCN2017110459-appb-000068
步骤1：制备方法同化合物35b-2，不同的是将35b-2制法中的吗啉换成化合物36b.1。MS m/z(ESI):230[M+H]+。
步骤2：制备方法同化合物35b，不同的是将35b制法中的化合物35b-2换成化合物36b-2。MS m/z(ESI):186[M+H]+。
中间体37b的制备
Figure PCTCN2017110459-appb-000069
步骤1：化合物35b-1(1g,6.98mmol)，三乙胺(1.41g,13.97mmol)，DMAP(128mg,1.05mmol)的二氯乙烷(30mL)溶液在冰浴下逐滴加入三氟乙酸酐(2.2g,10.48mmol)，混合物室温搅拌过夜。反应液倒入水中，二氯甲烷萃取，有机层分别经1M盐酸与水洗涤，干燥浓缩，得1.3g化合物37b-1。MS m/z(ESI):240[M+H]+。
步骤2：化合物37b-1(1.6g,6.69mmol)的THF(15mL)溶液在冰浴下逐滴加入硼烷-四氢呋喃(13.4mL,1M)，混合物回流搅拌过夜。体系加甲醇淬灭后浓缩，残留物用乙酸乙酯溶解，饱和食盐水洗涤，有机层干燥浓缩，得1.2g化合物37b-2。MS m/z(ESI):226[M+H]+。
步骤3：制备方法同化合物35b，不同的是将35b制法中的化合物35b-2换成化合物37b-2。MS m/z(ESI):182[M+H]+。
中间体38b的制备
Figure PCTCN2017110459-appb-000070
步骤1：化合物3a-4(1g,4.35mmol)的四氢呋喃(20mL)、水(4mL)溶液加入氯化铵(1.06g,20mmol)和铁粉(1.12g,20mmol)，混合物在80℃搅拌5小时。LC-MS跟踪至反应完全。反应液冷过滤，滤液浓缩得化合物38b-1。MS m/z(ESI):213[M+H]+。
步骤2：化合物38b-1(220mg,1mmol)的乙腈(30mL)溶液加入亚硝酸异戊酯(234mg,2mmol)，溴化亚铜(286mg,2mmol)和溴化铜(446mg,2mmol)，混合物室温搅拌6小时。LC-MS跟踪至反应完全。反应液浓缩后经combiflash纯化得化合物38b-2。MS m/z(ESI):275.9[M+H]+。
步骤3：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4换成化合物38b-2。MS m/z(ESI):392[M+H]+。
中间体39b的制备
Figure PCTCN2017110459-appb-000071
步骤1：制备方法同化合物35b-2，不同的是将35b-2制法中的吗啉换成化合物39b.1。MS m/z(ESI):228[M+H]+。
步骤2：制备方法同化合物35b，不同的是将35b制法中的化合物35b-2换成化合物39b-1。MS m/z(ESI):184[M+H]+。
中间体40b的制备
Figure PCTCN2017110459-appb-000072
化合物40b-1(450mg,3mmol)，碳酸钠(636mg,6mmol)，1,4-二氧六环20mL和水5mL的 混合物在冰浴下加入Fmoc-Cl(813mg,3.15mmol)，混合物在室温下搅拌16小时。LC-MS跟踪至反应结束。反应液经二氯甲烷萃取，有机层干燥浓缩，combiflash纯化得化合物40b。MS m/z(ESI):336[M+H]+。
中间体41b的制备
Figure PCTCN2017110459-appb-000073
步骤1：制备方法同化合物35b-2，不同的是将35b-2制法中的吗啉换成化合物41b.1。MS m/z(ESI):197[M+H]+。
步骤2：制备方法同化合物35b，不同的是将35b制法中的化合物35b-2换成化合物41b-1。MS m/z(ESI):154[M+H]+。
中间体42b的制备
Figure PCTCN2017110459-appb-000074
步骤1：化合物42b-1(20g,110.4mmol)和DCDMH(21.8g,110.4mmol)的浓硫酸(150mL)溶液加热至100℃搅拌过夜。反应液冷却后倒入冰水中，固体析出后过滤，滤饼减压干燥得32g固体化合物42b-2。MS m/z(ESI):N/A。
步骤2：化合物42b-2(32g,148.4mmol)的甲醇(150mL)溶液逐滴加入浓硫酸(10mL)，混合物加热至90℃搅拌过夜。LC-MS跟踪至反应完全。5g碳酸钾的水(10mL)缓慢加入反应液，浓缩，经乙酸乙酯/水萃取，有机层干燥浓缩得25g化合物42b-3。MS m/z(ESI):230.6[M+H]+。
步骤3：制备方法同化合物2a-2，不同的是将2a-2制法中的化合物2a-1换成化合物42b-3。MS m/z(ESI):226.7[M+H]+。
步骤4：制备方法同化合物2a-3，不同的是将2a-3制法中的化合物2a-2换成化合物42b-4。MS m/z(ESI):224.9[M+H]+。
中间体43b的制备
Figure PCTCN2017110459-appb-000075
步骤1：制备方法同化合物31b-2，不同的是将31b-2制法中的化合物31b-1换成化合物43b-1。MS m/z(ESI):249[M+H]+。
步骤2：制备方法同化合物9a，不同的是将9a制法中的化合物9a-1与2-碘丙烷换成化合物43b-2与吗啉。MS m/z(ESI):259[M+H]+。
中间体44b的制备
Figure PCTCN2017110459-appb-000076
制备方法同化合物9a，不同的是将9a制法中的化合物9a-1与2-碘丙烷换成化合物43b-2与14a。MS m/z(ESI):286[M+H]+。
中间体45b的制备
Figure PCTCN2017110459-appb-000077
制备方法同化合物31b-2，不同的是将31b-2制法中的化合物9a-1换成化合物45b-1。MS m/z(ESI):161[M+H]+。
中间体46b的制备
Figure PCTCN2017110459-appb-000078
步骤1：化合物46b-1(500mg,2.49mmol)的四氢呋喃(10mL)溶液在氩气氛围下于-78℃加二异丁基氢化铝(531mg,3.73mmol)，混合物在此温度搅拌3小时。LC-MS跟踪至反应完全。反应液倒入冰水中，乙酸乙酯萃取，有机层干燥浓缩，经combiflash纯化得210mg化合物46b-2。MS m/z(ESI):204[M+H]+。
步骤2：化合物46b-2(500mg,2.4mmol)的二氯甲烷(10mL)溶液在氩气氛围下加N-甲基哌嗪(430mg,4.9mmol)和三乙酰氧基硼氢化钠(1.56g,7.3mmol)，混合物室温搅拌16小时。LC-MS跟踪至反应完全。反应液加入饱和碳酸氢钠溶液，分离有机层，干燥浓缩，经combiflash纯化得210mg化合物46b。MS m/z(ESI):288[M+H]+。
中间体47b的制备
Figure PCTCN2017110459-appb-000079
制备方法同化合物46b，不同的是将46b制法中的化合物46b-2换成化合物47b-1。MS m/z(ESI):270.1[M+H]+。
中间体48b的制备
Figure PCTCN2017110459-appb-000080
制备方法同化合物46b，不同的是将46b制法中的化合物46b-2与N-甲基哌嗪换成化合物47b-1与二甲胺。MS m/z(ESI):215[M+H]+。
中间体49b的制备
Figure PCTCN2017110459-appb-000081
制备方法同化合物9a，不同的是将9a制法中的化合物9a-1与2-碘丙烷换成化合物49b-1与N-甲基哌嗪。MS m/z(ESI):139[M+H]+。
中间体50b的制备
Figure PCTCN2017110459-appb-000082
化合物50b-1(1g,5mmol)的二氯亚砜(10mL,138mmol)溶液在90℃搅拌2小时后，反应 液减压浓缩去除溶剂。冰浴下吗啉(523mg,6mmol)逐滴加入残留物的三乙胺(1.52g,1.5mmol)、二氯甲烷(20mL)溶液中，混合物室温搅拌过夜。反应液经二氯甲烷/水体系萃取，有机层干燥浓缩得1.34g化合物50b。MS m/z(ESI):271[M+H]+。
中间体51b的制备
Figure PCTCN2017110459-appb-000083
制备方法同化合物46b，不同的是将46b制法中的N-甲基哌嗪换成吗啉。MS m/z(ESI):275[M+H]+。
中间体52b的制备
Figure PCTCN2017110459-appb-000084
制备方法同化合物50b，不同的是将50b制法中的化合物50b-1换成N-甲基哌嗪。MS m/z(ESI):285[M+H]+。
中间体1c至6c的制备
通用步骤：化合物1c至6c是异喹啉化合物为原料，按照中间体6a的类似方法进行制备。其结构为式(Ia)中当X为NH；Z1为N；Z2、Z3为CH；R3、R5、R6为氢时；R0、R1、R2、R4为下表所示结构：
Figure PCTCN2017110459-appb-000085
中间体编号 R2 R4 R0 R1 MS[M+H]+
1c F CH3 H H 313
2c Cl CH3O H H 345
3c Cl CH3 H H 329
4c Cl CH3CH2 Bn H 435
5c Cl CH3 Bn H 420
6c Br CH3 H CH3O 403
中间体1d至5d的制备
通用步骤：化合物1d至5d是以异喹啉化合物为原料，按照化合物z-7的类似方法进行制备。其结构为式(I)中当X为NH；Z1为N；Z2、Z3为CH；R1、R3为氢时；R2、R4、NR5R6为下表所示结构：
Figure PCTCN2017110459-appb-000086
Figure PCTCN2017110459-appb-000087
实施例 1：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-7-(4-(吗啉代)苯基)异喹啉-1-基氨基)甲基)-4,6-二甲基吡啶-2(1H)-酮(化合物z-1)的制备
Figure PCTCN2017110459-appb-000088
步骤1：化合物2a(200mg,0.496mmol)，化合物1b(225mg,0.744mmol)，Pd(dppf)Cl2(1,8mg,0.025mmol)，碳酸钠(105mg,0.992mmol)，1,4-二氧六环(4mL)和0.4mL水的混合物在氩气氛围下100℃搅拌30分钟。LC-MS跟踪至反应完全。反应液冷却后倒入水中，过滤得200mg红色固体化合物1-1。MS m/z(ESI):500.3[M+H]+。
步骤2：化合物1-1(200mg,0.4mmol)的甲醇(20mL)溶液在氮气保护下加入钯炭(20mg)，混合物在氢气氛围下室温搅拌过夜。LC-MS跟踪至反应完全。过滤反应液，滤液浓缩得150mg油状化合物1-2粗产品。MS m/z(ESI):N/A。
步骤3：化合物1-2(130mg,0.277mmol)，化合物1.1(138mg,1.38mmol)，与醋酸0.5mL的二氯甲烷(20mL)溶液室温搅拌30分钟，冰浴下分批加入三乙酰氧基硼氢化钠(586mg,2.77mmol)，再室温搅拌7小时。LC-MS跟踪至反应完全。反应液倒入水中，用碳酸氢钠溶液调pH至8，二氯甲烷萃取后干燥，浓缩得200mg油状化合物1-3。MS m/z(ESI):554.1[M+H]+。
步骤4：化合物1-3(200mg,0.361mmol)，乙醛(159mg,3.61mmol)，与醋酸0.5mL的二氯甲烷(20mL)溶液冰浴搅拌30分钟，分批加入三乙酰氧基硼氢化钠(766mg,3.61mmol)，再室温搅拌过夜。LC-MS跟踪至反应完全。反应液倒入水中，用碳酸氢钠溶液调pH至8，二氯 甲烷萃取，干燥，浓缩后经Prep-HPLC纯化得白色固体化合物z-1(3mg,1.43％)。MS m/z(ESI):582.4[M+H]+。1H NMR(500MHz,DMSO)δ8.39(s,1H),8.22(s,1H),7.89(d,1H),7.75(d,2H),7.64(s,1H),7.42(d,2H),7.37(t,1H),7.17(d,1H),5.90(s,1H),4.50(d,2H),3.86-3.82(m,2H),3.60-3.68(m,4H),3.52(s,2H),3.22-3.18(m,5H),2.39-2.36(m,4H),2.22(s,3H),2.13(s,3H),1.76-1.70(m,2H),1.64-1.56(m,2H),0.88(t,3H).
实施例 2：3-((7-溴-5-(四氢-2H-吡喃-4-基氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-2)的制备
Figure PCTCN2017110459-appb-000089
制备方法同化合物z-1，不同的是将z-1制法中的化合物1-3和乙醛换成化合物4a和四氢吡喃酮。经Prep-HPLC纯化得白色固体化合物z-2(57mg,31％)。MS m/z(ESI):457.2[M+H]+。
实施例 3：3-((7-溴-5-(乙基(四氢-2H-吡喃-4-基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-3)的制备
Figure PCTCN2017110459-appb-000090
制备方法同化合物z-1，不同的是将z-1制法中的化合物1-3换成化合物z-2。经Prep-HPLC纯化得棕色油状化合物z-3(7mg,4.4％)。MS m/z(ESI):485.2[M+H]+。
实施例 4：3-((7-氯-5-(乙基(四氢-2H-吡喃-4-基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-4)的制备
Figure PCTCN2017110459-appb-000091
步骤1：制备方法同化合物z-1，不同的是将z-1制法中的化合物1-3和乙醛换成化合物3a和四氢吡喃酮。经Prep-TLC纯化得黄色固体化合物4-1(40mg,10.6％)。MS m/z(ESI):413[M+H]+。
步骤2：制备方法同化合物z-1，不同的是将z-1制法中的化合物1-3换成化合物4-1，甲苯作溶剂。经Prep-HPLC纯化得白色固体化合物z-4(3.5mg,10％)。MS m/z(ESI):441[M+H]+。1H NMR(500MHz,DMSO-d6):δ11.460(s,1H),8.140(s,1H),7.915(d,1H),7.356(s,1H),7.216(s,1H),7.105(d,1H),5.892(s,1H),4.434(d,2H),3.843(d,2H),3.232-3.169(m,5H),2.205(s,3H),2.133(s,3H),1.694-1.575(m,4H),0.853(t,3H).
实施例 5：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-5)的制备
Figure PCTCN2017110459-appb-000092
化合物z-3(100mg,0.206mmol)的甲醇(20mL)溶液在氮气保护下加入钯炭(20mg)，混合物在氢气氛围下室温搅拌过夜。LC-MS跟踪至反应完全。反应液经过滤，浓缩，Prep-HPLC纯化后得白色固体化合物z-5(4mg,5％)。MS m/z(ESI):407.3[M+H]+。
实施例 6：1-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基氨基)-5-(乙基(四氢-2H-吡喃-4-基)氨基)异喹啉-7-甲腈(化合物z-6)的制备
Figure PCTCN2017110459-appb-000093
化合物z-3(170mg,0.35mmol)，氰化锌(100mg,0.84mmol)和四三苯基膦钯(40mg,0.034mmol)的DMF(6mL)溶液，在氩气氛围下于120℃搅拌30分钟。LC-MS跟踪至反应完全。反应液过滤，滤液倒入水中，乙酸乙酯萃取浓缩，Prep-HPLC纯化后得白色固体化合物z-6(11mg,7％)。MS m/z(ESI):432.3[M+H]+。1H NMR(500MHz,DMSO)δ11.39(s,1H),8.56(s,1H),7.98(d,1H),7.56(s,1H),7.39-7.35(m,1H),7.07(d,1H),5.83(s,1H),4.38(d,2H),3.79-3.75(m,2H),3.18-3.07(m,5H),2.13(s,3H),2.06(s,3H),1.64-1.58(m,2H),1.55-1.47(m,2H),0.76(t,3H).
实施例 7：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-7-(1-甲基-1H-吡唑-4-基)异喹啉-1-基氨基)甲基)-4,6-二甲基吡啶-2(1H)-酮(化合物z-7)的制备
Figure PCTCN2017110459-appb-000094
化合物z-3(70mg,0.144mmol)，化合物7.1(60mg,0.288mmol)，Pd(dppf)Cl2(5mg,0.007mmol)，碳酸钠(46mg,0.433mmol)，1,4-二氧六环(6mL)和0.6mL水的混合物在氩气氛围下100℃微波反应30分钟。LC-MS跟踪至反应完全。反应液倒入水中，二氯甲烷萃取浓缩后经Prep-HPLC纯化得白色固体化合物z-7(12mg,17.1％)。MS m/z(ESI):487.3[M+H]+。
实施例 8：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-7-(4-(哌嗪-1-基甲基)苯基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-8)的制备
步骤1：制备方法同化合物z-7，不同的是将z-7制法中的化合物7.1换成化合物2b，微波反应15分钟。得82mg黄色油状化合物8-1。MS m/z(ESI):681.4[M+H]+。
步骤2：化合物8-1(82mg,0.12mmol)的二氯甲烷(6mL)溶液在氩气氛围下加入三氟乙酸4mL，室温搅拌2小时。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z-8(8mg,8.1％)。MS m/z(ESI):N/A。
实施例 9：3-((7-氯-5-(乙基(八氢环戊二烯并[c]吡咯-5-基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基吡啶-2-醇(化合物z-9)的制备
Figure PCTCN2017110459-appb-000096
步骤1：制备方法同化合物4-1，不同的是将4-1制法中的化合物3a和四氢吡喃酮换成化合物9-1和9.1。MS m/z(ESI):628[M+H]+。
步骤2：制备方法同化合物z-4，不同的是将z-4制法中的化合物4-1换成化合物9-1。MS m/z(ESI):656[M+H]+。
步骤3：化合物9-2(180mg,0.275mmol)的二氯甲烷(10mL)溶液加入4M的盐酸/1,4-二氧六环3mL，混合物室温搅拌2小时。LC-MS跟踪至反应结束。反应液浓缩后Prep-HPLC纯化得白色固体化合物z-9(5.1mg,11％)。MS m/z(ESI):466[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),9.83(s,1H),8.89-8.86(m,2H),8.44(d,1H),7.80-7.70(m,2H),7.36 (d,1H),6.25(s,1H),4.52(d,2H),3.20-2.97(m,7H),2.67-2.65(m,2H),2.38(s,3H),2.21(s,3H),2.05-1.97(m,2H),1.31-1.29(m,2H),0.76(t,3H).
实施例 10：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-7-异丙基异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-10)的制备
Figure PCTCN2017110459-appb-000097
步骤1：制备方法同化合物z-7，不同的是将z-7制法中的化合物7.1换成化合物10.1，乙腈做溶剂。经combiflash纯化得化合物10-1(66mg,72％)。MS m/z(ESI):447.4[M+H]+。
步骤2：化合物10-1(66mg,0.188mmol)，钯炭(10mg)的甲醇(20mL)溶液在氢气氛围下室温搅拌过夜。LC-MS跟踪至反应结束。反应液过滤，滤液浓缩后经Prep-HPLC纯化得白色固体化合物z-10(19mg,29％)。MS m/z(ESI):449.3[M+H]+。
实施例 11：3-((7-乙基-5-(乙基(四氢-2H-吡喃-4-基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-11)的制备
Figure PCTCN2017110459-appb-000098
步骤1：制备方法同化合物z-7，不同的是将z-7制法中的化合物7.1换成化合物11.1，乙腈做溶剂。经combiflash纯化得化合物11-1(70mg,79％)。MS m/z(ESI):433.4[M+H]+。
步骤2：制备方法同化合物z-10，不同的是将z-10制法中的化合物10-1换成化合物11-1。经Prep-HPLC纯化得白色固体化合物z-11(20mg,28.4％)。MS m/z(ESI):435.3[M+H]+。
实施例 12：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-7-氟异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-12)的制备
Figure PCTCN2017110459-appb-000099
步骤1：化合物1c(100mg,0.32mmol)的1,4-二氧六环(10mL)溶液加入四氢吡喃酮(70mg,0.64mmol)，与三氟乙酸(110mg,0.96mmol)，混合物室温搅拌1小时后加入三乙酰氧基硼氢 化钠(210mg,0.96mmol)，再室温搅拌1小时。反应液浓缩得80mg黄色固体化合物12-1并直接用于下一步。MS m/z(ESI):397[M+H]+。
步骤2：制备方法同化合物12-1，不同的是将12-1制法中的化合物1c与四氢吡喃酮换成化合物12-1与乙醛。经Prep-HPLC纯化得白色固体化合物z-12(0.85mg,1％)。MS m/z(ESI):425.3[M+H]+。
实施例 13：3-((5-(乙基(哌啶-4-基)氨基)-7-(三氟甲基)异喹啉-1-基氨基)甲基)-4,6-二甲基吡啶-2(1H)(化合物z-13)的制备
Figure PCTCN2017110459-appb-000100
步骤1：制备方法同化合物4-1，不同的是将4-1制法中的化合物3a和四氢吡喃酮换成化合物6a和13.1。MS m/z(ESI):546[M+H]+。
步骤2：制备方法同化合物z-4，不同的是将z-4制法中的化合物4-1换成化合物13-1。MS m/z(ESI):574[M+H]+。
步骤3：制备方法同化合物z-8，不同的是将z-8制法中的化合物17-1换成化合物13-2。经HPTLC纯化得白色固体化合物z-13(100mg,67.2％)。MS m/z(ESI):474[M+H]+。
实施例 14：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-7-(1H-吡唑-4-基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-14)的制备
Figure PCTCN2017110459-appb-000101
步骤1：制备方法同化合物z-7，不同的是将z-7制法中的化合物7.1换成化合物7b,经combiflash纯化得化合物14-1(80mg,70％)。MS m/z(ESI):557.4[M+H]+。
步骤2：化合物14-1(80mg,0.144mmol)加入盐酸/1,4-二氧六环(4mL)和二氯甲烷(4mL)，混合物在室温搅拌2小时。LC-MS跟踪至反应结束。反应液浓缩，残留物用饱和碳酸氢钠溶液洗涤，干燥浓缩后经Prep-HPLC纯化得白色固体化合物z-14(19mg,28％)。MS m/z(ESI):473.3[M+H]+。
实施例 15：3-((7-溴-5-((4-(二甲基氨基)环己基)(乙基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-15)的制备
Figure PCTCN2017110459-appb-000102
步骤1：化合物4a(800mg,0.22mmol)的1,4-二氧六环(20mL)溶液加入15.1(460mg,3.2mmol)，与三氟乙酸(740mg,6.4mmol)，混合物室温搅拌1小时后加入三乙酰氧基硼氢化钠(1.34g,6.4mmol)，再室温搅拌2小时。LC-MS跟踪至反应完全。反应液用饱和碳酸氢钠调pH至8，二氯甲烷萃取浓缩后经硅胶柱色谱(二氯甲烷/甲醇＝4:1)纯化得150mg黄色固体化合物15-1。MS m/z(ESI):498.0[M+H]+。
步骤2：制备方法同化合物15-1，不同的是将15-1制法中的化合物4a与15.1换成化合物15-1与化合物乙醛。经硅胶柱色谱(二氯甲烷/甲醇＝4:1)纯化得黄色固体化合物z-15(30mg,19％)。MS m/z(ESI):526.0[M+H]+。
实施例 16：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-7-(三氟甲基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-16)的制备
Figure PCTCN2017110459-appb-000103
步骤1：制备方法同化合物z-1，不同的是将z-1制法中的化合物1-3和乙醛换成化合物6a和四氢吡喃酮。MS m/z(ESI):448[M+H]+。
步骤2：制备方法同化合物z-1，不同的是将z-1制法中的化合物1-3换成化合物16-1。经Prep-HPLC纯化得白色固体化合物z-16(9.6mg,4％)。MS m/z(ESI):475.3[M+H]+。1H NMR(500MHz,DMSO-d6):δ11.48(br.s.,1H),8.45(s,1H),8.02(d,1H),7.57(br.s.,1H),7.49(s,1H),7.17(d,1H),5.90(s,1H),4.46(d,2H),3.82(m,2H),3.23-3.20(m,5H),2.20(s,3H),2.13(s,3H),1.69-1.58(m,4H),0.83(t,3H).
实施例 17：3-((5-(((1R，4R)-4-(二甲基氨基)环己基)(乙基)氨基)-7-(6-(1-甲基哌啶-4-基)吡啶-3-基)-基氨基)甲基)-4,6-二甲基吡啶-2(1H)-酮(化合物z-17)的制备
Figure PCTCN2017110459-appb-000104
步骤1：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3和7.1换成化合物22b和27b。MS m/z(ESI):620[M+H]+。
步骤2：化合物17-1(30mg,0.048mmol)的甲醇(10mL)溶液在氩气保护下加入钯炭(10mg,10％)，混合物在氢气氛围下室温搅拌过夜。LC-MS跟踪至反应结束。反应液过滤，浓缩滤液并经Prep-HPLC纯化得白色固体化合物z-17(3mg,10％)。MS m/z(ESI):622.5[M+H]+。1H NMR(400MHz,DMSO)δ8.90(s,1H),8.22(s,2H),8.07(d,1H),7.86(d,1H),7.58(s,1H),7.36(d,1H),7.29(br.s,1H),7.07(d,1H),5.86(s,1H),4.47-4.43(m,2H),3.25-3.18(m,2H),3.01-2.89(m,3H),2.74-2.50(m,3H),2.34-2.05(m,15H),1.97-1.72(m,8H),1.51-1.36(m,3H),1.25-1.14(m,2H),0.85(t,3H).
实施例 18：1-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基氨基)-5-(甲基(四氢-2H-吡喃-4-基)氨基)异喹啉-7-甲酰胺(化合物z-18)的制备
Figure PCTCN2017110459-appb-000105
化合物z-6(100mg,0.23mmol)的双氧水(4mL)和DMSO(12mL)溶液加入碳酸钾(138mg,0.92mmol)，混合物在室温搅拌2小时。LC-MS跟踪至反应结束。反应液倒入水中，经乙酸乙酯萃取浓缩后经Prep-HPLC纯化得白色固体化合物z-18(20mg,19.2％)。MS m/z(ESI):450.3[M+H]+。
实施例 19：N-(1-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基氨基)-5-(乙基(四氢-2H-吡喃-4-基)氨基)异喹啉-7-基)乙酰胺(化合物z-19)的制备
Figure PCTCN2017110459-appb-000106
步骤1:化合物z-18(245mg,0.54mmol)和氢氧化钠(108mg,2.7mmol)的1,4-二氧六环(5mL)和水(5mL)的溶液中逐滴加入次氯酸钠溶液(201mg,2.7mmol)，混合物在80℃搅拌3小时。LC-MS跟踪至反应结束。用4N盐酸溶液调反应液pH值至7～8，浓缩去除溶剂，残留物经二氯甲烷/水萃取，有机层干燥浓缩得250mg固体化合物19-1并直接用于下一步反应。MS m/z(ESI):422[M+H]+。
步骤2:化合物19-1(105mg,0.25mmol)和三乙胺(101mg,1mmol)的二氯甲烷(5mL)的溶液在冰浴下逐滴加入乙酸酐(51mg,0.5mmol)，混合物在室温搅拌3小时。LC-MS跟踪至反应结束。用碳酸钠溶液调淬灭反应，经乙酸乙酯/水萃取，有机层干燥浓缩，Prep-HPLC纯化得固体化合物z-19(8.2mg,7％)。MS m/z(ESI):464.3[M+H]+。
实施例 20：3-((7-溴-5-((4-(二甲基氨基)环己基)(乙基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基吡啶-2(1H)(化合物z-20)的制备
Figure PCTCN2017110459-appb-000107
化合物z-15(50mg,0.1mmol)，5a(30mg,0.25mmol)，碘化亚铜(2mg,0.01mmol)和pd(Pph3)2Cl2(7mg,0.01mmol)中加入DMF 1mL和三乙胺1mL，混合物在120℃封管反应1小时。LC-MS跟踪至反应完全。混合物冷却后过滤，滤液浓缩，经Prep-HPLC纯化得白色固体化合物z-20(37mg,65％)。MS m/z(ESI):571[M+H]+。
实施例 21：1-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基氨基)-5-((4-(二甲基氨基)环己基)(乙基)氨基)异喹啉-7-甲酰胺(化合物z-21)的制备
Figure PCTCN2017110459-appb-000108
步骤1：制备方法同化合物z-6，不同的是将z-6制法中的化合物z-3换成化合物12a。MS m/z(ESI):473.3[M+H]+。
步骤2：化合物21-1(70mg,0.148mmol)，氢氧化钠(4mL，1M)和乙醇(4mL)的混合物在室温搅拌2小时。LC-MS跟踪至反应结束。反应液倒入水中，调pH至3，乙酸乙酯萃取后水层浓缩，再加乙酸乙酯溶解残留物，合并有机层，浓缩，经Prep-HPLC纯化得白色固体化合物z-21(1mg,1.4％)。MS m/z(ESI):491.4[M+H]+。
实施例 23-194、195-215
化合物Z-23至Z-194和Z-195至Z-215的结构为式(I)中当X为NH；Z1为N；Z2、Z3为CH；R1、R3为氢；R2、R4、NR5R6为下表所示结构时的结构：
通用步骤：化合物Z-23至Z-131，z-191至z-193，z-195以化合物z-3和不同的硼酸与硼酸酯中间体为原料，参照实施例7的类似方法进行制备。
化合物Z-132至Z-150，z-158，z-197至z-199以化合物3a和不同的醛酮为原料，参照实施例4的类似方法进行制备。
化合物Z-151至Z-157，z-159，z-160和z-196以化合物z-3和不同的硼酸与硼酸酯为原料，参照实施例8的类似方法进行制备。
化合物Z-161至Z-176以不同的羧酸与胺为原料，参照化合物33b的类似方法进行制备。
化合物Z-177至Z-190以异喹啉的卤化物为原料，参照实施例20的类似方法进行制备。
化合物Z-199至Z-209，Z-215参照实施例13的类似方法进行制备。
化合物Z-210至Z-214，参照实施例17的类似方法进行制备。
Figure PCTCN2017110459-appb-000109
Figure PCTCN2017110459-appb-000110
Figure PCTCN2017110459-appb-000111
Figure PCTCN2017110459-appb-000112
Figure PCTCN2017110459-appb-000113
Figure PCTCN2017110459-appb-000114
Figure PCTCN2017110459-appb-000115
Figure PCTCN2017110459-appb-000116
Figure PCTCN2017110459-appb-000117
Figure PCTCN2017110459-appb-000118
Figure PCTCN2017110459-appb-000119
Figure PCTCN2017110459-appb-000120
Figure PCTCN2017110459-appb-000121
Figure PCTCN2017110459-appb-000122
Figure PCTCN2017110459-appb-000123
Figure PCTCN2017110459-appb-000124
Figure PCTCN2017110459-appb-000125
Figure PCTCN2017110459-appb-000126
Figure PCTCN2017110459-appb-000127
实施例 194：4-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基氨基)-8-(乙基(四氢-2H-吡喃-4-基)氨基)喹啉-6-甲腈(化合物z-194)的制备
Figure PCTCN2017110459-appb-000128
步骤1:化合物194-1(2.1g,10mmol)的CH(OEt)3(20mL)溶液中加入化合物194.1(2.1g,15mmol)，混合物在80℃搅拌1小时。LC-MS跟踪至反应结束，反应液冷却至室温，过滤，滤饼经正己烷洗涤后即为化合物194-2。MS m/z(ESI):369[M-H]+。
步骤2：化合物194-2(1.85g,5mmol)的二苯醚(15mL)溶液在250℃搅拌1小时。LC-MS跟踪至反应结束，反应液冷却至室温，过滤，滤液干燥浓缩后，combiflash纯化得化合物194-3。MS m/z(ESI):269[M-H]+。
步骤3：制备方法同化合物2a-4，不同的是将化合物2a-4制法中的化合物2a-3换成化合物194-3。MS m/z(ESI):287[M+H]+。
步骤4：制备方法同化合物2a，不同的是将化合物2a制法中的化合物2a-4换成化合物194-4。MS m/z(ESI):403[M+H]+。
步骤5：制备方法同化合物11a-1，不同的是将化合物11a-1制法中的化合物2a-4换成化合物194-5。MS m/z(ESI):373[M+H]+。
步骤6：制备方法同化合物11a-3，不同的是将化合物11a-3制法中的化合物11a-2换成化合物194-6。MS m/z(ESI):457[M+H]+。
步骤7：制备方法同化合物11a-4，不同的是将化合物11a-4制法中的化合物11a-3换成化合物194-7。MS m/z(ESI):485[M+H]+。
步骤8：制备方法同化合物z-7，不同的是将化合物z-7制法中的化合物z-3与7.1换成化合物194-8与氰基硼氢化钠。MS m/z(ESI):432[M+H]+。1H NMR(400MHz,DMSO)δ11.50(s,1H),8.42(s,1H),8.40(d,1H),7.39(t,1H),7.27(s,1H),6.74(d,1H),5.90(s,1H),4.27(d,2H),4.00-3.94(m,1H),3.86-3.83(m,2H),3.39(q,2H),3.22(t,2H),2.19(s,3H),2.13(s,3H),1.74-1.60(m,4H),0.87(t,3H).
实施例 206：3-((5-(乙基(4-异丙基环己基)氨基)-7-(2-甲氧乙氧基)异喹啉-1-基氨基) 甲基)-4,6-二甲基-2(1H)-酮(化合物z-206)的制备
Figure PCTCN2017110459-appb-000129
步骤1：制备方法同化合物1b，不同的是将1b制法中的化合物1b-2换成化合物2a-4。MS m/z(ESI):253[M+H]+。
步骤2：化合物206-1(1g,2.99mmol)的丙酮(20mL)溶液逐滴加入H3K5O18S4(2.02g,3.29mmol)的水(4mL)溶液，混合物室温搅拌15分钟。LC-MS跟踪至反应完全。体系加氯化铵溶液淬灭，二氯甲烷萃取，有机层干燥浓缩得化合物206-2。MS m/z(ESI):223[M+H]+。
步骤3：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4与1a换成化合物206-2与2-溴乙基甲基醚。MS m/z(ESI):283.1[M+H]+。
步骤4：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4换成化合物206-3。MS m/z(ESI):399.3[M+H]+。
步骤5：制备方法同化合物3a，不同的是将3a制法中的化合物3a-5换成化合物206-4。MS m/z(ESI):369.3[M+H]+。
步骤6：制备方法同化合物15-1，不同的是将15-1制法中的化合物4a换成化合物206-5。MS m/z(ESI):494.3[M+H]+。
步骤7：制备方法同化合物z-15，不同的是将z-15制法中的化合物15-1换成化合物206-6。经Prep-HPLC纯化得固体化合物z-206(38mg,18％)。MS m/z(ESI):522.4[M+H]+。
实施例 216：4-((5-((4-(二甲基氨基)环己基)(乙基)氨基)-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-1-基氨基)甲基)-1,5-二甲基-1H-吡唑-3-(2H)-酮(化合物z-216)的制备
Figure PCTCN2017110459-appb-000130
步骤1：化合物2a-4(100mg,0.34mmol)的DMF(2mL)溶液氩气氛围下加入化合物216.1(87mg,0.52mmol)和碳酸钾(140mg,1mmol)，混合物在80℃搅拌16小时。反应液中加水，过滤，滤饼用水洗涤后在低于50℃的温度下减压干燥得化合物216-1。MS m/z(ESI):418[M+H]+。
步骤2：化合物216-1(3g,7.1mmol)的二氯甲烷(18mL)溶液氩气氛围下加入三乙胺(18mL)，混合物室温搅拌2小时。反应液浓缩得化合物216-2。MS m/z(ESI):267.9[M+H]+。
步骤3：化合物216-2(470mg,1.7mmol)的DMSO(10mL)溶液在氩气氛围下加入化合物40a(600mg,1.7mmol)和DIPEA(450mg,3.5mmol)，混合物室温搅拌2小时。LC-MS跟踪至反应完全。反应液经二氯甲烷/水体系萃取，有机层干燥浓缩，combiflash纯化得化合物216-3。MS m/z(ESI):512[M+H]+。
步骤4：制备方法同化合物11a-1，不同的是将11a-1制法中的化合物2a-4换成化合物216-3。MS m/z(ESI):482.1[M+H]+。
步骤5：制备方法同化合物15-1，不同的是将15-1制法中的化合物4a换成化合物216-4。MS m/z(ESI):607[M+H]+。
步骤6：制备方法同化合物z-15，不同的是将z-15制法中的化合物15-1换成化合物216-5。MS m/z(ESI):515[M+H]+。
步骤7：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3与7.1换成化合物216-6与5b。MS m/z(ESI):612[M+H]+。
实施例 217：1-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基氨基)-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-5-甲腈(化合物z-217)的制备
Figure PCTCN2017110459-appb-000131
步骤1：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3与7.1换成化合物2a与5b。MS m/z(ESI):500[M+H]+。
步骤2：制备方法同化合物11a-1，不同的是将11a-1制法中的化合物2a-4换成化合物217-1。MS m/z(ESI):470.1[M+H]+。
步骤3：制备方法同化合物30b-4，不同的是将30b-4制法中的化合物30b-3换成化合物217-2。MS m/z(ESI):535[M+H]+。
步骤4：制备方法同化合物z-6，不同的是将z-6制法中的化合物z-3换成化合物217-3。经Prep-HPLC纯化得白色固体化合物z-217(3mg,3.4％)。MS m/z(ESI):480[M+H]+。
实施例 218：3-((5-((4-(二甲基氨基)环己基)(乙基)氨基)-6-氟-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-1-基氨基基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-218)的制备
Figure PCTCN2017110459-appb-000132
步骤1：制备方法同化合物15-1，不同的是将15-1制法中的化合物4a换成化合物11a-2。MS m/z(ESI):408[M+H]+。
步骤2：制备方法同化合物z-15，不同的是将z-15制法中的化合物15-1换成化合物218-1。MS m/z(ESI):428[M+H]+。
步骤3：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4与1a换成化合物218-2与38a。MS m/z(ESI):634[M+H]+。
步骤4：制备方法同化合物z-8，不同的是将z-8制法中的化合物8-1换成化合物218-3。MS m/z(ESI):544[M+H]+。
步骤5：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3与7.1换成化合物218-4与5b。经Prep-HPLC纯化得白色固体化合物z-218(1mg,3.4％)。MS m/z(ESI):641.5[M+H]+。1H NMR(400MHz,dmso)δ11.43(s,1H),8.34(s,1H),8.19(d,1H),7.86(d,1H),7.75(d,1H),7.28(s,1H),7.18(d,1H),6.90(d,1H),5.85(s,1H),4.42(s,2H),3.51(s,4H),3.00-2.91(m,2H),2.64(s,1H),2.38(s,4H),2.28-2.22(m,6H),2.19-2.06(m,7H),2.08(s,3H),1.99-1.92(m,4H),1.83-1.71(m,2H),1.45-1.38(m,2H),0.82(t,3H).
实施例 219：3-((5-((4-(二甲基氨基)环己基)(乙基)氨基)-3-甲氧基-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-1-基氨基基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-219)的制备
Figure PCTCN2017110459-appb-000133
步骤1：制备方法同化合物15-1，不同的是将15-1制法中的化合物4a换成化合物6c。MS m/z(ESI):530.3[M+H]+。
步骤2：制备方法同化合物z-15，不同的是将z-15制法中的化合物15-1换成化合物219-1。MS m/z(ESI):558.3[M+H]+。
步骤3：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3与7.1换成化合物219-2与5b。经Prep-HPLC纯化得白色固体化合物z-219(400mg,97％)。MS m/z(ESI):653.5[M+H]+。
实施例 220：3-((5-(乙基(2-甲基哌啶-4-基)氨基)-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-1-基氨基)甲基)-4,6-二甲基吡啶-2(1H)-酮(化合物z-220)的制备
Figure PCTCN2017110459-appb-000134
步骤1：制备方法同化合物15-1，不同的是将15-1制法中的化合物15.1换成化合物40b。MS m/z(ESI):692[M+H]+。
步骤2：制备方法同化合物z-15，不同的是将z-15制法中的化合物15-1换成化合物220-1。MS m/z(ESI):720[M+H]+。
步骤3：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3与7.1换成化合物220-2与5b。MS m/z(ESI):818[M+H]+。
步骤4：化合物220-3(20mg,0.025mmol)的二氯甲烷10mL溶液加入哌啶(1mL)，混合物在室温下搅拌2小时。LC-MS跟踪至反应结束。反应液浓缩并经Prep-HPLC纯化得到固体化合物z-220(8mg,44％)。MS m/z(ESI):595[M+H]+。
实施例 221：3-((5-(乙基(4-羟基-4-甲基环己基)氨基)-7-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)异喹啉-1-基氨基)甲基)-4,6-二甲基吡啶-2(1H)-酮(化合物z-221)的制备
Figure PCTCN2017110459-appb-000135
步骤1：化合物3d(100mg,1.1mmol)和TsOH(755mg,4.38mmol)的四氢呋喃(15mL)与水(15mL)溶液加热至75℃搅拌过夜。LC-MS跟踪至反应完全。反应液冷却至室温，倒入水中，乙酸乙酯萃取浓缩后经combiflash纯化得300mg固体化合物221-1。MS m/z(ESI):595.4[M+H]+。
步骤1：化合物221-1(280mg,0.47mmol)的四氢呋喃(15mL)溶液在冰浴下逐滴加入MeMgBr(0.94mL,2.82mmol)，混合物在冰浴下搅拌2小时。LC-MS跟踪至反应完全。反应液加氯化铵淬灭，乙酸乙酯萃取浓缩后，经Prep-HPLC纯化得到白色固体化合物z-221(6mg,1.8％)。MS m/z(ESI):612.5[M+H]+。
实施例 222：3-((4-((4-(二甲基氨基)环己基)(乙基)氨基)-2-乙氧基-1,7-二氮杂萘-8-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-222)的制备
Figure PCTCN2017110459-appb-000136
步骤1：化合物22-1(46g,407mmol)，干燥乙醇(20g,435mmol)的甲基叔丁基醚(40mL)溶液在冰浴下通盐酸气(24g)，混合物在冰浴下反应6小时后升至室温搅拌16小时。体系中的固体粉碎后经乙酸乙酯多次洗涤，减压干燥得化合物222-2。MS m/z(ESI):160[M+H]+。
步骤2：化合物222.1(25.4g,277mmol)在氮气氛围下加入化合物222-2(54g,277mmol)的乙醇(350mL)溶液，混合物室温反应24小时后升至50℃搅拌6小时。反应液浓缩后经combiflash纯化得28g化合物222-3。MS m/z(ESI):271[M+H]+。
步骤3：化合物222-3(13g,48mmol)的二苯醚(100mL)溶液，加热至210-230℃搅拌10分钟。反应液经combiflash纯化得化合物222-4。MS m/z(ESI):225[M+H]+。
步骤4：化合物222-4(1.1g,4.91mmol)与三乙胺(2g,19.64mmol)的二氯甲烷(30mL)溶液加入化合物N-苯基双(三氟甲烷磺酰)亚胺(4.4g,12.28mmol)，混合物在30℃搅拌4小时。LC-MS跟踪至反应完全。向反应液中加水，经二氯甲烷萃取，有机层干燥浓缩，combiflash纯化得3.4g化合物222-5。MS m/z(ESI):357[M+H]+。
步骤5：化合物222-5(4g,2.8mmol)，222.2(478mg,3.4mmol)，Xantphos(162mg,0.28mmol)，Pd2(dba)3(258mg,0.28mmol)，叔丁醇钠(444mg,4.64mmol)的甲苯(6mL)溶液，混合物在100℃微波反应12分钟。LC-MS跟踪至反应完全。反应液过滤，浓缩，经combiflash纯化得1.07g化合物222-6。MS m/z(ESI):349[M+H]+。
步骤6：化合物222-6(1.07g,3.07mmol)的DMF(25mL)溶液加入钠氢(129mg,3.23mmol)，混合物室温搅拌30分钟，再逐滴加入碘乙烷(504mg,3.23mmol)的DMF(5mL)溶液，混合物室温搅拌3小时。LC-MS跟踪至反应完全。反应液倒入水中，二氯甲烷萃取，有机层干燥，浓缩得化合物222-7。MS m/z(ESI):377[M+H]+。
步骤7：制备方法同化合物222-6，不同的是将222-6制法中的化合物222-5与222.2换成化合物222-7与1a。经Prep-HPLC纯化得白色固体化合物z-222(2.9mg,1％)。MS m/z(ESI):493[M+H]+。1H-NMR(400MHz,CDCl3):δ10.51(bs,1H),7.83(d,1H),6.83(d,1H),6.46(s,1H),5.85(s,1H),4.71(d,2H),4.40(q,2H),3.50(s,1H),3.26(q,2H),2.41(s,3H),2.31(s,5H),2.21(s,3H),2.02(s,1H),1.81(s,2H),1.59(s,4H),1.48(t,3H),1.37(t,3H),0.91(t,3H).
实施例 223：3-((5-((4-(二甲基氨基)环己基)(乙基)氨基)-4-氟-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-1-基氨基基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-223)的制备
Figure PCTCN2017110459-appb-000137
步骤1：制备方法同化合物11a-2，不同的是将11a-2制法中的化合物11a-1换成化合物2a-3。MS m/z(ESI):285[M-H]+。
步骤2：制备方法同化合物2a-4，不同的是将2a-4制法中的化合物2a-3换成化合物223-1。MS m/z(ESI):307[M+H]+。
步骤3：制备方法同化合物2a，不同的是将2a制法中的化合物2a-4换成化合物223-2。MS m/z(ESI):421[M+H]+。
步骤4：制备方法同化合物3a，不同的是将3a制法中的化合物3a-5换成化合物223-3。MS m/z(ESI):391[M+H]+。
步骤5：制备方法同化合物z-4，不同的是将z-4制法中的化合物4-1换成化合物223-4。MS m/z(ESI):516[M+H]+。
步骤6：制备方法同化合物z-15，不同的是将z-15制法中的化合物15-1换成化合物223-5。MS m/z(ESI):544[M+H]+。
步骤7：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3和7.1换成化合物223-6和5b。经Prep-HPLC纯化得白色固体化合物z-223(0.5mg,22％)。MS m/z(ESI):641[M+H]+。
实施例 224：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-6-氟-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-224)的制备
Figure PCTCN2017110459-appb-000138
制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3和7.1换成化合物11a和5b。经Prep-HPLC纯化得白色固体化合物z-224(13mg,12.7％)。MS m/z(ESI):600[M+H]+。1H NMR(400MHz,DMSO)δ11.64-11.17(m,1H),8.33(s,1H),8.20(d,1H),8.16(s,2H),7.86(d,1H),7.74(d,1H),7.31-7.24(m,1H),7.21(d,1H),6.89(d,1H),5.84(s,1H),4.41(d,2H),3.83(d,2H),3.68(d,2H),3.52-3.49(m,5.0H),2.41-2.33 (m,4H),2.18(s,3H),2.16(s,3H),2.07(s,3H),1.90(d,2H),1.50-1.40(m,2H),1.46-1.43(m,2H),0.81(t,3H).
实施例 225：N-(4-((1-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基氨基)-7-(6-(4-甲基哌嗪-1-基)吡啶吡啶-3-基)异喹啉-5-基)(乙基)氨基)环己基)乙酰胺(化合物z-225)的制备
Figure PCTCN2017110459-appb-000139
化合物z-156(40mg,0.064mmol)的四氢呋喃(8mL)溶液加入三乙胺(13mg,0.128mmol)和碘甲烷(9mg,0.064mmol)的四氢呋喃(0.3mL)溶液，混合物在室温搅拌1小时。LC-MS跟踪至反应结束。反应液倒入水中，乙酸乙酯萃取，有机层浓缩并经Prep-HPLC纯化得白色固体化合物z-225(5mg,9.8％)。MS m/z(ESI):637.5[M+H]+。
实施例 226：3-((7-氯-5-(乙基(1-甲基哌啶-4-基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-226)的制备
Figure PCTCN2017110459-appb-000140
化合物z-201(100mg,0.23mmol)和甲醛(5mL)的1,4-二氧六环(10mL)和三氟乙酸(0.5mL)溶液加入三乙酰氧基硼氢化钠(300mg,1.37mmol)，混合物在室温搅拌过夜。LC-MS跟踪至反应结束。向反应液中加入饱和碳酸氢钠溶液，乙酸乙酯萃取，有机层浓缩并经Prep-HPLC纯化得白色固体化合物z-226(16mg,15.2％)。MS m/z(ESI):454[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.07(d,1H),7.86(d,1H),7.27(d,1H),7.17(t,1H),7.02(d,1H),5.85(s,1H),4.39(d,2H),3.13-3.11(m,2H),2.90-2.88(m,1H),2.69-2.67(m,2H),2.16(s,3H),2.08-2.06(m,6H),1.76-1.53(m,6H),0.80(t,3H).
实施例 227：1-((4,6-二甲基-2-氧代-1,2-二氢吡啶-3-基)甲基氨基)-5-(((1R,4R)-4-(二甲基氨基)环己基)(乙基)氨基)异喹啉-7-甲酰胺(化合物z-227)的制备
Figure PCTCN2017110459-appb-000141
步骤1：制备方法同化合物z-6，不同的是将z-6制法中的化合物z-3换成化合物z-15。 MS m/z(ESI):473.3[M+H]+。
步骤2：化合物227-1(70mg,0.148mmol)和氢氧化钠(4mL,1M)的乙醇(4mL)溶液的混合物搅拌回流2小时。LC-MS跟踪至反应结束。反应液倒入水中，调pH至3，乙酸乙酯萃取除杂，水层浓缩后加乙酸乙酯萃取，有机层浓缩并经Prep-HPLC纯化得白色固体化合物z-227(1mg,1.4％)。MS m/z(ESI):491.4[M+H]+。
实施例 228：3-((5-(乙基(四氢-2H-吡喃-4-基)氨基)-7-((1-甲基哌啶-4-基氨基)甲基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-228)的制备
Figure PCTCN2017110459-appb-000142
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-1换成化合物z-6。MS m/z(ESI):436.3[M+H]+。
步骤2：制备方法同化合物z-2，不同的是将z-2制法中的化合物4a和四氢吡喃酮换成化合物228-1和化合物228.1。经Prep-HPLC纯化得白色固体化合物z-228(3.6mg,1.6％)。MS m/z(ESI):533.4[M+H]+。
实施例 229：3-((5-(乙基(1-(甲基磺酰基)哌啶-4-基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-229)的制备
Figure PCTCN2017110459-appb-000143
化合物z-201(150mg,0.34mmol)，化合物229.1(242mg,1.36mmol)的乙腈(5mL)溶液中加入碳酸钾(235mg,1.7mmol)，混合物在50℃搅拌过夜。LC-MS跟踪至反应结束。混合物冷却至室温，过滤，浓缩滤液，经Prep-HPLC纯化得白色固体化合物z-229(14.9mg,8.5％)。MS m/z(ESI):518[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.10(s,1H),7.87(d,1H),7.32(s,1H),7.19(s,1H),7.03(d,1H),5.85(s,1H),4.39(d,2H),3.48-3.46(m,2H),3.19-3.04(m,2H),2.76(s,3H),2.65-2.63(m,2H),2.16(s,3H),2.09(s,3H),1.81-1.78(m,2H),1.65-1.63(m,2H),0.81(t,3H).
实施例 230：3-((5-((4-(二甲基氨基)环己基)(乙基)氨基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-230)的制备
Figure PCTCN2017110459-appb-000144
制备方法同化合物z-5，不同的是将z-5制法中的化合物z-3换成化合物z-15。经Prep-HPLC纯化得白色固体化合物z-230(5mg,3％)。MS m/z(ESI):448.3[M+H]+。
实施例 231：3-((5-(((1S,4S)-4-(二甲基氨基)环己基)(乙基)氨基)-6-氟-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-231)的制备
Figure PCTCN2017110459-appb-000145
步骤1：制备方法同化合物218-3，不同的是将218-3制法中的化合物218-2换成化合物42a。MS m/z(ESI):634[M+H]+。
步骤2：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3与7.1换成化合物231-1与5b。MS m/z(ESI):731[M+H]+。
步骤3：制备方法同化合物z-8，不同的是将z-8制法中的化合物8-1换成化合物231-2。经Prep-HPLC纯化得白色固体化合物z-231(0.7mg,1％)。MS m/z(ESI):641.4[M+H]+。
实施例 232：3-((5-(((1R,4R)-4-(二甲基氨基)环己基)(乙基)氨基)-6-氟-7-(6-(4-甲基哌嗪-1-基)吡啶-3-基)异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-232)的制备
Figure PCTCN2017110459-appb-000146
步骤1：制备方法同化合物218-3，不同的是将218-3制法中的化合物218-2换成化合物43a。MS m/z(ESI):634[M+H]+。
步骤2：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3与7.1换成化合物232-1与5b。MS m/z(ESI):731[M+H]+。
步骤3：制备方法同化合物z-8，不同的是将z-8制法中的化合物8-1换成化合物232-2。经Prep-HPLC纯化得白色固体化合物z-232(23mg,24％)。MS m/z(ESI):641.4[M+H]+。1H NMR(400MHz,DMSO)δ11.48(s,1H),8.34(s,1H),8.27-8.14(m,2H),7.86(d,1H),7.74 (d,1H),7.29(s,1H),7.18(d,1H),6.90(d,1H),5.85(s,1H),4.42(d,2H),3.59-3.40(m,4H),3.28-3.05(m,3H),2.98-2.95(m,2H),2.41-2.34(m,4H),2.27(s,5H),2.19-2.16(m,5H),2.08(s,3H),1.86-1.67(m,4H),1.30-1.17(m,4H),0.82(t,3H).
实施例 233：3-((7-氯-5-(((1S,4S)-4-(二甲基氨基)环己基)(乙基)氨基)异喹啉-1-基氧基)甲基)-4,6-二甲基吡啶-2(1H)-酮(化合物z-233)的制备
实施例 234：3-((7-氯-5-(((1R,4R)-4-(二甲基氨基)环己基)(乙基)氨基)异喹啉-1-基氧基)甲基)-4,6-二甲基吡啶-2(1H)-酮(化合物z-234)的制备
Figure PCTCN2017110459-appb-000147
步骤1：化合物42b(277mg,1.233mmol)，化合物41a(300mg,1.233mmol)，PPh3(647mg,2.466mmol)和DIAD(499mg,2.466mmol)的四氢呋喃(15mL)，室温搅拌3小时。LC-MS跟踪至反应完全。反应液浓缩后经combiflash纯化得450mg化合物233-1。MS m/z(ESI):449.9[M+H]+。
步骤2：制备方法同化合物38b-1，不同的是将38b-1制法中的化合物3a-4换成化合物233-1。MS m/z(ESI):419.9[M+H]+。
步骤3：制备方法同化合物15-1，不同的是将15-1制法中的化合物4a换成化合物233-2。MS m/z(ESI):544.9[M+H]+。
步骤4：制备方法同化合物z-15，不同的是将z-15制法中的化合物15-1换成化合物233-3。MS m/z(ESI):573[M+H]+。
步骤5：制备方法同化合物z-8，不同的是将z-8制法中的化合物8-1换成化合物233-4。经Prep-HPLC纯化得固体化合物z-233(2.2mg,1.4％)和z-234(4.5mg,3％)。MS m/z(ESI):483[M+H]+。1H NMR(400MHz,DMSO-d6)：11.65(s,1H),7.95(d,1H),7.59(d,1H),7.53(d,1H),6.87(d,1H),5.93(s,1H),4.96(s,2H),3.07(q,2H),2.69(d,6H),2.27(3H),2.13(s,3H),2.00-1.86(m,3H),1.72-1.60(m,4H),1.52-1.38(m,3H),0.79(t,3H).
实施例 235：3-((5-(乙基(哌啶-4-基)氨基)-7-异丙基异喹啉-1-基氨基)甲基)-4,6-二甲基-2(1H)-酮(化合物z-235)的制备
Figure PCTCN2017110459-appb-000148
步骤1：制备方法同化合物z-7，不同的是将z-7制法中的化合物z-3与7.1换成化合物31a与235.1。MS m/z(ESI):546[M+H]+。
步骤2：制备方法同化合物z-10，不同的是将z-10制法中的化合物10-1换成化合物235-1。MS m/z(ESI):548[M+H]+。
步骤3：制备方法同化合物z-8，不同的是将z-8制法中的化合物8-1换成化合物235-2。经Prep-HPLC纯化得白色固体化合物z-235(1.3mg,1.8％)。MS m/z(ESI):448[M+H]+。
生物测试
测试例一 体外甲基转移酶活性测试
重组PRC2(EZH2-Y641F)购自Active motif公司，S-甲硫腺苷氨酸(SAM)和L-多聚赖氨酸(PLL)购自Sigma-Aldrich公司，H3(1-50)K27me1多肽购自Cisbio公司。检测体系采用Perkinelmer公司的LANCEUltra系统。酶活实验中，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100ng的重组酶。随后加入含有2.5μM SAM/250nM H3(1-50)K27me1预混物的缓冲液[20mM Tris pH8.5,2mM MgCl2,0.01％Tween-20,1mM TCEP]，室温下开始酶反应。反应3小时后，加入预混有PLL、检测抗体和Ulight的检测液，室温反应1小时后，在Tecan infinite 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所示：
表1 化合物对EZH2Y641F的抑制活性
Figure PCTCN2017110459-appb-000149
Figure PCTCN2017110459-appb-000150
Figure PCTCN2017110459-appb-000151
测试例二 细胞增殖测试
细胞增殖测试
使用的细胞株Pfeiffer(CRL-2632)、suDHL-6(CRL-2959)、suDHL-10(CRL-2963)均购自美国菌种保藏库(ATCC)。所有细胞株以含10％胎牛血清(Gibco)的RPMI-1640培养基(Gbico)进行培养。培养细胞通过离心收集，并在CounterStar计数仪上测定细胞密度。随后在96孔板中种入合适数量的细胞并孵育过夜。待测化合物以1:3的比例进行8个梯度点稀释后，加入对应孔中。继续培养6天后，以Cell counting kit-8检测活细胞数，在Tecan infinite pro上读取吸光度值。IC50通过XLfit软件中的四参数模型拟合进行计算。结果如表2所示：
表2 化合物对Pfeiffer细胞的抑制活性
Figure PCTCN2017110459-appb-000152
从表1和表2可以看出，本发明代表性化合物对EZH2的酶和细胞具有较高的抑制活性。
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 (35)

  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 PCTCN2017110459-appb-100001
    式中，X为NH或O；
    R1、R3各自独立地为氢、卤素、C1-8烷基、卤代C1-8烷基、C1-8烷氧基、C3-8环烷基或C3-8环烷氧基；
    R4为氢、卤素、羟基、CN、C1-8烷基、卤代C1-8烷基、C3-8环烷基、C1-8烷氧基、卤代C1-8烷氧基、C3-8环烷氧基、C6-10芳基、C(O)C1-8烷基、C(O)OC1-8烷基；
    Z1为N或CR8；Z2为N或CR9；Z3为N或CR10；
    R8、R9、R10各自独立地为氢、卤素、C1-8烷基；
    R2为氢、卤素、CN、C1-8烷基、C2-8炔基、卤代C1-8烷基、C3-8环烷基、C1-8烷氧基、C(O)NRa1Rb1、NRa2Rb2、NCORa3、ORa4、C6-10芳基、4至6元饱和或不饱和单杂环、5至6元单环杂芳基环；
    Ra1、Rb1、Ra2、Rb2、Ra3、Ra4各自独立地为氢、C1-8烷基、4至6元饱和单杂环、5至6元单环杂芳基环、C6-10芳基；
    或Ra1、Rb1和相连的氮原子共同形成5至6元饱和单杂环；
    R5为氢、C1-8烷基或C1-8烷氧基取代的C1-8烷基；
    R6为C1-8烷基、C3-8环烷基、4至6元饱和单杂环、螺环、螺杂环、桥环、桥杂环；
    所述烷基、环烷基、烷氧基、炔基、芳基、4至6元饱和或不饱和单杂环、5至6元单环杂芳基环、螺环、螺杂环、桥环、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：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、卤素、乙酰基、羟基、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、-SO2C1-8烷基、C6-10芳基、4至6元饱和单杂环、5至6元单环杂芳基、O(CH2)nOC1-8烷基或-Y-L取代；其中Y为一个键、CH2、NH、O、CON或C(O)；L为C6-10芳基、5至6元单环杂芳基环、4至6元饱和单杂环或NRa0Rb0；Ra0、Rb0各自独立地为氢、乙酰基、C1-8烷基、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，X为NH。
  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，R2为卤素、CN、C1-8烷基、卤代C1-8烷基、C3-8环烷基、C1-8烷氧基。
  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，R2为C2-8炔基；所述炔基被4至6元饱和单杂环取代；
    所述4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
  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，R2为C(O)NRa1Rb1；Ra1为氢或C1-8烷基；Rb1为氢、C1-8烷基、4至6元饱和单杂环、5至6元单环杂芳基环或苯基；或Ra1、Rb1和相连的氮原子共同形成4至6元饱和单杂环；
    所述4至6元饱和单杂环、5至6元单环杂芳基环或苯基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
  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，R2为NRa2Rb2；Ra2为氢或C1-8烷基；Rb2为氢、C1-8烷基、4至6元饱和单杂环、5至6元单环杂芳基环、C6-10芳基；
    所述4至6元饱和单杂环、5至6元单环杂芳基环或芳基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
  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，R2为NCORa3；Ra3为C1-8烷基。
  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，R2为ORa4；Ra4为C1-8烷氧基取代的C1-8烷基、5至6元单环杂芳基环、C6-10芳基；
    所述5至6元单环杂芳基环或芳基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
  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，R2为苯基；所述苯基为未取代的或被1、2或3个选自下组的基团取代：C1-8烷基、卤代C1-8烷基、C1-8烷氧基、卤素、-O(CH2)nOC1-8烷基或-Y1-L1；其中Y1为一个键、CH2、NH、O或CON；L1为C6-10芳基、5至6元单环杂芳基环、4至6元饱和单杂环或NRa0Rb0；Ra0、Rb0各自独立地为氢或C1-8烷基；
    所述芳基、4至6元饱和单杂环、5至6元单环杂芳基环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷 基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
  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，R2为式A所示结构：
    Figure PCTCN2017110459-appb-100002
    其中R1a、R2a、R3a、R4a各自独立地为氢、C1-8烷基、卤代C1-8烷基、C1-8烷氧基或卤素；Y1、L1如上所定义。
  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，R2为5至6元单环杂芳基环；所述5至6元单环杂芳基环为未取代的或被1、2或3个选自下组的基团取代：卤素、C1-8烷基、卤代C1-8烷基、C3-8环烷基或-Y2-L2；其中Y2为一个键、CH2或C(O)；L2为氢、C3-6环烷基、4至6元饱和单杂环或NRa0Rb0；Ra0、Rb0各自独立地为氢或C1-8烷基；
    所述4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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；Ra0、Rb0各自独立地为氢或C1-3烷基。
  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，R2为式B或C所示结构：
    Figure PCTCN2017110459-appb-100003
    其中R1b、R2b、R3b、R1c、R3c各自独立地为氢、卤素、C1-8烷基、卤代C1-8烷基、C3-8环烷基；Y2、L2如上所定义。
  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，R2为4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被NRa0Rb0、羟甲基、羟乙基、羧基、-C(O)OC1-6烷基、乙酰基、羟基、C1-3烷基、卤代C1-3烷基、C3-6环烷基、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取代；Ra0、Rb0各自独立地为氢或C1-3烷基。
  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，R2为氟、氯、溴、CN、甲基、乙基、正丙基、异丙基、环丙基、甲氧基、乙氧基、三氟甲基，或R2为如下结构：
    Figure PCTCN2017110459-appb-100004
  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，R5为氢、甲基、乙基或甲氧基取代的乙基。
  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，R6为C1-6烷基或CHRa5Rb5；其中Ra5为氢、甲基或乙基；Rb5为苯基、5至6元单环杂芳基环或4至6元饱和单杂环；所述烷基、苯基为未取代的或被1、2或3个选自下组的基团取代：C1-3烷氧基、NRa0Rb0或4至6元饱和单杂环；Ra0、Rb0各自独立地为氢、甲基或乙基。
  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，R6为C3-6环烷基；所述环烷基为未取代的或被1、2或3个选自下组的基团取代：NRa0Rb0、卤素、羟基、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；Ra0、Rb0各自独立地为氢、乙酰基、C1-8烷基、C1-8烷氧基取代的C1-8烷基；所述4至6元饱和单杂环为未取代的或被C1-8烷氧基取代。
  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，R6为式D所示的结构：
    Figure PCTCN2017110459-appb-100005
    其中R1d为氢、卤素或C1-8烷基；R2d为氢、NRa0Rb0、卤素、羟基、C1-8烷基、C1-8烷氧基、4至6元饱和单杂环；Ra0、Rb0各自独立地为氢、乙酰基、C1-8烷基、C1-8烷氧基取代的C1-8烷基；所述4至6元饱和单杂环为未取代的或被C1-8烷氧基取代。
  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，R6为4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个选自下组的基团取代：乙酰基、C1-8烷基、C1-8烷氧基取代的C1-8烷基、-SO2C1-8烷基、C3-8环烷基、4至6元饱和单杂环；所述乙酰基为未取代的或被CN或羟基取代。
  20. 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，R6为四氢吡喃或式E所示的结构：
    Figure PCTCN2017110459-appb-100006
    其中R1e、R2e、R3e、R4e各自独立地为氢或甲基；R0e为氢、乙酰基、C1-8烷基、C1-8烷氧基取代的C1-8烷基、-SO2C1-8烷基、卤代C1-8烷基、C3-8环烷基、4至6元饱和单杂环；所述乙酰基为未取代的或被CN或羟基取代。
  21. 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，R6为螺环、螺杂环、桥环、桥杂环。
  22. 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，R6为如下结构：
    Figure PCTCN2017110459-appb-100007
    Figure PCTCN2017110459-appb-100008
    Figure PCTCN2017110459-appb-100009
  23. 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为氢或卤素。
  24. 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，R3为氢或卤素。
  25. 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，R4为羟基、C1-3烷基或C1-3烷氧基。
  26. 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N；Z2为CR9；Z3为CR10；R9、R10各自独立地为氢、卤素、C1-8烷基，优选地R9、R10为氢。
  27. 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N；Z2为N；Z3为CR10；R10为氢、卤素、C1-8烷基，优选地R10为氢。
  28. 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N；Z2为CR9；Z3为N；R9为氢、卤素、C1-8烷基，优选地R9为氢。
  29. 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CR8；Z2为N；Z3为CR10；R8、R10各自独立地为氢、卤素、C1-8烷基，优选地R8、R10为氢。
  30. 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。
  31. 一种药物组合物，所述药物组合物包括权利要求1至30中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药；以及药学可接受的载体。
  32. 如权利要求1至30中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药、或如权利要求31所述药物组合物在制备EZH2抑制剂的应用。
  33. 如权利要求1至30中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药、或如权利要求31所述药物组合物在制备由EZH2介导的疾病或病症的应用。
  34. 一种治疗由EZH2介导的疾病或病症的方法，包括给予所需患者治疗有效量的权利要求1至30中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，或如权利要求31所述药物组合物。
  35. 一种治疗由EZH2介导的疾病或病症的方法，包括给予所需患者治疗有效量的权利要求1至30中任一项所述的化合物、或其药学上可接受的盐、溶剂化物、立体异构体或前药，以及另一种治疗活性试剂。
PCT/CN2017/110459 2016-11-11 2017-11-10 1,5,7-三取代的异喹啉衍生物、其制法与医药上的用途 WO2018086589A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201780008606.1A CN108699002B (zh) 2016-11-11 2017-11-10 1,5,7-三取代的异喹啉衍生物、其制法与医药上的用途
US16/306,331 US20200262813A1 (en) 2016-11-11 2017-11-10 1,5,7-trisubstituted isoquinoline derivatives, preparation thereof, and use thereof in medicines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610994495.3 2016-11-11
CN201610994495 2016-11-11

Publications (2)

Publication Number Publication Date
WO2018086589A1 true WO2018086589A1 (zh) 2018-05-17
WO2018086589A8 WO2018086589A8 (zh) 2023-03-30

Family

ID=62109088

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/110459 WO2018086589A1 (zh) 2016-11-11 2017-11-10 1,5,7-三取代的异喹啉衍生物、其制法与医药上的用途

Country Status (3)

Country Link
US (1) US20200262813A1 (zh)
CN (1) CN108699002B (zh)
WO (1) WO2018086589A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110577528A (zh) * 2019-09-29 2019-12-17 杰达维（上海）医药科技发展有限公司 咪唑并[1,2-a]吡啶-6-醇的制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20230128413A (ko) * 2020-12-01 2023-09-04 칼비스타 파마슈티컬즈 리미티드 효소 저해제
CN114409636B (zh) * 2022-03-08 2023-04-18 沈阳药科大学 一种喹唑啉酮化合物或其药学上可接受的盐及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102970869A (zh) * 2010-05-07 2013-03-13 葛兰素史密斯克莱有限责任公司 吲哚
CN104870435A (zh) * 2012-12-21 2015-08-26 辉瑞大药厂 芳基和杂芳基稠合的内酰胺类
CN105102431A (zh) * 2012-10-15 2015-11-25 Epizyme股份有限公司 经取代的苯化合物

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3971783A (en) * 1973-03-07 1976-07-27 Pfizer Inc. 4-Aminoquinazoline derivatives as cardiac stimulants
US5308854A (en) * 1990-06-18 1994-05-03 Merck & Co., Inc. Inhibitors of HIV reverse transcriptase
AR037641A1 (es) * 2001-12-05 2004-11-17 Tularik Inc Moduladores de inflamacion

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102970869A (zh) * 2010-05-07 2013-03-13 葛兰素史密斯克莱有限责任公司 吲哚
CN105102431A (zh) * 2012-10-15 2015-11-25 Epizyme股份有限公司 经取代的苯化合物
CN104870435A (zh) * 2012-12-21 2015-08-26 辉瑞大药厂 芳基和杂芳基稠合的内酰胺类

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110577528A (zh) * 2019-09-29 2019-12-17 杰达维（上海）医药科技发展有限公司 咪唑并[1,2-a]吡啶-6-醇的制备方法

Also Published As

Publication number Publication date
US20200262813A1 (en) 2020-08-20
CN108699002B (zh) 2021-11-09
WO2018086589A8 (zh) 2023-03-30
CN108699002A (zh) 2018-10-23

Similar Documents

Publication Publication Date Title
JP5010917B2 (ja) ｃ−Ｋｉｔ調節因子および使用方法
JP2021506966A (ja) Ｎｌｒｐ３インフラマソーム調節剤としてのスルホニル尿素誘導体
TW201738216A (zh) 吲哚胺２，３－雙加氧酶抑制劑及其製備方法與應用
WO2001083456A1 (fr) Derives d'heteroaryle condenses
CN105934425B (zh) Ebna1抑制剂和其使用方法
KR20080006614A (ko) 증식 질환의 치료에 유용한 ｈｓｐ90 억제제인2-아미노-퀴나졸린-5-온
JP2017520612A (ja) 抗がん剤としての官能化され置換されたインドール
CN111051300B (zh) 作为组蛋白脱乙酰基酶1和/或2(hdac1-2)的选择性抑制剂的新杂芳基酰胺衍生物
WO2018086589A1 (zh) 1,5,7-三取代的异喹啉衍生物、其制法与医药上的用途
WO2019154177A1 (zh) 嘧啶类化合物、其制备方法及其医药用途
JP2023085300A (ja) ヒストンデメチラーゼ阻害剤
JP2021512873A (ja) Ｔｎｉｋを阻害するための化合物及びその医学的使用
WO2019062328A1 (zh) 苯胺取代的1,2-二氢吡咯并[3,4-c]吡啶/嘧啶-3-酮衍生物及用途
WO2018137639A1 (zh) 一种组蛋白甲基转移酶ezh2抑制剂、其制备方法及其医药用途
CN108699029B (zh) 4,5,6-三取代吲唑类衍生物、其制法与医药上的用途
WO2017181849A1 (zh) 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用
CN112574174B (zh) 蛋白降解靶向嵌合体类化合物及其制备方法和医药用途
JP2023534492A (ja) ピリダジン誘導体遊離塩基の結晶形態、並びにその調製方法及びその使用
TW202140427A (zh) 一種苯并氮雜環類化合物、其製備方法及用途
CN109836385B (zh) 四氢喹啉类n-氧化衍生物及其制备方法和应用
JP2007534733A (ja) 血管損傷剤として使用する３，４−ジ置換マレイミド
WO2018086590A1 (zh) 砜基取代的苯并杂环衍生物、其制法与医药上的用途
CN115322158A (zh) 作为krasg12c蛋白抑制剂的取代喹唑啉类化合物
TW202146404A (zh) 嘧啶化合物及其醫藥用途
CN114341128A (zh) 双功能蛋白降解靶向嵌合体类化合物及其制备方法和医药用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17869917

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17869917

Country of ref document: EP

Kind code of ref document: A1