WO2017114510A1 - 具有erk激酶抑制活性的化合物、其制备方法和用途 - Google Patents

具有erk激酶抑制活性的化合物、其制备方法和用途 Download PDF

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WO2017114510A1
WO2017114510A1 PCT/CN2016/113838 CN2016113838W WO2017114510A1 WO 2017114510 A1 WO2017114510 A1 WO 2017114510A1 CN 2016113838 W CN2016113838 W CN 2016113838W WO 2017114510 A1 WO2017114510 A1 WO 2017114510A1
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unsubstituted
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mmol
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PCT/CN2016/113838
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French (fr)
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曹建华
耿美玉
黄敏
江磊
李磊
唐帅
冯加权
杨晓彤
郑红艳
吴英雄
任芳芳
丁健
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中国科学院上海药物研究所
上海海和药物研究开发有限公司
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Priority to CN201680004577.7A priority Critical patent/CN107922405B/zh
Publication of WO2017114510A1 publication Critical patent/WO2017114510A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry, and in particular, to a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, which is used as a modulator of the ERK pathway or as an ERK kinase, particularly It is an inhibitor of ERK1 and ERK2 kinase.
  • Extracellular signal-regulated kinase is a class of serine/threonine protein kinases discovered in the 1990s and is one of the important subfamilies of the mitogen-activated protein kinase MAPKs family. Activated ERK can transmit extracellular signals to the nucleus, promote phosphorylation of cytoplasmic target proteins or regulate the activity of other protein kinases, thereby regulating gene expression. Its signaling is central to signaling networks that regulate cell growth, development, and differentiation. Therefore, ERK is involved in various biological effects such as cell proliferation, differentiation, migration, invasion and apoptosis.
  • the Ras/Raf/MEK/ERK pathway is the main signaling pathway related to ERK function. Since this pathway regulates cell proliferation, differentiation and apoptosis, the nodule on this pathway has become a hot spot in the development of cancer-targeted drugs.
  • the MEK1/2 inhibitor trametinib was also marketed in 2013 for the treatment of melanoma. However, inhibition of these upstream pathway nodes has its limitations.
  • Tumors can rapidly produce drug resistance to B-Raf and MEK inhibitors.
  • the mechanisms of drug production include point mutations, protein polymorphism changes, and protein peptide chain length changes. This is a great obstacle to the next generation of anti-drug resistant Raf and MEK drugs.
  • ERK is the key node downstream of this pathway. No drug-resistant mutations have been found yet. ERK targeted drugs may greatly improve the treatment of patients with resistance to upstream target inhibitors. It is a potential anticancer drug. Research and development field.
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently selected from: substituted or unsubstituted CR 5 or N, wherein said “substituted” means having a group selected from group A One or more (eg 1, 2 , 3 or 4) substituents: -CN, -NH 2 , -CONH 2 , or -CON-(C 1 -C 3 alkyl);
  • R 1 is selected from the group: H, a substituted or unsubstituted aryl group an acetyl group;
  • R 2 is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted a 3-8 membered cycloalkyl group, and a substituted or unsubstituted 3-8 membered heterocyclic group; or R 1 and R 2 together with an adjacent N atom form a substituted or unsubstituted 5-8 membered heterocyclic group;
  • R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, -OH, cyano, halogen, C 1 -C 8 alkylene hydroxy, substituted or unsubstituted 3-8 membered ring
  • R 3 and X 4 and the adjacent C and N atoms together form a substituted or unsubstituted 4-8 membered ring wherein said ring contains at least 1 N heteroatom and a total of 1-3 selected from O a hetero atom of S and N, and said ring is a saturated or unsaturated ring;
  • R 4 is selected from H, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, -CO(CR 6 R 7 ) m R 8 , -SO 2 (CR 6 R 7 ) m R 8 , -CONR 9 (CR 6 R 7 ) m R 8 , -COO(CR 6 R 7 ) m R 8 , amino group, C 1 -C 8 carboxyl group; wherein m is 0, 1, 2 or 3;
  • R 5 is selected from the group consisting of H, D, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, -OH, cyano, -CON(C 1 -C 4 alkyl) 2 , -CONH 2 , halogen, -CF 3 , amino, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C 1 -C 8 alkylcarbonyl, substituted Or unsubstituted C 1 -C 8 alkoxycarbonyl, substituted or unsubstituted C 1 -C 8 carboxyl group, substituted or unsubstituted C 1 -C 8 ester group, substituted or unsubstituted 3-8 membered naphthenic group a substituted, unsubstituted or unsubstituted 3-8 membered heterocyclic group, a substituted or un
  • Each of R 6 and R 7 is independently selected from the group consisting of H, D, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkylene hydroxy, substituted or unsubstituted C 1 -C 8 alkoxy and halogen, or R 6 and R 7 are bonded to form a substituted or unsubstituted 3 to 6 membered ring;
  • Each R 8 is selected from the group consisting of: H, substituted or unsubstituted C 1 -C 8 alkyl group, a substituted or unsubstituted 5-8 membered aryl group, a substituted or unsubstituted 5-8 membered heteroaryl, substituted or An unsubstituted 3-8 membered cycloalkyl group, and a substituted or unsubstituted 3-8 membered heterocyclic group;
  • Each R 9 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl
  • substitution means having one or more selected from the group B (such as 1, 2, 3, 4 or 5) substituents: D, halogen, -OH, -CN, -CD 3 , -COOH, -NH 2 , -NO 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -C 1 -C 4 alkyl-OR 11 , C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, (C 1 -C 6 alkyl)COO-, C 1 -C 6 alkoxycarbonyl, substituted or unsubstituted 5-8 membered heteroarylcarbonyl, N(R 11 R 12 )CO-, substituted or unsubstituted C 3 -C 6 heterocyclylcarbonyl, substituted or not
  • the aryl group is a phenyl group.
  • the heteroaryl group is selected from the group consisting of pyridyl, pyrazolyl, thiazolyl, imidazolyl, isoxazolyl, or oxazolyl.
  • the X 1 , X 2 , X 3 , X 4 , X 5 , X 6 are each independently selected from CR 5 or N; and at least one of X 1 , X 2 , X 5 is N.
  • At least one or two of X 1 , X 2 , X 5 , and X 6 are N, the remainder being C; and X 3 and X 4 are C.
  • the X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are all substituted or unsubstituted CR 5 .
  • the X 5 is a substituted CR 5 and the substituent is selected from the group consisting of -CN, -NH 2 , or -CONH 2 .
  • R 2 is a substituted or unsubstituted 4-6 membered saturated or unsaturated heterocyclic group, wherein said substitution has one or more (eg, 1-3) selected from the group consisting of Substituents: halogen, C 1 -C 3 alkyl, -OH, amino, cyano, CF 3 -, CF 3 CH 2 -, CD 3 -, C 1 -C 8 alkoxy, C 1 -C 8 An alkylamino group, a C 1 -C 4 alkoxycarbonyl group, a C 1 -C 4 alkylsulfonyl group, a C 1 -C 4 hydroxyalkyl group, a benzyloxycarbonyl group, a (C 1 -C 3 alkyl) 2 NCO-, An unsubstituted piperidinyl group or a piperidinyl group substituted by one or more (e.g., 1-3) C 1 -C 4 alk
  • R 2 is a substituted or unsubstituted 5-membered heterocyclic group.
  • R 2 is selected from a 5-membered heterocyclic group having 1 to 3 N atoms, a 6-membered heterocyclic group having 1 to 2 N atoms, or 4 to 6 members containing 1 oxygen atom. Heterocyclic group.
  • R 2 is a 5-6 membered heteroaryl group containing from 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, -OH, amino, cyano, CF 3 -, CF 3 CH 2 -, CD 3 -, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyloxycarbonyl, (C 1 -C 3 alkyl) 2 NCO-, unsubstituted piperidinyl, or by one or more (eg 1-3) C 1 -C 4 -alkoxycarbonyl-substituted piperidinyl.
  • substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, -OH, amino, cyano, CF 3 -, CF
  • R 2 is a substituted or unsubstituted saturated or unsaturated 4-6 membered cycloalkyl group, and said substituent means having one or more (eg, 1-3) selected from the group consisting of Substituents: halogen, -OH, -NH 2 , -CN, -COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, substituted or unsubstituted aminocarbonyl, C 1 -C 4 alkoxy Alkylcarbonyl, tetrahydropyrrolecarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, substituted or unsubstituted piperazinylcarbonyl, substituted or unsubstituted tetrahydropyrrolecarbonyl, substituted or not a substituted piperazinyl sulfonyl group, wherein said substituent has one or more (e.
  • R 2 is a substituted or unsubstituted phenyl group.
  • R 4 is -CO(CR 6 R 7 ) m
  • R 8 is selected from the group consisting of: H, substituted or unsubstituted 5-8 membered aryl, substituted or unsubstituted 5-8 a heteroaryl group, a substituted or unsubstituted 3-8 membered cycloalkyl group, and a substituted or unsubstituted 3-8 membered heterocyclic group, wherein said substitution has one or more (eg, 1-5) Substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, -OH, amino, cyano, -CF 3 , C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, or C 3- C 8 cycloalkyl.
  • R 8 is selected from the group consisting of H, substituted or substituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted Or an unsubstituted thienyl group, a substituted or unsubstituted pyrimidinyl group, or a substituted or unsubstituted cyclohexyl group.
  • R 4 is -CO(CR 6 R 7 ) m R 8 , wherein R 6 and R 7 are each independently selected from H, D, or substituted or unsubstituted C 1 -C 8 alkyl a substituted or unsubstituted C 1 -C 8 alkylene hydroxy group, a substituted or unsubstituted C 1 -C 8 alkoxy group and a halogen, and m is 0, 1 or 2, wherein R 8 is selected from H, substituted Or an unsubstituted pyridyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted thienyl group, or a substituted or unsubstituted pyrimidinyl group.
  • the compound of formula I is as shown in formula Ia below:
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 are each independently selected from substituted or unsubstituted CR 5 or N, wherein said “substituted” means having one selected from the group A Or a plurality (eg 1, 2 , 3 or 4) of substituents: -CN, -NH 2 , -CONH 2 , or -CON-(C 1 -C 3 alkyl);
  • R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, -OH, cyano, halogen, C 1 -C 8 alkylene hydroxy, substituted or unsubstituted 3-8 membered ring
  • R 2 , R 4 and R 5 are the same as defined above.
  • the compound of formula Ia is as follows:
  • R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, -OH, cyano, halogen, C 1 -C 8 alkylene hydroxy, substituted or unsubstituted 3-8 a cycloalkylene group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted 3-8 membered aryl group, and a substituted or unsubstituted 3-8 membered heteroaryl group;
  • R 2 , R 4 and R 5 are the same as defined above.
  • R 2 is selected from the group consisting of
  • each Ra is independently selected from the group consisting of: H, halogen, C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkyl, -OH, cyano, amino, -COOH, CF 3 -, CF 3 CH 2 -, CD 3 -, C 1 -C 8 alkylamino, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 hydroxyalkyl, benzyloxycarbonyl, substituted or Unsubstituted piperidinyl, C 1 -C 4 alkoxy, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted piperazinylcarbonyl, substituted or unsubstituted tetrahydropyrrolecarbonyl, substituted or unsubstituted piperazine a sulfonyl group, a substituted or unsubstituted C 1
  • R 3 is selected from H, substituted or unsubstituted C 1 -C 8 alkyl, -OH, cyano, halo, C 1 -C 8 alkyl hydroxy alkylene, substituted or unsubstituted 3-8 membered cycloalkyl, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group;
  • R 4 is selected from substituted or unsubstituted C 1 -C 8 alkyl group, a substituted or unsubstituted C 1 -C 8 alkoxy, -CO (CR 6 R 7) m R 8, -SO 2 (CR 6 R 7 ) m R 8 , -CONR 9 (CR 6 R 7 ) m R 8 , -COO(CR 6 R 7 ) m R 8 , amino group, C 1 -C 8 carboxyl group; wherein m is 0, 1, 2 or 3;
  • Each of R 6 and R 7 is independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkylene hydroxy, substituted or unsubstituted C 1 -C 8 alkane An oxy group, and a halogen, or a combination of R 6 and R 7 to form a substituted or unsubstituted 3 to 6 membered ring;
  • Each R 8 is selected from the group consisting of H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-8 membered cycloalkyl And a substituted or unsubstituted 3-8 membered heterocyclic group;
  • Each R 9 is selected from the group consisting of H, -OH, a substituted or unsubstituted C1-C8 alkyl group, a C1-C8 alkylene hydroxyl group, and a substituted or unsubstituted C1-C8 alkoxy group;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently selected from CR 5 or N;
  • R 5 is selected from H, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, -OH, cyano, halogen, amino, substituted or unsubstituted C1- a C8 alkylamino group, a substituted or unsubstituted C1-C8 alkylcarbonyl group, a substituted or unsubstituted C1-C8 alkoxycarbonyl group, a substituted or unsubstituted C1-C8 carboxyl group, a substituted or unsubstituted C1-C8 ester group, A substituted or unsubstituted 3-8 membered cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group.
  • R 5 is selected from H or cyano.
  • the compound of formula I is as shown in formula Ib below:
  • X 1 , X 2 , X 3 , X 5 , X 6 are each independently selected from substituted or unsubstituted CR 5 or N, wherein said “substituted” means having one or more selected from the group A (eg 1, 2 , 3 or 4) substituents: -CN, -NH 2 , -CONH 2 , or -CON-(C 1 -C 3 alkyl);
  • p 0, 1, 2, 3 or 4;
  • q 1, 2, 3, 4 or 5;
  • R 2 , R 4 and R 5 are the same as defined above.
  • the compound of formula I is:
  • q 1, 2, 3, 4 or 5;
  • R 2 , R 4 and R 5 are the same as defined above.
  • R 2 is selected from the group consisting of
  • each Ra is independently selected from the group consisting of: H, halogen, C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkyl, -OH, cyano, amino, -COOH, CF 3 -, CF 3 CH 2 -, CD 3 -, C 1 -C 8 alkylamino group, C 1 -C 4 alkoxycarbonyl group, C 1 -C 4 alkylsulfonyl group, C 1 -C 4 hydroxyalkyl group, benzyloxycarbonyl group, substituted Or unsubstituted piperidinyl, C 1 -C 4 alkoxy, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted piperazinylcarbonyl, substituted or unsubstituted tetrahydropyrrolecarbonyl, substituted or unsubstituted a piperazinylsulfonyl group, a substituted or unsubsti
  • each Ra is independently selected from the group consisting of: C 1 -C 4 alkyl
  • Rb is selected from halogen, -OH, cyano, amino, substituted or unsubstituted C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or the unsubstituted C 3 -C 8 heterocycloalkyl;
  • n 0, 1, 2 or 3;
  • p 0, 1, 2, 3 or 4;
  • q 1, 2, 3, 4 or 5;
  • R 4 is selected from substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, -CO(CR 6 R 7 ) m R 8 , -SO 2 (CR 6 R 7 ) m R 8 , -CONR 9 (CR 6 R 7 ) m R 8 , -COO(CR 6 R 7 ) m R 8 , an amino group, a carboxyl group; wherein m is 0, 1, 2 or 3;
  • Each of R 6 and R 7 is independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkylene hydroxy, substituted or unsubstituted C 1 -C 8 alkane An oxy group, and a halogen, or a combination of R 6 and R 7 to form a substituted or unsubstituted 3 to 5 membered ring;
  • Each R 8 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 3-8 membered ring An alkyl group, and a substituted or unsubstituted 3-8 membered heterocyclic group;
  • Each R 9 is selected from the group consisting of H, -OH, substituted or unsubstituted C 1 -C 8 alkyl, C 1 -C 8 alkylene hydroxy, and substituted or unsubstituted C 1 -C 8 alkoxy .
  • R 1 H
  • R 2 a methyl-substituted five-membered heterocyclic ring
  • the compound of formula I is compound A1-A252.
  • the compound I is selected from the group consisting of:
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the first invention of the present invention, a stereoisomer thereof, a racemate, or a pharmaceutically acceptable salt thereof One or more of the following and a pharmaceutically acceptable excipient.
  • the invention provides a compound according to the first aspect of the invention, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the second aspect of the invention, which is used in the preparation Use in the prevention and treatment of ERK kinase-associated diseases and drugs for ERK kinase targeting inhibitors.
  • a method of preparing a compound according to the first aspect of the invention comprising the steps of:
  • each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 is as defined in the first aspect of the invention
  • LG 2 is a leaving group selected from the group consisting of: halogen, sulfonate, methylthio, methyl sulfone.
  • the method further comprises the steps (a-1) and (a-2) to produce a compound of the formula (1e):
  • LG 1 is a leaving group selected from the group consisting of halogen, sulfonate, boric acid, boric acid ester, borate, organotin, organic zinc;
  • LG 2 is a leaving group selected from the group consisting of halogen, sulfonate, methylthio, methylsulfone;
  • LG 3 is a leaving group selected from the group consisting of halogen, sulfonate, boric acid, boric acid ester, borate;
  • FG is selected from the group consisting of carboxylic acids, aldehydes, halogens;
  • each group of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 and R 3 is as defined in the first aspect of the invention.
  • the reaction is carried out in an inert solvent selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, and N-methyl.
  • an inert solvent selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, and N-methyl. Pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, two Oxyhexane, or a combination thereof.
  • the condensation reaction is carried out in the presence of a condensing agent selected from the group consisting of 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride O-benzotriazole-tetramethylurea hexafluorophosphate, or a combination thereof.
  • a condensing agent selected from the group consisting of 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride O-benzotriazole-tetramethylurea hexafluorophosphate, or a combination thereof.
  • the reductive amination reaction is carried out in the presence of a catalyst selected from the group consisting of titanium tetraisopropoxide, trifluoroacetic acid, and a reducing agent.
  • a catalyst selected from the group consisting of titanium tetraisopropoxide, trifluoroacetic acid, and a reducing agent.
  • Acetic acid formic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or a combination thereof
  • the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium borohydride hydride, sodium trifluoroacetoxyborohydride, Polymer supported sodium borohydride reducing agent, sodium trimethoxyborohydride, triethyl Sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, or a combination thereof.
  • the metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine) Palladium (Pd(PPh 3 ) 4 ), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-double (two Phenylphosphino)ferrocene]palladium dichloride, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, or a combination thereof .
  • the reaction is carried out in the presence of a catalyst ligand selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, Tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-o-phenylmethylphosphine, or a combination thereof.
  • a catalyst ligand selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, Tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tricyclohexylphosphine tetrafluorobo
  • the reaction is carried out in the presence of a base including an inorganic base and an organic base.
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride, Barium fluoride, potassium phosphate, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, or a combination thereof.
  • the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[ 5.4.0] undec-7-ene (DBU), hexamethyldisilazide, hexamethyldisilazide, lutidine, or a combination thereof.
  • the reaction is carried out in the presence of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, and formic acid. , acetic acid, or a combination thereof.
  • the temperature of the step a) is from -78 °C to 250 °C.
  • the step a) is carried out under normal temperature conditions.
  • said step a) is carried out in a dry ice bath or ice bath.
  • the step a) is carried out under heating conditions selected from the group consisting of electric heating, microwave heating, or a combination thereof.
  • a method of preparing a compound according to the first aspect of the invention comprising the steps of:
  • each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 is as defined in the first aspect of the invention
  • LG 1 is a leaving group selected from the group consisting of halogen, sulfonate, boric acid, boric acid ester, borate, organotin, organic zinc;
  • LG 3 is a leaving group selected from the group consisting of halogen, sulfonate, boric acid, boric acid ester, borate.
  • the method further comprises: steps (b-1) and/or (b-2):
  • LG 1 is a leaving group selected from the group consisting of halogen, sulfonate, boric acid, boric acid ester, borate, organotin, organic zinc;
  • LG 2 is a leaving group selected from the group consisting of halogen, sulfonate, methylthio, methylsulfone;
  • LG 3 is a leaving group selected from the group consisting of halogen, sulfonate, boric acid, boric acid ester, borate; FG selection
  • each group of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 and R 3 is as defined in the first aspect of the invention.
  • the (b-1) is carried out in an inert solvent selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, and Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane Or a combination thereof.
  • an inert solvent selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, and Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
  • the condensation reaction is carried out in the presence of a condensing agent selected from the group consisting of 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, O - benzotriazole-tetramethylurea hexafluorophosphate, or the like, or a combination thereof.
  • a condensing agent selected from the group consisting of 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, O - benzotriazole-tetramethylurea hexafluorophosphate, or the
  • the reductive amination reaction is carried out in the presence of a catalyst selected from the group consisting of titanium tetraisopropoxide, trifluoroacetic acid, acetic acid, and a reducing agent.
  • the reducing agent is selected from the group consisting of sodium borohydride, sodium borohydride, sodium borohydride, sodium trifluoroacetoxyborohydride, polymerization
  • sodium borohydride reducing agent sodium trimethoxyborohydride, sodium triethylborohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, or a combination thereof.
  • (1c) and (1g) are coupled in the presence of a metal catalyst selected from the group consisting of tris(dibenzylideneacetone)dipalladium ( Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenyl Palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenyl Alkylphosphino)ethane palladium dichloride, or a combination thereof.
  • a metal catalyst selected from the group consisting of tris(dibenzylideneacetone)dipalladium ( Pd 2 (d
  • (1c) is coupled with (1g) in the presence of a metal catalyst ligand selected from the group consisting of tri-tert-butylphosphine, tetrafluoro Tri-tert-butylphosphine borate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tricyclohexylphosphine tetrafluoroborate, tri-o-phenylmethylphosphine, or a combination thereof.
  • a metal catalyst ligand selected from the group consisting of tri-tert-butylphosphine, tetrafluoro Tri-tert-butylphosphine borate, tri-n-butylphosphine, triphenylphosphine, tri-p-phenylmethylphosphine, tricyclohexylphosphine, tricyclohexylphosphin
  • (1d) and (1f) are coupled in the presence of a base including an inorganic base and an organic base.
  • (1d) and (1f) are coupled in the presence of an inorganic base selected from the group consisting of sodium hydroxide and ditrimethylsilane.
  • an inorganic base selected from the group consisting of sodium hydroxide and ditrimethylsilane.
  • (1d) and (1f) in (b-2) are coupled in the presence of an organic base selected from the group consisting of pyridine, triethylamine, N, N- Diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), hexamethyldisilazide, hexamethyldisilazide, dimethyl Pyridine, or a combination thereof.
  • an organic base selected from the group consisting of pyridine, triethylamine, N, N- Diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), hexamethyldisilazide, hexamethyldisilazide, dimethyl Pyridine, or a combination thereof.
  • (1d) and (1f) are coupled in the presence of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and toluene.
  • an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and toluene.
  • the temperature of the step b) is from -78 °C to 250 °C.
  • step b) is carried out under normal temperature conditions.
  • said step b) is carried out in a dry ice bath or ice bath.
  • the step b) is carried out under heating conditions selected from the group consisting of electric heating, microwave heating, or a combination thereof.
  • a sixth aspect of the invention provides a method for non-therapeutic inhibition of ERK kinase activity, comprising the steps of: the compound of the first aspect of the invention, a stereoisomer thereof, a racemate, or a pharmaceutically acceptable thereof
  • the accepted salt is contacted with ERK kinase to inhibit ERK kinase.
  • the contacting is by contacting a purified ERK kinase or a cell expressing ERK kinase.
  • a method for preventing and/or treating a disease associated with ERK kinase activity in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of the first aspect of the invention, a stereo Isomer, racemate, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition according to the second aspect of the invention of the invention.
  • the ERK kinase comprises ERK1, ERK2 or a combination.
  • the disease associated with ERK kinase activity refers to a disease associated with high expression or high activity of ERK kinase.
  • the disease associated with ERK kinase activity is selected from the group consisting of tumors.
  • the disease associated with ERK kinase activity is selected from the group consisting of skin cancer, colorectal cancer, ovarian cancer, pancreatic cancer, lung cancer, kidney cancer, liver cancer, melanoma, colorectal cancer, acute bone marrow.
  • Leukemia myelodysplastic syndrome, breast cancer, glioma.
  • the use of the compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing and/or treating a disease associated with ERK kinase activity is provided.
  • the disease associated with ERK kinase activity refers to a disease associated with high expression or high activity of ERK kinase.
  • the disease associated with ERK kinase activity is selected from the group consisting of tumors.
  • the disease associated with ERK kinase activity is selected from the group consisting of skin cancer, colorectal cancer, ovarian cancer, pancreatic cancer, lung cancer, kidney cancer, liver cancer, melanoma, colorectal cancer, acute bone marrow.
  • Leukemia myelodysplastic syndrome, breast cancer, glioma.
  • the present inventors have unexpectedly discovered, for the first time, a compound of the formula I or a pharmaceutically acceptable salt thereof which can be used as an ERK kinase inhibitor with high inhibitory activity.
  • the present invention has been completed on this basis.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
  • Niro means -NO 2 .
  • Amino means -NH 2 .
  • Substituted amino means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino.
  • Carboxyl means -COOH.
  • alkyl means a fully saturated straight or branched hydrocarbon chain group, It consists solely of carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is bonded to the rest of the molecule by a single bond, for example including but not limited to Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl , n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
  • alkyl means a fully saturated straight or branched hydrocarbon chain group, It consists solely of carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more
  • alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) And more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl and the like.
  • alkynyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond, optionally containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, ethynyl, C 1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
  • cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic alkyl group consisting solely of carbon atoms and hydrogen atoms, which may include thick a ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and can be passed through any A suitable carbon atom is attached to the remainder of the molecule by a single bond. Unless otherwise specifically indicated in the specification, a carbon atom in a cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]hept
  • heterocyclyl as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. Stable 3 yuan to 20 yuan non-fang Aromatic cyclic group.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene.
  • Alkan-7-yl 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, diaza naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl
  • heteroarylalkyl refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
  • “optionally” or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
  • “optionally substituted aryl” means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
  • substituents described in the claims and the specification of the present invention are selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro
  • a chemical moiety refers to a particular fragment or functional group in a molecule.
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
  • the compounds of the invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
  • the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate Cinnamate, Laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesul
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the invention may form true solvates, but in some cases, it is also possible to retain only a defined amount of water or a mixture of water plus a portion of the indefinite solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the invention also includes prodrugs of the above compounds.
  • prodrug means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • pharmaceutically acceptable excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, supplements approved by the relevant government authorities for acceptable use by humans or domestic animals.
  • tumor include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventing include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting group include a hydroxyl group, an amino group, a thiol group, and a carboxylic acid.
  • Suitable hydroxyl protection The protecting group includes a trialkylsilyl group or a diarylalkylsilyl group (for example, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydrogen Pyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • reaction schemes illustratively illustrate a method of preparing a compound of Formula I, a stereoisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
  • the starting materials and intermediates in the preparation of the compounds of the invention may contain functional groups that require protection during the synthesis.
  • the exactity of any protecting groups used will depend on the nature of the functional group being protected, as will be apparent to those skilled in the art.
  • Guidance for the selection of suitable protecting groups and synthetic strategies for their attachment and removal can be found, for example, in Green & Wuts, Green'sProtective Groups in Organic Synthesis, 3d Edition, Jon Wiley & Sons, Inc., New York (1999) and the literature cited in the book.
  • a protecting group refers to an atomic group that masks, reduces or prevents the reactivity of a functional group when attached to a reactive functional group in the molecule.
  • the protecting group can be selectively removed as needed during the synthesis.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R 4 , LG 1 and LG 2 are as in the embodiment of the compound of formula I above. As described in the section.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 1 , R 2 , R 3 , R 4 , LG 1 , LG 2 and LG 3 are all as in the embodiment of the compound of formula I above Said in the middle.
  • a class of pharmaceutical compositions for treating diseases associated with ERK kinase activity is provided.
  • the present invention can be used to obtain the following 6-44 compounds using a similar method as above:
  • the microwave was heated to 100 ° C and reacted for 1 hour. After the completion of the reaction by LCMS, the catalyst was removed by filtration, and 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL ⁇ 3), and the organic phase was combined. The mixture was washed with saturated brine (20 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated.
  • a 73-94 compound was prepared in a similar manner to Example 72:
  • N 2 was protected in a dry 250 mL round bottom flask, and compound 67 (2.3 g, 54 mmol), THF (100 ml), LiHDMS (100 ml, 100 mmol).
  • 50 ml of a solution of acetonitrile (4.0 g, 28 mmol) in tetrahydrofuran was slowly added, and the mixture was replaced with nitrogen three times, and the mixture was stirred at room temperature for 2 hours. After LC/MS detection, the reaction was completed, 50 ml of ice water was quenched, EA (50 mL*3) was extracted, washed with saturated brine (30 mL), dried, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 104 5-[2-(4-Bromo-2-methyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yl]-1-[2-(2-fluoro-phenyl) -acetyl]-2,3-dihydro-1H-indole-7-carbonitrile (A104)
  • Example 111 5-[2-(3-Fluoro-4-methoxyphenylamino)-pyrimidin-4-yl]-1-[2-(2-fluoro-phenyl)-acetyl]-2 ,3-dihydro-1H-indole-7-carbonitrile (A111)
  • Example 112 1-[2-(2,6-Difluoro-phenyl)-acetyl]-5-[2-(2-methyl-2H-pyrazol-3-ylamine)-pyridine-4 -yl]-2,3-dihydro-1H-indole-7-carbonitrile (A112)
  • Example 120 4-(4-(7-Cyano-1-(2-(2-fluorophenyl)acetyl)indol-5-yl)pyridin-2-ylamino)phenyl)(pyrrolidine) Synthesis of -1-yl) ketone compounds (A120)
  • Example 122 1-[2-(2-Fluoro-phenyl)-acetyl]-5-[2-(tetrahydrofuran-3-ylamino)-pyrimidin-4-yl]-2,3-dihydro- 1H- ⁇ -7-carbonitrile (A122)
  • Example 123 4-(4- ⁇ 7-Cyano-1-[2-(2-fluoro-phenyl)-acetyl]-2,3-dihydro-1H-indol-5-yl ⁇ - Pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (A123)
  • Example 128 1-[2-(2-Chloro-phenyl)-acetyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2 -yl)-2,3-dihydro-1H-indole-7-carbonitrile (73)
  • Example 129 1-[2-(2-Fluoro-phenyl)-acetyl]-5-[2-(1-methanesulfonyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl ]-2,3-dihydro-1H-indole-7-carbonitrile (A129)

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Abstract

公开了一种具有ERK激酶抑制活性的化合物、其制备方法和用途，具体地，公开了式I化合物、其立体异构体、外消旋体、或其药学上可接受的盐，并公开了其在制备用于预防和治疗与ERK激酶相关的疾病的药物中的应用。

Description

具有ERK激酶抑制活性的化合物、其制备方法和用途 技术领域
本发明属于药物化学领域，具体地，本发明涉及的化合物或其药学上可接受的盐，以及含有该化合物或盐的药物组合物，其用作ERK通路的调节剂或用作ERK激酶，特别是ERK1和ERK2激酶的抑制剂。
背景技术
细胞外信号调节激酶(ERK)是发现于20世纪90年代的一类丝氨酸/苏氨酸蛋白激酶，是有丝分裂原活化蛋白激酶MAPKs家族的重要亚族之一。活化的ERK能将胞外信号传递至细胞核，促进细胞质靶蛋白的磷酸化或调节其他蛋白激酶的活性，进而调节基因的表达。其信号传导是涉及调节细胞生长、发育及分化的信号网络的中心。因此，ERK参与细胞的增殖、分化、迁移、侵袭和凋亡等多种生物学效应。
Ras/Raf/MEK/ERK通路是与ERK功能相关的主要信号通路，由于该通路调控细胞的增殖、分化和凋亡，因此近年来该通路上的节点蛋白成为癌症靶向药物研发的热点所在。特异性的B-Raf抑制剂Vemurafenib和dabrafenib分别于2011年和2013年上市用于黑色素瘤的治疗，其中dabrafenib用于治疗B-RafV600E突变型非小细胞肺癌，获得了FDA的突破性药物资格。MEK1/2抑制剂trametinib也于2013年上市用于黑色素瘤的治疗。然而抑制这些上游通路节点有其局限性，肿瘤对B-Raf和MEK抑制剂可以快速的产生抗药性，药性产生的机制包括点突变、蛋白多聚形式改变、蛋白肽链长度改变等多种方式，这对于下一代抗耐药Raf、MEK药物是极大的阻碍。ERK作为该通路的下游关键节点，目前尚未发现有耐药性突变发生，ERK的靶向药物可能极大地改善对上游靶点抑制剂产生耐药的病人的治疗，是极具潜力的抗癌药研发领域。
综上所述，本领域迫切需要研发出新的ERK抑制剂药物。
发明内容
本发明的目的在于提供一结构新颖的、可有效抑制ERK激酶的化合物，及其制法和应用。
本发明第一方面，提供一种式I化合物、其立体异构体、外消旋体、或其药学上可接受的盐：
Figure PCTCN2016113838-appb-000001
式中，X1、X2、X3、X4、X5和X6各自独立地选自：取代或未取代的CR5或N，其中，所述的“取代”指具有选自A组的一个或多个(如1、2、3或4个)取代基：-CN、-NH2、-CONH2、或-CON-(C1-C3烷基)；
R1选自下组：H、取代或未取代的芳基乙酰基；
R2选自下组：取代或未取代的C1-C10烷基、取代或未取代的5-8元芳基、取代或未取代的5-8元杂芳基、取代或未取代的3-8元环烷基、和取代或未取代的3-8元杂环基；或者R1和R2与相邻的N原子共同形成取代或未取代的5-8元杂环基；
R3选自下组：H、取代或未取代的C1-C8烷基、-OH、氰基、卤素、C1-C8亚烷基羟基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的3-8元芳基、和取代或未取代的3-8元杂芳基；
或者，R3和X4以及相邻的C和N原子共同形成取代或未取代的4-8元环，其中所述的环含有至少1个N杂原子并且总共含有1-3个选自O、S和N的杂原子，并且所述环为饱和或不饱和环；
R4选自H、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、-CO(CR6R7)mR8、-SO2(CR6R7)mR8、-CONR9(CR6R7)mR8、-COO(CR6R7)mR8、氨基、C1-C8羧基；其中，m为0、1、2或3；
其中，R5选自下组：H、D、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、-OH、氰基、-CON(C1-C4烷基)2、-CONH2、卤素、-CF3、氨基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷基羰基、取代或未取代的C1-C8烷氧基羰基、取代或未取代的C1-C8羧基、取代或未取代的C1-C8酯基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的芳基、和取代或未取代的杂芳基；
各R6和R7各自独立地选自下组：H、D、取代或未取代的C1-C8烷基、C1-C8亚烷基羟基、取代或未取代的C1-C8烷氧基和卤素，或者R6与R7相连形成取代或未取代的3至6元环；
各R8选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的5-8元芳基、取代或未取代的5-8元杂芳基、取代或未取代的3-8元环烷基、和取代或未取代的3-8元杂环基；
各R9选自下组：H、取代或未取代的C1-C8烷基；
其中，所述R1、R2、R3、R4、R5、R6、R7、R8、R9中，所述的“取代”指具有选自B组的一个或多个(如1、2、3、4或5个)取代基：D、卤素、-OH、-CN、-CD3、-COOH、-NH2、-NO2、C1-C4烷基、C1-C4卤代烷基、-C1-C4烷基-O-R11、C1-C8烷氧基、C1-C8烷胺基、(C1-C6烷基)COO-、C1-C6烷氧基羰基、取代或未取代的5-8元杂芳基羰基、N(R11R12)CO-、取代或未取代的C3-C6杂环基羰基、取代或未取代的C1-C4烷基磺酰基、C1-C4羟基烷基、C1-C4烷基氨基、氨基磺酰基、哌嗪磺酰基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、苄氧酰基、苄氧羰基；其中，R11、R12各自独立地选自：C1-C3烷基和H，其中，所述的“取代”指具有选自C组的一个或多个(如1、2、3个)取代基：C1-C6烷氧羰基、C1-C4烷基、C1-C4烷氧基、-OH、-NH2、Boc。
在另一优选例中，所述的R3和X4以及相连的“＝C-N-”或“-C-N-”共同形成取代或未取代的4-8元环。
在另一优选例中，所述的R3和X4以及相连的“＝C-N-”或“-C-N-”共同形成的4-8元环包括稠环、螺环、或桥环。
在另一优选例中，所述的芳基为苯基。
在另一优选例中，所述的杂芳基选自下组：吡啶基、吡唑基、噻唑基、咪唑基、异噁唑基、或噁唑基。
在另一优选例中，所述X1、X2、X3、X4、X5、X6各自独立地选自CR5或N；并且，X1、X2、X5中至少一个为N。
在另一优选例中，所述X1、X2、X5、X6中至少一个或两个为N，其余为C；并且X3、X4为C。
在另一优选例中，所述X1、X2、X3、X4、X5、X6均为取代或未取代的CR5。
在另一优选例中，所述X5为取代的CR5，并且所述取代基选自下组：-CN、-NH2、或-CONH2。
在另一优选例中，R2为取代或未取代的4-6元饱和或不饱和的杂环基，其中所述的取代指具有一个或多个(如1-3个)选自下组的取代基：卤素、C1-C3烷基、-OH、氨基、氰基、CF3-、CF3CH2-、CD3-、C1-C8烷氧基、C1-C8烷胺基、C1-C4烷氧基羰基、C1-C4烷基磺酰基、C1-C4羟基烷基、苄氧羰基、(C1-C3烷基)2NCO-、未取代的哌啶基、或被一个或多个(如1-3个)C1-C4烷氧羰基取代的哌啶基。
在另一优选例中，R2为取代或未取代的5元杂环基。
在另一优选例中，R2选自含1-3个N原子的5元杂环基、含1-2个N原子的六元杂环基、或含有1个氧原子的4-6元杂环基。
在另一优选例中，R2为含有1-3个选自下组取代基的5-6元杂芳基：卤素、C1-C3烷基、-OH、氨基、氰基、CF3-、CF3CH2-、CD3-、C1-C8烷氧基、C1-C8烷胺基、C1-C4烷氧基羰基、C1-C4烷基磺酰基、C1-C4羟基烷基、苄氧羰基、(C1-C3烷基)2NCO-、未取代的哌啶基、或被一个或多个(如1-3个)C1-C4烷氧羰基取代的哌啶基。
在另一优选例中，R2为取代或未取代的饱和或不饱和4-6元环烷基，所述的取代基指具有一个或多个(如1-3个)选自下组的取代基：卤素、-OH、-NH2、-CN、-COOH、C1-C4烷基、C1-C4烷氧基、取代或未取代的氨基羰基、C1-C4烷氧基羰基、四氢吡咯羰基、C1-C4烷基磺酰基、C1-C4烷基氨基、取代或未取代的哌嗪基羰基、取代或未取代的四氢吡咯羰基、取代或未取代的哌嗪磺酰基，其中所述的取代指具有一个或多个(如1-3个)选自下组的取代基：C1-C3烷基、C1-C4烷氧羰基、C1-C4烷氧基。
在另一优选例中，R2为取代或未取代的苯基。
在另一优选例中，R4为-CO(CR6R7)mR8，且R8选自：H、取代或未取代的5-8元芳基、取代或未取代的5-8元杂芳基、取代或未取代的3-8元环烷基、和取代或未取代的3-8元杂环基，其中所述的取代指具有一个或多个(如1-5个)选自下组的取代基：卤素、C1-C3烷基、-OH、氨基、氰基、-CF3、C1-C8烷氧基、C1-C8烷胺基、或C3-C8环烷基。
在另一优选例中，R8选自下组：H、取代或取代基的苯基、取代或未取代的吡啶基、取代或未取代的吡唑基、取代或未取代的咪唑基、取代或未取代的噻吩基、取代或未取代的嘧啶基、或取代或未取代的环己基。
在另一优选例中，对于R3和X4以及相连的“＝C-N-”或“-C-N-”共同形成的取代或未被取代的4-8元环，优选为5-8元环，更优选地为含1或2个N的5、6、7 或8元环，或含N和O的5、6、7和8元环。
在另一优选例中，R4为-CO(CR6R7)mR8，其中R6和R7各自独立地选自H、D、或取代或未取代的C1-C8烷基、取代或未取代的C1-C8亚烷基羟基，取代或未取代的C1-C8烷氧基和卤素，且m为0、1或2，其中，R8选自H、取代或未取代的吡啶基、取代或未取代的苯基、取代或未取代的吡唑基、取代或未取代的咪唑基、取代或未取代的噻吩基、或取代或未取代的嘧啶基。
在另一优选例中，所述式I化合物如下式Ia所示：
Figure PCTCN2016113838-appb-000002
其中，X1、X2、X3、X4、X5、X6各自独立地选自取代或未取代的CR5或N，其中，所述的“取代”指具有选自A组的一个或多个(如1、2、3或4个)取代基：-CN、-NH2、-CONH2、或-CON-(C1-C3烷基)；
R3选自下组：H、取代或未取代的C1-C8烷基、-OH、氰基、卤素、C1-C8亚烷基羟基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的3-8元芳基、和取代或未取代的3-8元杂芳基；
R2、R4、R5的定义与前述定义相同。
在另一优选例中，所述式Ia化合物如下式所示：
Figure PCTCN2016113838-appb-000003
其中，R3选自下组：H、取代或未取代的C1-C8烷基、-OH、氰基、卤素、C1-C8亚烷基羟基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的3-8元芳基、和取代或未取代的3-8元杂芳基；
R2、R4、R5的定义与前述定义相同。
在另一优选例中，R2选自下组：
Figure PCTCN2016113838-appb-000004
其中，各Ra独立地选自：H、卤素、C1-C4烷氧基羰基、C1-C3烷基、-OH、氰基、氨基、-COOH、CF3-、CF3CH2-、CD3-、C1-C8烷胺基、C1-C4烷氧基羰基、C1-C4烷基磺酰基、C1-C4羟基烷基、苄氧羰基、取代或未取代的哌啶基、C1-C4烷氧基、取代或未取代的氨基羰基、取代或未取代的哌嗪基羰基、取代或未取代的四氢吡咯羰基、取代或未取代的哌嗪磺酰基、取代或未取代的C1-C4烷基羧基；其中，所述的取代基为具有一个或多个(如1-3个)选自下组的取代基：C1-C3烷基、C1-C4烷氧羰基、C1-C4 烷氧基，其中，n为0、1、2或3；
R3选自H、取代或未取代的C1-C8烷基、-OH、氰基、卤素、C1-C8亚烷基羟基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基；
或者，R3和X4以及相连的“＝C-N-”或“-C-N-”共同形成取代或未被取代的4-8元环，其中所述的环含有至少1个N杂原子并且总共含有1-3个选自下组：O、S和N的杂原子，并且所述环为饱和或不饱和环；
R4选自取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、-CO(CR6R7)mR8、-SO2(CR6R7)mR8、-CONR9(CR6R7)mR8、-COO(CR6R7)mR8、氨基、C1-C8羧基；其中，m为0、1、2或3；
各R6、R7各自独立地选自下组：H、取代或未取代的C1-C8烷基、C1-C8亚烷基羟基、取代或未取代的C1-C8烷氧基、和卤素，或者R6与R7相连形成取代或未被取代的3至6元环；
各R8选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的3-8元环烷基、和取代或未取代的3-8元杂环基；
各R9选自下组：H、-OH、取代或未取代的C1-C8烷基、C1-C8亚烷基羟基、和取代或未取代的C1-C8烷氧基；
X1、X2、X3、X4、X5和X6各自独立地选自CR5或N；
R5选自H、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、-OH、氰基、卤素、氨基、取代或未取代的C1-C8烷氨基、取代或未取代的C1-C8烷基羰基、取代或未取代的C1-C8烷氧基羰基、取代或未取代的C1-C8羧基、取代或未取代的C1-C8酯基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的芳基、和取代或未取代的杂芳基。
在另一优选例中，R5选自H或氰基。
在另一优选例中，所述式I化合物如下式Ib所示：
Figure PCTCN2016113838-appb-000005
其中，X1、X2、X3、X5、X6各自独立地选自取代或未取代的CR5或N，其中，所述的“取代”指具有选自A组的一个或多个(如1、2、3或4个)取代基：-CN、-NH2、-CONH2、或-CON-(C1-C3烷基)；
p为0、1、2、3或4；
q为1、2、3、4或5；
且p+q≤5；
Y和Z各自独立地选自-CRcRd、O、S、-NRc；其中，各Rc、Rd各自独立地选自：H、取代或未取代的C1-C8烷基、-OH、氨基、卤素、氰基、取代或未取代的C1-C8亚烷基羟基、取代或未取代的C1-C8烷氧基、取代或未取代的胺基C1-C8烷基-、取代或未取代的C1-C8烷胺基，或者-CRcRd为-C(＝O)-；
R2、R4、R5的定义与前述定义相同。
在另一优选例中，所述式I化合物为：
Figure PCTCN2016113838-appb-000006
其中，p为0、1、2、3或4；
q为1、2、3、4或5；
且p+q≤5；
Y和Z各自独立地选自-CRcRd、O、S、-NRc；其中各Rc、Rd各自独立地选自：H、取代或未取代的C1-C8烷基、-OH、氨基、卤素、氰基、取代或未取代的C1-C8亚烷基羟基、取代或未取代的C1-C8烷氧基、取代或未取代的胺基C1-C8烷基、取代或未取代的C1-C8烷胺基，或者-CRcRd为-C(＝O)；
R2、R4、R5的定义与前述定义相同。
在另一优选例中，在所述式Ib化合物中，R2选自下组：
Figure PCTCN2016113838-appb-000007
其中，各Ra各自独立地选自：H、卤素、C1-C4烷氧基羰基、C1-C3烷基、-OH、氰基、氨基、-COOH、CF3-、CF3CH2-、CD3-、C1-C8烷胺基、C1-C4烷氧基羰基、C1-C4烷基磺酰基、C1-C4羟基烷基、苄氧羰基、取代或未取代的哌啶基、C1-C4烷氧基、取代或未取代的氨基羰基、取代或未取代的哌嗪基羰基、取代或未取代的四氢吡咯羰基、取代或未取代的哌嗪磺酰基、取代或未取代的C1-C4烷基羧基；其中，所述的取代基为具有一个或多个(如1-3个)选自下组的取代基：C1-C3烷基、C1-C4烷氧羰基、C1-C4烷氧基，n为0、1、2或3；
其中，各Ra独立地选自：C1-C4烷基；
Rb选自卤素、-OH、氰基、氨基、取代或未取代的C1-C3烷基、C1-C3卤代烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8杂环烷基；
n为0、1、2或3；
p为0、1、2、3或4；
q为1、2、3、4或5；
且p+q≤5；
Y和Z各自独立地选自-CRcRd、O、S、-NRc；其中Rc、Rd各自独立地选自：H、取代或未取代的C1-C8烷基、-OH、氨基、卤素、氰基、C1-C8亚烷基羟基、取代或未取代的C1-C8烷氧基、胺基C1-C8烷基、取代或未取代的C1-C8烷胺基，或者-CRcRd为-C(＝O)；
R4选自取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、-CO(CR6R7)mR8、-SO2(CR6R7)mR8、-CONR9(CR6R7)mR8、-COO(CR6R7)mR8、氨基、羧 基；其中，m为0、1、2或3；
各R6、R7各自独立地选自下组：H、取代或未取代的C1-C8烷基、C1-C8亚烷基羟基、取代或未取代的C1-C8烷氧基、和卤素，或者R6与R7相连形成取代或未被取代的3至5元环；
各R8选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的芳基、取代或未取代的杂芳基、取代或未取代的3-8元环烷基、和取代或未取代的3-8元杂环基；
各R9选自下组：H、-OH、取代或未取代的C1-C8烷基、C1-C8亚烷基羟基、和取代或未取代的C1-C8烷氧基。
在另一优选例中，所述的化合物I中，R1＝H，R2＝甲基取代的五元杂环，R4＝-CO(CR6R7)mR8，其中R6＝R7＝H、烷基、烷基羟基，且m＝1或2，R8＝取代或未取代的苯基、吡啶基、或H。
在另一优选例中，所述的式I化合物为化合物A1-A252。
在另一优选例中，所述的化合物I选自下组：
Figure PCTCN2016113838-appb-000008
Figure PCTCN2016113838-appb-000009
Figure PCTCN2016113838-appb-000010
Figure PCTCN2016113838-appb-000011
Figure PCTCN2016113838-appb-000012
Figure PCTCN2016113838-appb-000013
Figure PCTCN2016113838-appb-000014
Figure PCTCN2016113838-appb-000015
本发明第二方面，提供一种药物组合物，其包含治疗有效量的选自如本发明第一发明所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐中的一种或多种以及药学上可接受的赋形剂。
本发明第三方面，提供一种如本发明第一方面所述的化合物，其立体异构体或其药学上可接受的盐，或本发明第二方面所述的药物组合物在制备用于预防和治疗与ERK激酶相关的疾病和ERK激酶靶向抑制剂的药物中的用途。
本发明第四方面，提供一种制备如本发明第一方面所述化合物的方法，包括步骤：
a)在惰性溶剂中，在金属催化或者酸/碱催化下，(1e)与(1f)化合物进行反应，制得式I化合物；
Figure PCTCN2016113838-appb-000016
其中，X1、X2、X3、X4、X5、X6、R1、R2、R3各基团的定义如本发明第一方面所述；
LG2为选自下组的离去基团：卤素、磺酸酯、甲硫基、甲基砜。
在另一优选例中，所述方法还包括：步骤(a-1)和(a-2)，从而制得式(1e)化合物：
Figure PCTCN2016113838-appb-000017
(a-1)在惰性溶剂中，(1a)与(1b)通过缩合反应或还原胺化反应，得到化合物(1c)；
(a-2)在惰性溶剂中，在金属催化剂下，(1c)与(1d)化合物进行偶联反应，得到化合物(1e)；
式中，LG1为选自下组的离去基团：卤素、磺酸酯、硼酸、硼酸酯、硼酸盐、有机锡，有机锌；
LG2为选自下组的离去基团：卤素、磺酸酯、甲硫基、甲基砜；
LG3为选自下组的离去基团：卤素、磺酸酯、硼酸、硼酸酯、硼酸盐；
FG选自下组：羧酸，醛，卤素；
X1、X2、X3、X4、X5、X6、R1、R2、R3各基团的定义如本发明第一方面所述。
在另一优选例中，所述(a-1)中，反应在惰性溶剂中进行，所述惰性溶剂选自下组：水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃、甲苯、二氯甲烷、氯仿、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环、或其组合。
在另一优选例中，所述(a-1)中，所述缩合反应在缩合剂存在下进行，所述缩合剂选自下组：2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯、1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、O-苯并三氮唑-四甲基脲六氟磷酸酯、或其组合。
在另一优选例中，所述(a-1)中，所述还原胺化反应在催化剂和还原剂存在下进行，所述催化剂选自下组：四异丙氧基钛、三氟乙酸、乙酸、甲酸、盐酸、硫酸、对甲苯磺酸、或其组合；所述还原剂选自下组：硼氢化钠、氰化硼氢化钠、醋酸硼氢化钠、三氟乙酰氧基硼氢化钠、聚合物负载的硼氢化钠还原剂、三甲氧基硼氢化钠、三乙基 硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化锂、四氢铝锂、或其组合。
在另一优选例中，所述(a-2)中，所述金属催化剂选自下组：三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1’-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1，2-二(二苯基膦基)乙烷二氯化钯、或其组合。
在另一优选例中，所述(a)中，所述反应在催化剂配体存在下进行，所述催化剂配体选自下组：三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、四氟硼酸三环己基膦、三邻苯甲基膦、或其组合。
在另一优选例中，所述(a)中，所述反应在碱存在下进行，所述碱包括无机碱和有机碱。
在另一优选例中，所述(a)中，所述无机碱选自下组：氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠、或其组合。
在另一优选例中，所述(a)中，所述有机碱选自下组：吡啶、三乙胺、N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶、或其组合。
在另一优选例中，所述(a)中，所述反应在酸存在下进行，所述酸选自下组：盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸、或其组合。
在另一优选例中，所述步骤a)的温度为-78℃-250℃。
在另一优选例中，所述步骤a)在常温条件下进行。
在另一优选例中，所述步骤a)在干冰浴或冰浴条件下进行。
在另一优选例中，所述步骤a)在加热条件下进行，所述加热选自下组：电加热、微波加热、或其组合。
本发明第五方面，提供一种制备如本发明第一方面所述化合物的方法，包括步骤：
b)在惰性溶剂中，在金属催化下，(1c)与(1g)化合物进行偶联反应，制得式I化合物；
Figure PCTCN2016113838-appb-000018
其中，X1、X2、X3、X4、X5、X6、R1、R2、R3各基团的定义如本发明第一方面所述；
LG1为选自下组的离去基团：卤素、磺酸酯、硼酸、硼酸酯、硼酸盐、有机锡、有机锌；
LG3为选自下组的离去基团：卤素、磺酸酯、硼酸、硼酸酯、硼酸盐。
在另一优选例中，所述方法还包括：步骤(b-1)和/或(b-2)：
(b-1)(1a)与(1b)在惰性溶剂中，通过缩合或还原胺化等反应进行偶联，得到(1c)；
Figure PCTCN2016113838-appb-000019
(b-2)(1d)与(1f)在惰性溶剂中、碱存在下进行偶联，得到(1g)；
Figure PCTCN2016113838-appb-000020
式中，LG1为选自下组的离去基团：卤素、磺酸酯、硼酸、硼酸酯、硼酸盐、有机锡、有机锌；
LG2为为选自下组的离去基团：卤素、磺酸酯、甲硫基、甲基砜；
LG3为为选自下组的离去基团：卤素、磺酸酯、硼酸、硼酸酯、硼酸盐；FG选
自下组：羧酸，醛，卤素；
X1、X2、X3、X4、X5、X6、R1、R2、R3各基团的定义如本发明第一方面所述。
在另一优选例中，所述(b-1)在惰性溶剂中进行，所述惰性溶剂选自下组：水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜、四氢呋喃、甲苯、二氯甲烷、氯仿、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环、或其组合。
在另一优选例中，所述(b-1)中，缩合反应在缩合剂存在下进行，所述缩合剂选自下组：2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯、1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、O-苯并三氮唑-四甲基脲六氟磷酸酯等、或其组合。
在另一优选例中，所述(b-1)中，所述还原胺化反应在催化剂和还原剂存在下进行，所述催化剂选自下组四异丙氧基钛、三氟乙酸、乙酸、甲酸、盐酸、硫酸、对甲苯磺酸、或其组合；所述还原剂选自下组，硼氢化钠、氰化硼氢化钠、醋酸硼氢化钠、三氟乙酰氧基硼氢化钠、聚合物负载的硼氢化钠还原剂、三甲氧基硼氢化钠、三乙基硼氢化钠、三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化锂、四氢铝锂、或其组合。
在另一优选例中，所述(b)中，(1c)与(1g)在金属催化剂存在下进行偶联，所述金属催化剂选自下组：三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1’-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1，2-二(二苯基膦基)乙烷二氯化钯、或其组合。
在另一优选例中，所述(b)中，(1c)与(1g)在金属催化剂配体存在下进行偶联，所述催化剂配体选自下组：三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、四氟硼酸三环己基膦、三邻苯甲基膦、或其组合。
在另一优选例中，所述(b-2)中，(1d)与(1f)在碱存在下进行偶联，所述碱包括无机碱和有机碱。
在另一优选例中，所述(b-2)中，(1d)与(1f)在无机碱存在下进行偶联，所述无机碱选自下组：氢氧化钠、双三甲基硅基胺基锂、双三甲基硅基胺基钠、双三甲基硅基胺基钾、丁基锂、二异丙基氨基锂、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇 钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠、或其组合。
在另一优选例中，所述(b-2)中(1d)与(1f)在有机碱存在下进行偶联，所述有机碱选自下组：吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶、或其组合。
在另一优选例中，所述(b-2)中，(1d)与(1f)在酸存在下进行偶联，所述酸选自下组：盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸，甲酸，乙酸、或其组合。
在另一优选例中，所述步骤b)的温度为-78℃-250℃。
在另一优选例中，所述步骤b)在常温条件下进行。
在另一优选例中，所述步骤b)在干冰浴或冰浴条件下进行。
在另一优选例中，所述步骤b)在加热条件下进行，所述加热选自下组：电加热、微波加热、或其组合。
本发明第六方面，提供一种非治疗性地抑制ERK激酶活性的方法，包括步骤：将本发明第一方面所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐与ERK激酶接触，从而抑制ERK激酶。
在另一优选例中，所述的接触是将纯化的ERK激酶或表达ERK激酶的细胞进行接触。
本发明第七方面，提供一种预防和/或治疗哺乳动物中与ERK激酶活性相关的疾病的方法，包括对需要的哺乳动物给予治疗有效量的本发明第一方面所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，或给予治疗有效量的如本发明本发明第二方面所述的药物组合物。
在另一优选例中，所述ERK激酶包括ERK1、ERK2或组合。
在另一优选例中，所述的与ERK激酶活性相关的疾病指与ERK激酶高表达或高活性相关的疾病。
在另一优选例中，所述的与ERK激酶活性相关的疾病选自下组：肿瘤。
在另一优选例中，所述的与ERK激酶活性相关的疾病选自下组：皮肤癌、大肠癌、卵巢癌、胰腺癌、肺癌、肾癌、肝癌、黑色素瘤、结直肠癌、急性骨髓性白血病、骨髓增生异常综合症、乳腺癌、胶质瘤。
本发明第八方面，提供一种本发明第一方面所述的化合物或其药学上可接受的盐在制备预防和/或治疗与ERK激酶活性相关的疾病的药物中的用途。
在另一优选例中，所述的与ERK激酶活性相关的疾病指与ERK激酶高表达或高活性相关的疾病。
在另一优选例中，所述的与ERK激酶活性相关的疾病选自下组：肿瘤。
在另一优选例中，所述的与ERK激酶活性相关的疾病选自下组：皮肤癌、大肠癌、卵巢癌、胰腺癌、肺癌、肾癌、肝癌、黑色素瘤、结直肠癌、急性骨髓性白血病、骨髓增生异常综合症、乳腺癌、胶质瘤。
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
本发明人通过广泛而深入的研究，首次意外地发现一种式I所示的化合物或其药学上可接受的盐，其可作为ERK激酶抑制剂，抑制活性高。在此基础上完成了本发明。
术语说明
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
除非另有定义，否则在说明书和权利要求书中所使用的下述术语具有的含义为所属领域技术人员通常理解的涵义。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(＝O)-基团。
“硝基”是指-NO2。
“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言，术语“烷基”指含有1至6个碳原子的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“炔基”是指仅由碳原子和氢原子组成、含有至少一个三键，任选含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烷基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、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、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳 香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b] 哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选地”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。本发明权利要求书和说明书部分所述的“任选地”的取代基选自烷基、烯基、炔基、卤素、卤代烷基、卤代烯基、卤代炔基、氰基、硝基、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环烷基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、 月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保 护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
式I化合物的制备
下列反应方案示例性的说明了制备式I化合物、其立体异构体或其混合物、或其药学上可接受的盐的方法：
Figure PCTCN2016113838-appb-000021
其中，
X1、X2、X3、X4、X5、X6、R1、R2、R3、R4均如在上文式I化合物的实施方案部分中所述。应理解在下列反应方案中，所述通式中取代基和/或变量的组合只有在这类组合导致稳定的化合物时才是可允许的。还应理解其他的通式，如通式(Ia)、(Ia-1)、(Ia-2)、(Ia-3)、(Ia-4)、(Ib)、(Ib-1)、(Ib-2)、(Ib-3)、(Ib-4)，以及本文中具体公开的其他式I化合物可由有机化学领域的技术人员通过本文公开的方法(通过应用适当取代的起始材料并利用本领域技术人员公知的方法根据需要修改合成参数)或已知方法进行制备。
技术人员会理解在某些情况下，在本发明化合物的制备中起始材料和中间体可包含在合成过程中需要保护的官能团。所用的任何保护基的确切性将取决于被保护的官能团的特性，这对本领域技术人员来说是显而易见的。选择合适的保护基以及使其连接和脱除的合成策略的指导可以参见例如，Green&Wuts,Green’sProtective Groups in Organic Synthesis,(《有机合成中的保护基》)3d Edition,Jon Wiley&Sons,Inc.,New York(1999)及该书中引用的文献。
因此，保护基指当与分子中的活性官能团连接时，掩蔽、减低或防止该官能团的反应性的原子团。通常保护基可以在合成过程中根据需要而选择性地脱除。
反应方案1：
Figure PCTCN2016113838-appb-000022
各式中，X1、X2、X3、X4、X5、X6、R1、R2、R3、R4、LG1和LG2均如在上文式I化合物的实施方案部分中所述。
反应方案2：
Figure PCTCN2016113838-appb-000023
X1、X2、X3、X4、X5、X6、R1、R2、R3、R4、LG1、LG2和LG3均如在上文式I化合物的实施方案部分中所述。
本发明的主要优点在于：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的ERK激酶抑制剂、其制备方法和应用，所述的抑制剂对ERK激酶有较高抑制活性。
3.提供了一类治疗与ERK激酶活性相关疾病的药物组合物。
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，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1：1-(5-溴二氢吲哚-1-基)-2-苯基乙酮的合成
Figure PCTCN2016113838-appb-000024
在干燥的50mL三口瓶中依次加入化合物1(1.10g，5.55mmol)、苯乙酰氯(858mg，5.55mmol)、三乙胺(1.68g，16.66mmol)，溶于二氯甲烷(20mL)。LCMS检测反应完毕后，直接减压浓缩，用硅胶柱(乙酸乙酯：石油醚＝1：10)，得到产物2(1.2g，白色固体)，产率：68％.
LCMS:m/z 318.1(M+H)；RT＝1.40min(2min).
2-苯基-1-(5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)二氢吲哚-1-基)乙酮的合成
Figure PCTCN2016113838-appb-000025
在干燥的50mL三口瓶中依次加入加入化合物2(1.4g，4.42mmol)，联硼酸频那醇酯(2.25g，8.84mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(322mg，0.44mmol)，醋酸钾(866mg，8.84mmol)，1,4-二氧六环(20mL)。氮气保护下加热到100摄氏度反应3个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱(乙酸乙酯：石油醚＝1：20)，得到产物3(1.3g，黄色固体)，产率：94％.
LCMS:m/z 364.4(M+H)；RT＝1.53min(2min).
1-(5-(2-氯嘧啶-4-基)二氢吲哚-1-基)-2-苯基乙酮的合成
Figure PCTCN2016113838-appb-000026
在干燥的50mL三口瓶中依次加入化合物3(700mg，1.92mmol)、2,4-二氯嘧啶(286mg，1.92mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(139mg，0.19mmol)，碳酸钾(400mg，2.89mmol)，1,4-二氧六环(8mL)和水(2mL)。氮气保护下加热到100摄氏度，反应3个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用厚制备板(乙酸乙酯：石油醚＝1：5)，得到产物5(250mg，黄色固体)，产率：37％.
LCMS:m/z 350.1(M+H)；RT＝1.48min(2min).
1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)-2-苯基乙酮的合成
Figure PCTCN2016113838-appb-000027
在干燥的50mL三口瓶中依次加入化合物4(200mg，0.57mmol)，1-甲基-5-氨基吡唑(55mg，0.57mmol)，三(二亚苄基丙酮)二钯(55mg，0.06mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(35mg，0.06mmol)，碳酸铯(279mg,0.86mmol)1,4-二氧六环(10mL)。氮气保护下加热到100摄氏度，反应4个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用反向制备柱，得到产物HE153(16mg，黄色固体)，产率：7％.
LCMS:m/z 411.4(M+H)；RT＝1.27min(2min).
1H-NMR(MeOD 400MHz):8.38-8.39(m,1H),8.19-8.21(m,1H),7.96-7.98(m,2H),7.56(s,1H),7.26-7.38(m,7H),4.19-4.23(m,2H),3.89(s,2H),3.79(s,3H),3.20-3.23(m,2H).
实施例2：1-(5-溴-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)-2-苯基乙酮的合成
Figure PCTCN2016113838-appb-000028
在干燥的50mL的单口瓶中依次加入化合物5(398mg,2.0mmol)，苯乙酸(272mg,2.0mmol),HATU(1.1g,3.0mmol)和DMF(10mL)，滴加N,N-二异丙基乙胺(517mg,4.0mmol)后，室温反应过夜。反应完毕后，加入15毫升水，用乙酸乙酯(20毫升×2)萃取，合并有机相。有机相用饱和食盐水(15毫升×3)洗涤，无水硫酸钠干燥,减压浓缩，粗产品用硅胶柱层析(石油醚:乙酸乙酯＝6:1)纯化得到黄色固体化合物6(539mg,产率：85％)。
LCMS:m/z 318.8(M+H)+；RT＝1.652min(254nm)。
1-(2-苯基乙酰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-5-基硼酸的合成
Figure PCTCN2016113838-appb-000029
在干燥的50mL三口烧瓶中加入化合物7(317mg,1.0mmol),1,4-二氧六环(8mL)，双联频哪硼酸酯(381mg,1.5mmol)，醋酸钾(194mg,2.0mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(73mg,0.1mmol)。抽真空用氮气换气3次,在氮气保护下，90℃搅拌反应6h,TLC检测反应完全.反应液冷却到室温,减压浓缩.粗产品用硅胶柱层析纯化(二氯甲烷:甲醇＝5:1)得到黄色固体化合物8(169mg,产率：60％)。
LCMS:m/z 282.9(M+H)+。
1-(5-(2-氯嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)-2-苯基乙酮的合成
Figure PCTCN2016113838-appb-000030
在干燥的50mL三口烧瓶中加入化合物9(169mg,0.6mmol),2,4-二氯嘧啶(134mg，0.9mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(44mg，0.06mmol)，碳酸铯(391mg，1.2mmol)，1,4-二氧六环(8mL)和水(0.5mL)。抽真空用氮气换气3次,在氮气保护下，90℃搅拌反应6h,反应液冷却到室温,减压浓缩.粗产品用硅胶柱层析纯化(石油醚:乙酸乙酯＝2:1)得到黄色固体化合物10(105mg,产率：50％)。
LCMS:m/z 350.9(M+H)+。
1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)-2-苯基乙烷-1-酮的合成
Figure PCTCN2016113838-appb-000031
在干燥的50mL三口瓶中依次加入化合物10(70mg，0.2mmol)，1-甲基-5-氨基吡唑(29mg，0.3mmol)，三(二亚苄基丙酮)二钯(18mg，0.02mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(10mg，0.02mmol)，碳酸铯(130mg,0.4mmol)和1,4-二氧六环(6mL)。氮气保护下加热到105摄氏度，反应过夜。反应完毕后，加入乙酸乙酯(15mL)稀释，饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,减压浓缩粗产品用硅胶柱层析纯化(石油醚:乙酸乙酯＝1:2)得到黄色固体化合物A2(5mg,产率：6％)。
1HNMR(400MHz,CDCl3-d)δ8.81(s,1H)，8.46(d,1H,J＝5.2Hz)，8.09(s,1H)，7.51(d,1H,J＝2.0Hz)，7.39(d,2H,J＝7.2Hz)，7.32-7.17(m,4H)，6.89(s,1H)，6.35(d,1H,J＝2.0Hz)，4.61(s,2H)，4.18(t,2H,J＝8.8Hz)，3.82(s,3H)，3.12(t,2H,J＝8.4Hz)。
LCMS:m/z 412.1(M+H)+；RT＝1.179min(254nm)。
实施例3：N-(5-溴吡啶-2-基)-2-苯乙酰胺的合成
Figure PCTCN2016113838-appb-000032
在干燥的50mL的单口瓶中依次加入化合物11(2.00g,14.71mmol)，2-氨基-5-溴吡啶(2.54g,14.71mmol),HATU(5.59g,14.71mmol)溶于DMF(20mL)，滴加N,N-二异丙基乙胺(1.91g,14.71mmol)后，室温反应4小时。LCMS检测完毕后，向反应液加入水，再用乙酸乙酯萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后通过硅胶柱(展开剂为乙酸乙酯：石油醚＝1：10)得到化合物2(2.8g,白色固体)，产率：67％.
LCMS:m/z291.1(M+H)；RT＝1.33min(2.0min).
(6-(2-苯基乙酰氨基)吡啶-3-基)硼酸的合成
Figure PCTCN2016113838-appb-000033
在干燥的50mL三口瓶中依次加入化合物12(1.4g，4.81mmol)，联硼酸频那醇酯(2.44g，9.62mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(351mg，0.48mmol)，醋酸钾(942mg，9.62mmol)，1,4-二氧六环(20mL)。氮气保护下加热到100摄氏度反应3个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱(乙酸乙酯：石油醚＝1：3)，得到产物13(1.0g，黄色固体)，产率：81％.
LCMS:m/z257.1(M+H)；RT＝0.39min(2min).
N-(5-(2-氯嘧啶-4-基)吡啶-2-基)-2-苯乙酰胺的合成
Figure PCTCN2016113838-appb-000034
在干燥的50mL三口瓶中依次加入化合物13(1.0g，3.91mmol)，2,4-二氯嘧啶(582mg，3.91mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(293mg，0.40mmol)，碳酸钾(810mg，5.87mmol)，1,4-二氧六环(20mL)和水(5mL)。氮气保护下加热到100摄氏度，反应3个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用后制备板(乙酸乙酯：石油醚＝1：3)，得到产物14(500mg，黄色固体)，产率：40％.
LCMS:m/z325.2(M+H)；RT＝1.28min(2min).
N-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)-2-苯基乙酰胺的合成
Figure PCTCN2016113838-appb-000035
在干燥的50mL三口瓶中依次加入化合物14(50mg，0.15mmol)，1-甲基-5-氨基吡唑(15mg，0.15mmol)，三(二亚苄基丙酮)二钯(18mg，0.02mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(12mg，0.02mmol)，碳酸铯(49mg,0.15mmol)1,4-二氧六环(10mL)。氮气保护下加热到100摄氏度，反应2个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用反向制备柱，得到产物A3(16mg，黄色固体)，产率：28％.
LCMS:m/z386.2(M+H)；RT＝1.26min(2min).
1H-NMR(MeOD 400MHz):9.01-9.02(m,1H),8.46-8.47(m,2H),8.15-8.16(m,1H),7.52-7.53(m,1H),7.33-7.40(m,6H),6.42-6.43(m,1H),3.78-3.79(m,5H).
实施例4：2-苯基-N-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙酰胺的合成
Figure PCTCN2016113838-appb-000036
在干燥的50mL的单口瓶中依次加入化合物15(500mg,2.28mmol)，苯乙酸(310mg,2.28mmol),HATU(1.30g,3.42mmol)溶于DMF(10mL)，滴加三乙胺(461mg,4.56mmol)后，室温反应3小时。LCMS检测完毕后，向反应液加入水，再用乙酸乙酯萃取，有机相再用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩后通过硅胶柱(展开剂为乙酸乙酯：石油醚＝1：20)得到化合物16(520mg,白色固体)，产率：68％.
LCMS:m/z338.2(M+H)；RT＝1.09min(2.0min).
N-(5-(2-氯嘧啶-4-基)吡啶-2-基)-2-苯乙基的合成
Figure PCTCN2016113838-appb-000037
在干燥的50mL三口瓶中依次加入化合物16(520mg，1.54mmol)，2,4-二氯嘧啶(275mg，1.85mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(110mg，0.15mmol)，碳酸钾(319mg，2.31mmol)，1,4-二氧六环(8mL)和水(2mL)。氮气保护下加热到100摄氏度，反应3个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用后制备板(乙酸乙酯：石油醚＝1：5)，得到产物17(480mg，黄色固体)，产率：96％.
LCMS:m/z324.3(M+H)；RT＝1.10min(2min).
N-(4-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)苯基)-2-苯基乙酰胺的合成
Figure PCTCN2016113838-appb-000038
在干燥的50mL三口瓶中依次加入化合物17(200mg，0.62mmol)，1-甲基-5-氨基吡唑(60mg，0.62mmol)，三(二亚苄基丙酮)二钯(155mg，0.06mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(35mg，0.06mmol)，碳酸铯(302mg,0.93mmol)1,4-二氧六环(10mL)。氮气保护下加热到100摄氏度，反应2个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用反向制备柱，得到产物A4(50mg，黄色固体)，产率：21％.
LCMS:m/z385.4(M+H)；RT＝1.13min(2min).
1H-NMR(CDCl3,400MHz):8.22-8.24(m,1H),8.00(d,j＝8.4,2H),7.62(d,j＝8.4,2H),7.50-7.54(m,2H),7.34-7.44(m,6H),6.47(s,1H),3.79-3.88(m,5H).
实施例5：4-溴-2-氟苯胺的合成
Figure PCTCN2016113838-appb-000039
在100mL圆底烧瓶中加入4-溴-2-氟-1-硝基苯(2.2g,10mmol),铁粉(2.8g,50mmol)和四氢呋喃(20mL),室温搅拌下滴加盐酸(30mL，2N),室温下搅拌2h,加入无水碳酸钠(2g)和无水硫酸钠,过滤，乙酸乙酯洗涤，减压浓缩得到黄色固体化合物19(1.65g,产率：87％)。
LCMS:m/z 191.1(M+H)+；RT＝1.405min。
N-(4-溴-2-氟苯基)-2-苯基乙酰胺
Figure PCTCN2016113838-appb-000040
在干燥的50mL的单口瓶中依次加入化合物19(950mg,5mmol)，苯乙酸(680mg, 5mmol),HATU(3.42g,9mmol)，DMF(15mL)和N,N-二异丙基乙胺(1.29g,10mmol)。室温下搅拌6h,加乙酸乙酯(20mL)稀释,饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,减压浓缩，粗产品用硅胶柱层析(石油醚:乙酸乙酯＝8:1)纯化得到黄色固体化合物20(1.07g,产率：70％)。
LCMS:m/z 309.8(M+H)+；RT＝1.457min。
N-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)-2-苯基乙酰胺的合成
Figure PCTCN2016113838-appb-000041
在干燥的50mL三口烧瓶中加入化合物20(1.01g,3.3mmol),1,4-二氧六环(10mL)，双联频哪硼酸酯(4.2g,16.7mmol)，醋酸钾(648mg,6.6mmol)和[1,1’-双(二苯基膦基)二茂铁]二氯化钯(220mg,0.3mmol)。抽真空用氮气换气3次,在氮气保护下，90℃搅拌反应6h,TLC检测反应完全.反应液冷却到室温,减压浓缩.粗产品用硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)得到黄色固体化合物21(703mg,产率：60％)。
LCMS:m/z 355.8(M+H)+；RT＝1.699min。
N-(4-(2-氯嘧啶-4-基)-2-氟苯基)-2-苯基乙酰胺的合成
Figure PCTCN2016113838-appb-000042
在干燥的10mL圆底烧瓶中室温下依次加入21(355mg,1.0mmol)，2,4-二氯嘧啶(222mg，1.5mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(73mg，0.1mmol)，碳酸铯(652mg，2.0mmol)，1,4-二氧六环(6mL)和水(1mL)。抽真空用氮气换气3次,在氮气保护下，90℃搅拌反应6h,TLC检测反应完全.反应液冷却到室温,减压浓缩.粗产品用硅胶柱层析纯化(石油醚:乙酸乙酯＝3:1)得到黄色固体化合物22(174mg,产率：51％)。
LCMS:m/z 341.9(M+H)+；RT＝1.677min。
N-(2-氟-4-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)苯基)-2-苯基乙酰胺的合成
Figure PCTCN2016113838-appb-000043
在干燥的25mL三口瓶中依次加入化合物22(68mg，0.2mmol)，1-甲基-5-氨基吡唑(29mg，0.3mmol)，三(二亚苄基丙酮)二钯(18mg，0.02mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(12mg，0.02mmol)，碳酸铯(130mg,0.4mmol)和1,4-二氧六环(3mL)。氮气保护下微波加热到100摄氏度，反应2个小时。反应完毕后，加入乙酸乙酯(20mL)稀释，饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,减压浓缩，粗产品用酸性prep-HPLC纯化得到黄色固体化合物A5(6mg,产率：7％)。
1HNMR(400MHz,CDCl3-d)δ8.49(t,1H,J＝8.4Hz)，8.41(d,1H,J＝5.2Hz)，7.78(s,1H)，7.76(d,1H,J＝4.8Hz)，7.50-7.35(m,7H),7.16(d,1H,J＝5.6Hz)，6.35 (d,1H,J＝1.6Hz)，3.81(s,5H)。
LCMS:m/z 402.9(M+H)+；RT＝1.385min。
本发明使用以上类似方法可制得如下6-44化合物：
实施例6：叔丁基-5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)二氢吲哚-1-羧酸叔丁酯的合成
Figure PCTCN2016113838-appb-000044
1HNMR(400MHz,CDCl3-d)δ8.38(d,1H,J＝5.2Hz)，7.85(s,2H)，7.49(d,1H,J＝1.6Hz)，7.15(d,1H,J＝5.2Hz)，6.87(s,1H)，6.35(d,1H,J＝1.2Hz)，4.03(t,2H,J＝8.8Hz)，3.80(s,3H)，3.15(t,2H,J＝8.8Hz)，1.58(s,9H)。
LCMS:m/z 393.3(M+H)+；RT＝1.461min(254nm)。
实施例7：1-(5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)二氢吲哚-1-基)-3-苯基丙-1-酮的合成
Figure PCTCN2016113838-appb-000045
1HNMR(400MHz,CDCl3-d)δ8.40(d,1H,J＝5.2Hz)，8.32(d,1H,J＝8.4Hz)，7.88-7.86(m,2H)，7.49(d,1H,J＝1.6Hz)，7.32-7.16(m,6H)，6.95(s,1H)，6.35(d,1H,J＝1.6Hz)，4.03(t,2H,J＝8.4Hz)，3.80(s,3H)，3.21(t,2H,J＝8.4Hz)，3.08(t,2H,J＝7.6Hz)，2.76(t,2H,J＝7.6Hz)。
LCMS:m/z 425.0(M+H)+；RT＝1.339min(254nm)。
实施例8：4-(二氢吲哚-5-基)-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺的合成
Figure PCTCN2016113838-appb-000046
1HNMR(400MHz,DMSO-d6)δ8.38(d,1H,J＝5.6Hz)，7.93-7.91(m,3H)，7.47(d,1H,J＝1.6Hz)，7.40(d,1H,J＝5.6Hz)，6.82(d,1H,J＝8.0Hz)，6.36(d,1H,J＝1.6Hz)，5.74(d,1H,J＝2.8Hz)，3.73(s,3H)，3.64(t,2H,J＝8.4Hz)，3.09(t,2H,J＝8.4Hz)。
LCMS:m/z 293.2(M+H)+；RT＝0.958min(254nm)。
实施例9：2-(2-氯苯基)-1-(5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)二氢吲哚-1-基)乙酮的合成
Figure PCTCN2016113838-appb-000047
1HNMR(400MHz,CDCl3-d)δ8.41(d,1H,J＝5.2Hz)，8.31(d,1H,J＝8.8Hz)，7.91 (s,1H)，7.86(d,1H,J＝8.4Hz)，7.49(d,1H,J＝1.6Hz)，7.43(d,1H,J＝2.0Hz)，7.42-7.24(m,3H)，7.17(d,1H,J＝5.2Hz)，6.80(s,1H)，6.35(d,1H,J＝2.0Hz)，4.23(t,2H,J＝8.8Hz)，3.95(s,2H)，3.81(s,3H)，3.30(t,2H,J＝8.4Hz)。
LCMS:m/z 445.4(M+H)+；RT＝1.36min(254nm)。
实施例10：2-(3-氯苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)乙酮的合成
Figure PCTCN2016113838-appb-000048
1H-NMR(CDCl3,400MHz)：8..30-8.35(m,2H),7.88-7.91(m,2H),7.51-7.52(d,J＝1.2Hz,1H),7.29-7.32(m,3H),7.20-7.25(m,2H),6.41(d,J＝1.2Hz,1H),4.15-4.19(m,2H),3.85(s,3H),3.82(s,2H),3.25-3.29(m,2H).
LCMS:m/z444.9(M+H)；RT＝1.475min(2.50min).
实施例11：2-(4-氯苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)乙酮的合成
Figure PCTCN2016113838-appb-000049
LCMS:m/z445.4(M+H)；RT＝1.39min(2.0min).
1H-NMR(CDCl3,400MHz):8.28-8.34(m,2H),7.88-7.91(m,2H),7.52(s,1H),7.33-7.35(m,2H),7.24-7.26(m,4H),6.42(s,1H),4.17(t,j＝8.0,2H),3.85(s,3H),3.81(s,2H),3.26(t,j＝8.0,2H).
实施例12：3-羟基-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)-2-苯基丙-1-酮的合成
Figure PCTCN2016113838-appb-000050
LCMS:m/z441.3(M+H)；RT＝1.15min(2.0min).
1H-NMR(CDCl3,400MHz):7.95-7.97(m,1H),7.83-7.85(m,1H),7.69(s,1H),7.52(s,1H)，7.31-7.39(m,5H),7.09-7.10(m,1H),6.43-6.54(m,2H),4.00-4.11(m,2H),3.85(s,3H),3.47-3.67(m,2H),3.43-3.61(m,1H),3.02-3.07(m,2H).
实施例13：1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)-2-苯基丙-1-酮的合成
Figure PCTCN2016113838-appb-000051
1H-NMR(CDCl3,400MHz)：8..43-8.45(d,J＝7.6Hz,1H),7.19-8.20(d,J＝7.6Hz, 1H),7.91-7.93(d,J＝8.4Hz,1H),7.81(s,1H),7.54-7.55(d,J＝2.0Hz,1H),7.27-7.37(m,6H),6.45-6.46(d,J＝2.0Hz,1H),4.17-4.22(m,1H),3.86-3.91(m,5H),3.04-3.12(m,2H),1.54-1.55(d,J＝6.8Hz,3H).
LCMS:m/z425.3(M+H)；RT＝1.462min(2.50min).
实施例14：2-(2-氯苯基)-N-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)乙酰胺
Figure PCTCN2016113838-appb-000052
1H-NMR(CDCl3,400MHz)：8.92(d,J＝2.0Hz,1H),7.99-8.01(d,J＝9.2Hz,1H),8.49-8.52(m,1H),8.44-8.46(d,J＝6.0Hz,1H),7.61-7.62(d,J＝3.6Hz,1H),7.7.43-7.46(dd,J1＝3.6Hz,J2＝7.2Hz,1H),7.37-7.39(dd,J1＝3.6Hz,J2＝7.2Hz,1H),7.28-7.32(m,3H),6.50-6.51(d,J＝2.4Hz,1H),4.01(s,2H),3.92(s,3H).
LCMS:m/z419.9(M+H)；RT＝1.375min(2.50min).
实施例15：3N-(5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)吡啶-2-基)乙酰胺的合成
Figure PCTCN2016113838-appb-000053
1HNMR(400MHz,CDCl3-d)δ10.77(s,1H)，9.49(s,1H)，9.04(s,1H)，8.52(d,1H,J＝4.8Hz)，8.44(d,1H,J＝8.4Hz)，8.21(d,1H,J＝8.8Hz)，7.47(d,1H,J＝4.8Hz)，7.36(s,1H)，6.28(s,1H)，3.70(s,3H)，2.13(s,3H)。
LCMS:m/z 310.0(M+H)+；RT＝0.771min。
实施例17：N-(1-甲基-1H-吡唑-5-基)-4-(6-(苯乙基氨基)吡啶-3-基)嘧啶-2-胺的合成
Figure PCTCN2016113838-appb-000054
1H-NMR(CDCl3,400MHz):8.74(s,1H),8.35(d,j＝5.6,1H),8.06-8.08(m,1H),7.47-7.48(m,1H),7.30-7.34(m,2H),7.22-7.24(m,2H),6.95-7.09(m,2H),6.34-6.43(m,2H),4.93(s,1H),3.80(s,3H),3.62-3.66(m,2H),2.93-2.97(m,2H).
LCMS:m/z372.2(M+H)；RT＝1.08min(2.0min).
实施例18：4N-(2-氯-4-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)苯基)-2-苯基乙酰胺的合成
Figure PCTCN2016113838-appb-000055
1HNMR(400MHz,CDCl3-d)δ8.44(d,1H,J＝8.8Hz)，8.32(d,1H,J＝5.2Hz)， 7.92(d,1H,J＝2.0Hz)，7.78(dd,1H,J＝2.0Hz,8.8Hz)，7.72(s,1H),7.39-7.27(m,6H),7.03(d,1H,J＝6.0Hz)，6.86(s,1H)，6.24(d,1H,J＝2.4Hz)，3.73(s,2H)，3.70(s,3H)。
LCMS:m/z 418.9(M+H)+；RT＝1.504min。
实施例19：N-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)-1-苯基甲磺酰胺的合成
Figure PCTCN2016113838-appb-000056
1H-NMR(CDCl3 400MHz):8.47-8.57(m,2H),8.18-8.21(m,1H),7.52-7.53(m,1H),7.30-7.33(m,1H),7.25-7.26(m,1H),7.00-7.23(m,5H),6.36(s,1H),4.46(s,2H),3.83(m,3H).
LCMS:m/z421.9(M+H)；RT＝1.14min(2.5min).实施例20：2-(2,6-二氯苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)乙酮的合成
Figure PCTCN2016113838-appb-000057
1H-NMR(CDCl3,400MHz):8.41(d,j＝5.2,1H),8.26(d,j＝8.8,1H),7.94(s,1H),7.84(d,j＝8.4,1H)，7.49-7.50(m,1H),7.36-7.38(m,2H),7.16-7.22(m,2H),6.81(m,1H),6.35-6.36(m,1H),4.34(t,j＝8.4,2H),4.16(s,2H),3.81(s,3H),3.37(t,j＝8.4,2H),2.80(s,1H).
LCMS:m/z479.3(M+H)；RT＝1.43min(2.0min).
实施例21：2-(2-氯苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2，3-b]吡啶-1-基)乙酮的合成
Figure PCTCN2016113838-appb-000058
1H-NMR(CDCl3 400MHz):8.90(s,1H),8.44-8.45(m,1H),8.29(s,1H),7.26-7.49(m,7H),6.39(s,1H),4.65-4.66(m,2H),4.18-4.19(m,2H),3.77(s,3H),3.21-3.23(m,2H).
LCMS:m/z446.2(M+H)；RT＝1.30min(2min).
实施例22：2-(2,6-二氯苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并并[2,3-b]吡啶-1-基)乙酮的合成
Figure PCTCN2016113838-appb-000059
1H-NMR(CDCl3 400MHz):8.81(s,1H),8.45(s,1H),8.13(s,1H),7.51(s,1H), 7.33-7.35(m,2H),7.17-7.19(m,2H),6.96(s,1H),6.35(s,1H),4.88(s,2H),4.23(t,j＝8.4,2H),3.82(s,3H),3.18(t,j＝8.4,2H).
LCMS:m/z480.2(M+H)；RT＝1.41min(2min).
实施例23：N-甲基N-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)-2-苯基乙酰胺的合成
Figure PCTCN2016113838-appb-000060
1H-NMR(CDCl3 400MHz):9.08(s,1H),8.50-8.51(m,1H),8.27-8.29(m,1H),7.49-7.50(m,2H),7.26-7.27(m,1H),7.05-7.27(m,6H),6.36(s,1H),3.82-3.86(m,5H),3.46(s,2H).
LCMS:m/z400.3(M+H)；RT＝0.99min(2min).
实施例24：3-甲基-N-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)丁酰胺的合成
Figure PCTCN2016113838-appb-000061
LCMS:m/z352.3(M+H)；RT＝0.91min(2min).
1H-NMR(CDCl3 400MHz):8.85(s,1H),8.57(s,1H),8.38(d,j＝5.2,1H),8.23-8.30(m,2H),7.59(s,1H),7.43(s,1H),7.08(d,j＝5.2,1H),6.26(s,1H),3.73(s,3H),2.21-2.22(m,2H),2.15-2.16(m,1H),0.93-0.94(d,j＝6.4,6H).
实施例25：2-(3-氯苯基)-N-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)乙酰胺的合成
Figure PCTCN2016113838-appb-000062
LCMS:m/z419.91(M+H)；RT＝1.429min(2.5min).
1H-NMR(CDCl3 400MHz):δ8.83(s,1H),8.39(d,J＝5.6Hz,1H),8.25(s,1H),8.01(s,1H),7.42(d,J＝2.0Hz,1H),7.27(m,3H),7.18(m,1H),7.09(d,J＝5.2,1H),6.83(s,1H),6.27(d,J＝2.0Hz,1H),3.74(s,3H),3.69(s,2H).
实施例26：1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)-3-苯基脲的合成
Figure PCTCN2016113838-appb-000063
1H-NMR(MeOD,400MHz):9.03(s,1H),8.48-8.52(m,2H),7.53-7.58(m,4H), 7.31-7.43(m,4H),7.08-7.09(m,1H),6.48(s,1H),3.81(s,3H).
LCMS:m/z387.3(M+H)；RT＝1.09min(2min).
实施例27：N-(2-氰基-4-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)苯基)-2-苯基乙酰胺的合成
Figure PCTCN2016113838-appb-000064
1H-NMR(DMSO,400MHz):9.55(s,1H),8.86(s,1H),8.54(d,j＝4.2,1H),8.46-8.48(m,1H),7.73(d,j＝8.8,1H),7.56(d,j＝4.2,1H),7.25-7.41(m,6H),6.29(s,1H),3.97(s,2H),3.71(s,3H).
LCMS:m/z410.3(M+H)；RT＝0.97min(2min).
实施例28：2-(2-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2，3-b]吡啶-1-基)乙-1-酮的合成
Figure PCTCN2016113838-appb-000065
1H-NMR(CDCl3 400MHz):8.86(s,1H),8.31(d,J＝6.4,1H),8.10(S,1H),7.61(s,1H),7.36(d,J＝6.4,2H),7.06-7.12(m,2H),6.50(s,2H),4.56(s,2H),4.22-4.26(m,2H).3.93(s,3H)3.17-3.21(m,2H)。
LCMS:m/z430.0(M+H)；RT＝1.339min(2min)
实施例29：2-(3-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙-1-酮的合成
Figure PCTCN2016113838-appb-000066
1H-NMR(CDCl3 400MHz):8.86(s,1H),8.31(d,J＝6.4,1H),8.09(s,1H),7.58(s,1H),7.33(d,J＝6.0Hz,2H),7.08-7.15(m,2H),6.46(s,1H),4.59(s,2H),4.19-4.23(m,2H).3.90(s,3H)3.14-3.18(m,2H)，
LCMS:m/z430.0(M+H)；RT＝1.352min(2min)
实施例30：2-环己基-N-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)乙酰胺的合成(A30)
Figure PCTCN2016113838-appb-000067
1H-NMR(MeOD,400MHz):9.03(s,1H),8.57-8.60(m,1H),8.51(d,j＝5.2,1H),8.07(d,j＝8.8,1H),7.57(s,1H),7.44(d,j＝5.2,1H),6.47(s,1H),3.80(s,3H),2.37(d,j ＝7.2,2H),1.80-1.81(m,1H),1.68-1.77(m,5H),1.31-1.34(m,3H),1.05-1.08(m,2H).
LCMS:m/z392.0(M+H)；RT＝1.40min(2.5min).
实施例31：2-(2-氯-4-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A31)
Figure PCTCN2016113838-appb-000068
1H-NMR(MeOD,400MHz):8.90(s,1H),8.34-8.50(m,2H),7.03-7.62(m,6H),4.55-4.88(m,2H),4.14-4.21(m,2H),3.82(s,3H),3.15(s,2H).
LCMS:m/z464.2(M+H)；RT＝1.34min(2min).
实施例32：2-(2,3-二氯苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并并[2,3-b]吡啶-1-基)乙酮的合成(A32)
Figure PCTCN2016113838-appb-000069
1H-NMR(CDCl3,400MHz):8.78(s,1H),8.45(d,j＝4.2,1H),8.12(s,1H),7.51(s,1H),7.38-7.40(m,1H),7.16-7.20(m,3H),6.92(s,1H),6.34(s,1H),4.69(s,2H),4.22(t,j＝8.4,2H),3.81(s,3H),3.17(t,j＝8.4,2H).
LCMS:m/z480.2(M+H)；RT＝1.42min(2min).
实施例33：2-(2-氯-6-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A33)
Figure PCTCN2016113838-appb-000070
1H-NMR(CDCl3,400MHz):8.72(s,1H),8.38(d,j＝4.2,1H),8.04(s,1H),7.44(s,1H),7.09-7.19(m,4H),6.93-6.94(m,1H),6.28(s,1H),4.63(s,2H),4.13(t,j＝8.4,2H),3.74(s,3H),3.09(t,j＝8.4,2H).
LCMS:m/z464.2(M+H)；RT＝1.34min(2min).
实施例34：2-(2-氯-3-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A34)
Figure PCTCN2016113838-appb-000071
1H-NMR(DMSO-d4,400MHz):9.49(s,1H),8.91(s,1H),8.52(d,j＝4.2,1H),8.32(s,1H),7.48(d,j＝4.2,1H),7.25-7.38(m,4H),6.29(s,1H),4.65(s,2H),4.08(t,j＝8.4,2H),3.70(s,3H),3.18(t,j＝8.4,2H).
LCMS:m/z464.2(M+H)；RT＝1.33min(2min).
实施例35：2-(2-氯吡啶-3-基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A35)
Figure PCTCN2016113838-appb-000072
1H-NMR(DMSO-d4,400MHz):9.50(s,1H),8.91(s,1H),8.52(d,j＝4.2,1H),8.32(s,1H),7.86(d,j＝7.2,1H),7.48(d,j＝4.2,1H),7.37-7.43(m,2H),6.29(s,1H),4.62(s,2H),4.09(t,j＝8.4,2H),3.70(s,3H),3.18(t,j＝8.4,2H).
LCMS:m/z447.2(M+H)；RT＝1.02min(2min).
实施例36：2-(3-氯-4-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A36)
Figure PCTCN2016113838-appb-000073
1H-NMR(DMSO-d4,400MHz):9.50(s,1H),8.92(s,1H),8.52(d,j＝4.2,1H),8.31(s,1H),7.31-7.53(m,5H),6.30(s,1H),4.50(s,2H),4.06(t,j＝8.4,2H),3.70(s,3H),3.15(t,j＝8.4,2H).
LCMS:m/z464.2(M+H)；RT＝1.46min(2min).
实施例37：2-(3-氯-2-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A37)
Figure PCTCN2016113838-appb-000074
LCMS:m/z464.2(M+H)；RT＝1.37min(2min).
1H-NMR(DMSO-d4,400MHz):9.50(s,1H),8.91(s,1H),8.52(d,j＝4.2,1H),8.32(s,1H),7.47-7.49(m,2H),7.34-7.38(m,2H),7.18-7.20(m,1H),6.30(s,1H),4.57(s,2H),4.08(t,j＝8.4,2H),3.70(s,3H),3.17(t,j＝8.4,2H).
实施例38：2-(4-氯-3-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A38)
Figure PCTCN2016113838-appb-000075
LCMS:m/z464.2(M+H)；RT＝1.39min(2min).
1H-NMR(DMSO-d4,400MHz):9.49(s,1H),8.91(s,1H),8.52(d,j＝4.2,1H),8.31(s,1H),7.47-7.53(m,2H),7.34-7.38(m,2H),7.16-7.18(m,2H),6.30(s,1H),4.52(s,2H),4.06(t,j＝8.4,2H),3.70(s,3H),3.15(t,j＝8.4,2H).
实施例39：2-(2-氯苯基)-1-(5-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A39)
Figure PCTCN2016113838-appb-000076
LCMS:m/z450.2(M+H)；RT＝1.31min(2min).
1H-NMR(DMSO-d4,400MHz):8.91(s,1H),8.33-8.36(m,2H),7.38-7.46(m,3H),7.29-7.31(m,2H),7.20-7.22(m,1H),4.60(s,2H),4.06-4.10(m,2H),3.87-3.89(m,2H),3.40-3.44(m,2H),3.15-3.19(m,2H),1.85-1.88(m,2H),1.52-1.56(m,2H).
实施例40：2-(2-氯苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)-2,3-二氢-1H-吡咯并[2，3-b]吡啶-1-基)乙酮的合成(A40)
Figure PCTCN2016113838-appb-000077
LCMS:m/z445.2(M+H)；RT＝1.09min(2min).
1H-NMR(MeOD,400MHz):8.60(s,1H),8.06-8.07(m,2H),7.64(s,1H),7.24-7.49(m,7H),6.49(s,1H),4.62-4.63(m,2H),4.20(s,2H),3.84(s,3H),3.2-3.26(m,2H).
实施例41：2-(2-氯-5-氟苯基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A41)
Figure PCTCN2016113838-appb-000078
LCMS:m/z464.2(M+H)；RT＝1.34min(2min).
1H-NMR(DMSO-d4,400MHz):9.50(s,1H),8.91(s,1H),8.52(d,j＝4.2,1H),8.32(s,1H),7.47-7.51(m,2H),7.31-7.38(m,2H),7.16-7.18(m,1H),6.30(s,1H),4.61(s,2H),4.08(t,j＝8.4,2H),3.70(s,3H),3.17(t,j＝8.4,2H).
实施例42：2-(3-氯吡啶-4-基)-1-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)乙酮的合成(A42)
Figure PCTCN2016113838-appb-000079
LCMS:m/z447.2(M+H)；RT＝0.88min(2min).
1H-NMR(DMSO-d4,400MHz):9.50(s,1H),8.89(s,1H),8.63(s,1H),8.47-8.53(m,2H),8.33(s,1H),7.47-7.49(m,2H),7.37-7.38(m,1H),6.29(s,1H),4.66(s,2H),4.05-4.11(m,2H),3.70(s,3H),3.18(t,j＝8.4,2H).
实施例43：(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)(苯基)甲酮的合成(A43)
Figure PCTCN2016113838-appb-000080
LCMS:m/z398.2(M+H)；RT＝0.94min(2min).
1H-NMR(DMSO-d4,400MHz):9.49(s,1H),8.46-8.53(m,1H),8.29(s,1H),7.50-7.55(m,3H),7.39-7.44(m,4H),6.28(s,1H),4.61(s,2H),4.18(t,j＝8.4,2H),3.69(s,3H),3.20(t,j＝8.4,2H).
实施例44：2-(2-氯苯基)-1-(5-(6-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并[2，3-b]吡啶-1-基)乙酮的合成(A44)
Figure PCTCN2016113838-appb-000081
LCMS:m/z446.2(M+H)；RT＝1.25min(2min).
1H-NMR(MeOD,400MHz):8.66(s,1H),8.74(s,1H),8.11(s,1H),7.56-7.57(m.1H),7.38-7.39(m,1H),7.20-7.24(m,2H),6.74(s,1H),6.24-6.25(m,1H),5.31-5.32(m,1H),4.64(s,2H),4.21(t,j＝8.4,2H),3.80(s,3H),3.16(t,j＝8.4,2H).
实施例45：1-(5-(5-氯-2-(异丙基氨基)吡啶-4-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基)-2-(2-氯苯基)乙酮的合成(A45)
Figure PCTCN2016113838-appb-000082
LCMS:m/z441.1(M+H)；RT＝1.62min(2min).
1H-NMR(MeOD,400MHz):8.29(s,1H),8.04(s,1H),7.83(s,1H),7.25-7.41(m,4H),6.94(s,1H),4.66(s,2H),4.19(t,j＝8.4,2H),3.91-3.95(m,1H),3.23(t,j＝8.4,3H),1.29-1.33(m,2H).
实施例46：3-((2-溴吡啶-3-基)氧基)丙-1-胺的合成(27)
Figure PCTCN2016113838-appb-000083
在干燥的500mL三口瓶中氮气保护下依次加入化合物26(7.0g，40.30mmol),3-氨基-1-丙醇(3.63g，48.28mmol)以及三苯基磷(12.66g，48.28mmol)溶于1,4-二氧六环(250mL)中，室温下滴加偶氮二甲酸二乙酯(8.41g,48.28mmol)，加热回流反应过夜。反应完毕后，直接减压浓缩，用酸性硅胶柱(二氯甲烷：甲醇＝100:7)得到产物27(3.5g，黄色油状)，产率：38％
LCMS:m/z233.0(M+H)；RT＝0.32min(2min).
1H-NMR(CDCl3 400MHz):7.95-7.97(m,1H),7.14-7.22(m,2H),4.14(t,j＝6.0,2H),2.97(t,j＝6.4,2H),1.98-2.03(m,2H).
2,3,4,5-四氢吡啶并[3,2-B][1,4]氧氮杂的合成(28)
Figure PCTCN2016113838-appb-000084
在干燥的100mL三口瓶中依次加入化合物27(2.0g，8.63mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(498mg,0.90mmol),醋酸钯(193mg,0.86mmol)以及碳酸铯(2.81g,8.63mmol)在氮气的保护下溶于1.4-二氧六环(60mL)。加热到100摄氏度反应3小时，反应完毕后，加食盐水，再用二氯甲烷萃取，再减压浓缩，得到粗产物再用酸性硅胶柱(石油醚：乙酸乙酯＝2:1)得到产物28(750mg，无色油状)产率：58％。
1H-NMR(CDCl3 400MHz):7.80(d,j＝4.4,1H),7.15(d,j＝4.4,1H),6.65-6.68(m,1H),4.67(s,1H),4.16(t,j＝6.0,2H),3.35-3.39(m,2H),2.01-2.07(m,2H).
8-溴-2,3,4,5-四氢吡啶并[3,2-B][1,4]氧氮杂的合成(29)
Figure PCTCN2016113838-appb-000085
在干燥的50mL三口瓶中依次加入化合物28(750mg，5.00mmol)，溴(958mg，6.00mmol)，碳酸钾(1035mg，7.50mmol)溶于二氯甲烷(30mL)。室温反应0.5小时。反应完毕后，倒入适量亚硫酸氢钠溶液中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗产物29(900mg，黄色固体)，产率：79％
LCMS:m/z231.0(M+H)；RT＝1.17min(2min).
1-(8-溴-3,4-二氢吡啶并[3,2-B][1,4]氧氮杂-5(2H)-基)-2-(2-氯苯基)乙酮的合成(30)
Figure PCTCN2016113838-appb-000086
在干燥的50mL三口瓶中依次加入化合物29(600mg，2.62mmol)，邻氯苯乙酸(535mg,3.14mmol),HATU(1.19g,3.14mmol)，三乙胺(397mg，3.93mmol)，溶于N,N-二甲基甲酰胺(10mL)。50摄氏度反应过夜，LCMS检测反应完毕后，直接倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用酸性硅胶柱得到产物30(310mg，黄色固体)，产率：31％
LCMS:m/z 383.0(M+H)；RT＝1.51min(2min).
1-(2-(3-氯吡啶-4-基)乙酰基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-5-基)硼酸的合成(31)
Figure PCTCN2016113838-appb-000087
在干燥的50mL三口瓶中依次加入化合物30(150mg，0.39mmol)，联硼酸频那醇酯(150mg，0.59mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(29mg，0.04mmol)，醋酸钾(58mg，0.59mmol)，1,4-二氧六环(4mL)。氮气保护下微波加热到100摄氏度反应1.5个小时。反应完毕后，减压浓缩，得到粗产物31为红色固体。
LCMS:m/z429.3(M+H)；RT＝1.69min(2.0min).
2-(2-氯苯基)-1-(8-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-3,4-二氢吡啶并[3,2-B)(1,4)氧氮杂-5(2H)-基)乙酮的合成(A46)
Figure PCTCN2016113838-appb-000088
在干燥的50mL三口瓶中依次加入化合物31(103mg，0.24mmol)，4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺(50mg，0.24mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(22mg，0.03mmol)，碳酸钾(50mg，0.36mmol)，1,4-二氧六环(4mL)和水(1mL)。氮气保护下加热到100摄氏度，反应2个小时。反应完毕后，倒入20mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用反向制备柱得到产物A46(81mg，黄色固体)，产率：71％
LCMS:m/z476.2(M+H)；RT＝1.18min(2min).
1H-NMR(DMSO-d4,400MHz):9.59(s,1H),8.89(s,1H),8.57-8.59(m,1H),8.10(s,1H),8.57-8.58(m,1H),7.22-7.40(m,5H),6.30(s,1H),4.23(s,2H),3.87-3.89(m,4H),3.70(s,3H),1.99-2.00(m,2H).
采用实施例5类似的方法制备如下47-50化合物：
实施例47：2-(2-氯苯基)-N-(2-氰基-4-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)苯基)乙酰胺的合成(A47)
Figure PCTCN2016113838-appb-000089
LCMS:m/z444.2(M+H)；RT＝1.23min(2min).
1H-NMR(DMSO,400MHz):10.61(s,1H),9.54(s,1H),8.53-8.56(m,2H),8.39-8.41(m,1H),7.63-7.66(m,1H),7.31-7.54(m,6H),6.29(s,1H),3.96(s,2H),3.69(s,3H).
实施例48：2-(2-氯吡啶-3-基)-N-(2-氰基-4-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4- 基)苯基)乙酰胺的合成(A48)
Figure PCTCN2016113838-appb-000090
LCMS:m/z445.2(M+H)；RT＝1.14min(2min).
1H-NMR(CDCl3,400MHz):8.52-8.59(m,3H),8.23-8.31(m,2H),7.96(s,1H),7.81-7.83(m,1H),7.53(s,1H),7.34-7.37(m,1H),7.17-7.19(m,1H),6.83(s,1H),6.36(s,1H),3.99(s,2H),3.83(s,3H).
实施例49：2-(2-氯吡啶-3-基)-1-(5-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)-2,3-二氢-1H-吡咯并并[2,3-b]吡啶-1-基)乙酮的合成(A49)
Figure PCTCN2016113838-appb-000091
LCMS:m/z451.2(M+H)；RT＝1.23min(2min).
1H-NMR(DMSO-d4,400MHz):8.94(s,1H),8.35-8.38(m,3H),7.85-7.87(m,1H),7.61-7.65(m,1H),7.27-7.41(m,2H),4.63(s,2H),4.20(s,3H),3.90-3.95(m,2H),3.42-3.43(m,2H),3.18-3.19(m,2H),1.87-1.88(m,2H),1.55-1.57(m,2H).
实施例50：2-((2-氯苯乙基)氨基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)苯腈的合成(A50)
Figure PCTCN2016113838-appb-000092
LCMS:m/z430.4(M+H)；RT＝1.47min(2min).
1H-NMR(CDCl3,400MHz):8.31(d,j＝4.2,1H),8.00-8.04(m,2H),7.43(s,1H),7.34(d,j＝6.0,1H),7.15-7.17(m,2H),6.99-7.00(s,1H),6.74-6.76(m,1H),6.67(s,1H),6.27(s,1H),4.97(s,1H),3.74(s,3H),3.49-3.54(m,2H),3.03-3.06(m,2H).
实施例51：5-溴-1-(2-氯苯乙基)-2,3-二氢-1H-吡咯并[2,3-b)吡啶的合成(33)
在干燥的50mL三口瓶中依次加入化合物32(250mg，0.72mmol)，溶于硼烷四氢呋喃(4mL)。加热回流过夜。反应完毕后，减压浓缩，得到粗产物33。
LCMS:m/z339.0(M+H)；RT＝1.46min(2.0min).
1-(2-氯苯乙基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-5-基)硼酸的合成(34)
Figure PCTCN2016113838-appb-000094
在干燥的50mL三口瓶中依次加入化合物33(160mg，0.47mmol)，联硼酸频那醇酯(180mg，0.71mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(37mg，0.05mmol)，醋酸钾(70mg，0.71mmol)，1,4-二氧六环(4mL)。氮气保护下微波加热到100摄氏度反应1.5个小时。反应完毕后，减压浓缩，得到粗产物34为红色固体。
LCMS:m/z302.7(M+H)；RT＝0.71min(2.5min).
4-(1-(2-氯苯乙基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-5-基)-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺的合成(A51)
Figure PCTCN2016113838-appb-000095
在干燥的50mL三口瓶中依次加入化合物34(72mg，0.24mmol)，4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺(50mg，0.24mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(22mg，0.03mmol)，碳酸钾(50mg，0.36mmol)，1,4-二氧六环(4mL)和水(1mL)。氮气保护下加热到100摄氏度，反应2个小时。反应完毕后，倒入20mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用反向制备柱得到产物A51(18mg，黄色固体)，产率：17％
LCMS:m/z432.4(M+H)；RT＝1.03min(2min).
1H-NMR(MeOD,400MHz):8.45(d,j＝4.2,1H),8.25(s,1H),8.15(s,1H),7.39-7.48(m,3H),7.25-7.30(m,3H),6.34(s,1H),3.80-3.91(m,4H),3.75(s,3H),3.18-3.25(m,2H).
实施例52：5-氯-4-碘-N-(四氢-2H-吡喃-4-基)吡啶-2-胺的合成(36)
Figure PCTCN2016113838-appb-000096
在干燥的25mL圆底烧瓶中室温下依次加入化合物35(300mg,1.17mmol),四氢-2H-吡喃-4-胺盐酸盐(241mg,1.755mmol)，DIPEA(454mg,3.51mmol)，和DMSO(2mL)，氮气置换3次。搅拌加热至90摄氏度，反应16小时。TLC板检测反应完毕后，加入10mL水，用乙酸乙酯萃取(20mL×3)，合并有机相。饱和食盐水(10mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用柱层析法(乙酸乙酯:石油醚＝1:4)纯化所得残余物，得到产物5-氯-4-碘-N-(四氢-2H-吡喃-4-基)吡啶-2-胺36(160mg,黄色固体)，产率：40.4％
LCMS:m/z338.9，340.9(M+H)；RT＝4.1min(9min)。
1-(5-(5-氯-2-(四氢-2H-吡喃-4-基氨基)吡啶-4-基)-2,3-二氢吡咯并[2,3-b]吡啶-1-基)-2-(2-氯苯基)乙酮的合成(A52)
Figure PCTCN2016113838-appb-000097
在干燥的25mL圆底烧瓶中室温下依次加入5-氯-4-碘-N-(四氢-2H-吡喃-4-基)吡啶-2-胺2(120mg,0.354mmol),1,4-二氧六环(4mL)和水(0.5mL)，GE010-04(112mg,0.354mmol)(该化合物的合成见GE010)，Pd(dppf)2Cl2.CH2Cl2(28mg,0.0354mmol),碳酸氢钠(59mg,0.708mmol)，氮气置换3次。升温至105摄氏度，搅拌1个小时。反应完毕后，减压浓缩，加入10mL水，用乙酸乙酯萃取(30mL×3)，合并有机相。饱和食盐水洗涤(10mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝1:4至乙酸乙酯:石油醚＝10:1)纯化所得残余物，得到产物1-(5-(5-氯-2-(四氢-2H-吡喃-4-基氨基)吡啶-4-基)-2,3-二氢吡咯并[2,3-b]吡啶-1-基)-2-(2-氯苯基)乙酮A52(33mg,淡黄色固体)，产率：19.3％。
LCMS:m/z483.1，485.1(M+H)；RT＝4.78min(9min).
1H-NMR(CDCL3,400MHz):δ8.18(d,J＝2.0Hz,1H),8.12(s,1H),7.61(d,J＝1.1Hz,1H),7.41–7.33(m,1H),7.28(dd,J＝6.3,3.0Hz,1H),7.21(dd,J＝6.1,2.1Hz,2H),6.31(s,1H),4.64(s,2H),4.47(s,1H),4.21(t,J＝8.6Hz,2H),3.99(d,J＝11.6Hz,2H),3.85(s,1H),3.59–3.46(m,2H),3.15(t,J＝8.6Hz,2H),2.03(t,J＝5.3Hz,2H),1.55–1.46(m,2H).
实施例53：2-(2-氯苯基)-1-(5-(2,5-二氯吡啶-4-基)-2,3-二氢吡咯并[2,3-b]吡啶-1-基)乙酮的合成(37)
Figure PCTCN2016113838-appb-000098
在干燥的25mL圆底烧瓶中室温下依次加入化合物32(700mg,1.99mmol)(化合物1的合成见GE010),2,5-二氯吡啶-4-硼酸(420mg,2.19mmol)，1,4-二氧六环(5mL)和水(1.0mL)，Pd(dppf)2Cl2(147mg,0.199mmol),碳酸钾(328mg,2.387mmol)，氮气置换3次。搅拌加热至105摄氏度，反应3小时。TLC板检测反应结果后，加入10mL水，用乙酸乙酯萃取(20mL×3)，合并有机相。饱和食盐水(10mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用柱层析法(乙酸乙酯:石油醚＝4:6)纯化所得残余物，得到产物2-(2-氯苯基)-1-(5-(2,5-二氯吡啶-4-基)-2,3-二氢吡咯并[2,3-b]吡啶-1-基)乙酮37(410mg,黄色固体)，产率：49.2％。
LCMS:m/z418.6，420.6(M+H)；RT＝5.53min(9min)。
1-(5-(5-氯-2-(1-甲基-1H-吡唑-5-基氨基)吡啶-4-基)-2,3-二氢吡咯并[2,3-b]吡啶-1-基)-2-(2-氯苯基)乙酮的合成(A53)
Figure PCTCN2016113838-appb-000099
在干燥的10mL微波管中室温下依次加入2-(2-氯苯基)-1-(5-(2,5-二氯吡啶-4-基)-2,3-二氢吡咯并[2,3-b]吡啶-1-基)乙酮37(150mg,0.36mmol),THF(3mL)，1-甲基-1H-吡唑-5-胺(35mg,0.36mmol)，Pd2(dba)3(33mg,0.036mmol),Xtanphos(21mg,0.036mmol)，碳酸铯(126mg,0.396mmol)，氮气置换3次。升温至155摄氏度，搅拌4个小时。反应完毕后，用少量硅胶快速过滤，固体用THF洗涤(5mL×3)，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(DCM:MeOH＝30:1)纯化所得残余物，再用制备色谱柱分离，冷冻干燥后，得到产物1-(5-(5-氯-2-(1-甲基-1H-吡唑-5-基氨基)吡啶-4-基)-2,3-二氢吡咯并[2,3-b]吡啶-1-基)-2-(2-氯苯基)乙酮A53(26mg,淡黄色固体)，产率：15％。
LCMS:m/z479.0，481.0(M+H)；RT＝4.65min(9min).
1H-NMR(CDCL3,400MHz):δ10.95(s,1H),8.15(d,J＝28.3Hz,2H),7.55(d,J＝14.4Hz,2H),7.48–7.33(m,1H),7.26(d,J＝9.4Hz,1H),7.24–7.17(m,2H),6.84(s,1H),6.21(s,1H),4.60(s,2H),4.23(d,J＝8.4Hz,2H),3.84(s,3H),3.17(t,J＝8.4Hz,2H).
采用实施例53类似的方法制备如下54-64化合物：
实施例54：(4-{1-[2-(2-氯-苯基)-乙基]-1H-吡咯并[2,3-b]吡啶-5-基}-嘧啶-2-基)-(2-甲基-2H-吡唑-3-基)-胺的合成(A54)
Figure PCTCN2016113838-appb-000100
LCMS:m/z430.1(M+H)；RT＝4.59min(9min).
1H-NMR(CDCL3,400MHz):δ8.99(d,J＝1.8Hz,1H),8.52(d,J＝1.8Hz,1H),8.43(d,J＝5.3Hz,1H),7.50(d,J＝1.6Hz,1H),7.35(d,J＝7.8Hz,1H),7.32–7.21(m,2H),7.15(t,J＝7.0Hz,1H),7.06(t,J＝7.2Hz,1H),6.99–6.84(m,3H),6.41(dd,J＝22.0,2.4Hz,2H),4.58(t,J＝7.0Hz,2H),3.82(s,3H),3.30(t,J＝7.0Hz,2H).
实施例55：2-(2-氯-4-氟-苯基)-N-{2-氰基-4-(2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-苯基}-乙酰胺的合成(A55)
Figure PCTCN2016113838-appb-000101
LCMS:m/z462.0(M+H)；RT＝4.01min(9min).
1H-NMR(DMSO,400MHz):δ10.59(s,1H),9.51(s,1H),8.51(dd,J＝9.8,3.5Hz,2H),8.36(dd,J＝8.7,1.8Hz,1H),7.80(d,J＝8.7Hz,1H),7.58–7.37(m,3H),7.34(d,J＝1.8Hz,1H),7.26–7.13(m,1H),6.25(d,J＝1.5Hz,1H),3.92(s,2H),3.66(s,3H).
实施例56：2-(2-氟-苯基)-N-{2-氰基-4-(2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-苯基}-乙酰胺的合成(A56)
Figure PCTCN2016113838-appb-000102
LCMS:m/z428.1(M+H)；RT＝3.75min(9min).
1H-NMR(DMSO,400MHz):δ10.57(s,1H),9.51(s,1H),8.63–8.44(m,2H),8.37(d,J＝8.5Hz,1H),7.81(d,J＝8.8Hz,1H),7.51(d,J＝5.1Hz,1H),7.46–7.23(m,3H),7.23–7.05(m,2H),6.25(s,1H),3.84(s,2H),3.66(s,3H).
实施例57：1-{5-[5-氯-2-(2-甲基-2H-吡唑-3-基胺)-吡啶-4-基]-2,3-二氢吡咯并[2,3-b]吡啶-1-基}-2-(2-氯-吡啶-3-基)-乙酮的合成(A57)
Figure PCTCN2016113838-appb-000103
LCMS:m/z480.1，482.1(M+H)；RT＝4.11min(9min).
1H NMR(400MHz,dmso):δ8.35–8.24(m,2H),8.19–8.03(m,2H),7.90–7.80(m,2H),7.63(d,J＝2.3Hz,1H),7.39(dd,J＝7.3,4.8Hz,1H),7.28(d,J＝1.2Hz,1H),5.95(s,1H),4.59(s,2H),4.06(t,J＝8.4Hz,2H),3.55(s,3H),3.12(t,J＝8.3Hz,2H).
实施例58：2-(2-氯-苯基)-N-{2-氰基-4-[5-氟-2-(2-甲基-2H-吡唑-3-基胺)-嘧啶-4-基]-苯基}-乙酰胺的合成(A58)
Figure PCTCN2016113838-appb-000104
LCMS:m/z462.1(M+H)；RT＝4.18min(9min).
1H NMR(400MHz,dmso):δ10.64(s,1H),9.61(s,1H),8.63(d,J＝3.3Hz,1H),8.31(s,1H),8.23(d,J＝9.8Hz,1H),7.86(d,J＝8.8Hz,1H),7.55–7.38(m,2H),7.37–7.21(m,3H),6.24(d,J＝1.5Hz,1H),3.94(s,2H),3.66(s,3H).
实施例59：2-(2-氯-3-氟-苯基)-N-{2-氰基-4-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-苯基}乙酰胺的合成(A59)
Figure PCTCN2016113838-appb-000105
LCMS:m/z462.1(M+H)；RT＝3.98min(9min).
1H-NMR(DMSO-d6,400MHz):10.64(s,1H),9.50(s,1H),8.52(dd,J＝4.0Hz,2H),8.37(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.34-7.32(m,4H),6.25(s,1H),4.00(s,2H),3.67(s,3H).
实施例60：1-{5-[5-氯-2-(2-氯-4-氟-苯基氨基)-吡啶-4-基]-2,3-二氢吡咯并[2,3-b]吡啶-1-基}-2-(2-氯-苯基)-乙酮的合成(A60)
Figure PCTCN2016113838-appb-000106
LCMS:m/z527.9(M+H)；RT＝6.16min(9min).
1H NMR(400MHz,dmso):δ8.71(s,1H),8.20(d,J＝18.5Hz,2H),7.91–7.74(m,2H),7.44(ddd,J＝9.2,7.1,3.3Hz,2H),7.36(dd,J＝5.6,3.7Hz,1H),7.27(dd,J＝5.7,3.5Hz,2H),7.22–7.14(m,1H),6.94(s,1H),4.56(s,2H),4.05(t,J＝8.4Hz,2H),3.13(t,J＝8.4Hz,2H).
实施例61：1-{5-[2-(2-氯-4-氟-苯基氨基)-嘧啶-4-基]-2,3-二氢吡咯并[2,3-b]吡啶-1-基}-2-(2-氯-苯基)-乙酮的合成(A61)
Figure PCTCN2016113838-appb-000107
LCMS:m/z494.1,496.1(M+H)；RT＝7.46min(9min).
1H NMR(400MHz,CDCL3):δ8.81(s,1H),8.58–8.39(m,2H),8.16(s,1H),7.48(s,1H),7.39(dd,J＝6.0,3.1Hz,1H),7.33–7.25(m,1H),7.18(ddd,J＝16.5,8.4,4.8Hz,4H),7.06(dd,J＝11.5,5.5Hz,1H),4.66(s,2H),4.22(t,J＝8.6Hz,2H),3.18(t,J＝8.5Hz,2H).
实施例62：N-(2-氰基-4-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)苯基)-2-(吡啶-3-基)乙酰胺化合物的合成(A62)
Figure PCTCN2016113838-appb-000108
LCMS:m/z411.2(M+H)；RT＝2.22min(9min).
1H NMR(dmso,400MHz)δ10.61(s,1H),9.50(s,1H),8.57–8.42(m,4H),8.36(d,J＝8.7Hz,1H),7.82–7.71(m,2H),7.50(d,J＝5.2Hz,1H),7.39–7.29(m,2H),6.25(s,1H),3.81(s,2H),3.66(s,3H).
实施例63：2-(2-氯苯基)-N-(2-氰基-4-(2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)苯基)乙酰胺化合物的合成(A63
Figure PCTCN2016113838-appb-000109
LCMS:m/z443.1(M+H)；RT＝3.02min(9min).
1H NMR(dmso,400MHz)δ10.57(s,1H),9.16(s,1H),8.22–8.12(m,2H),7.99(dd,J＝8.6,2.0Hz,1H),7.77(d,J＝8.6Hz,1H),7.49–7.40(m,2H),7.38(d,J＝1.7Hz,1H),7.33–7.24(m,2H),7.19(d,J＝5.0Hz,1H),7.08(s,1H),6.30(d,J＝1.8Hz,1H),3.92(s,2H),3.67(s,3H).
实施例64：N-{4-[5-氯-2-(2-甲基-2H-吡唑-3-基胺)-吡啶-4-基]-2-氰基-苯基}-2-(2- 氯-苯基)-乙酰胺的合成(A64)
Figure PCTCN2016113838-appb-000110
LCMS:m/z477(M+H)；RT＝4.50min(9min).
1H-NMR(CD3OD,400MHz):8.06(s,1H),7.92(s,1H),7.83(d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.46(dd,J＝4.0Hz,1H),7.43-7.40(m,3H),7.29(d,J＝8.0Hz,2H),6.11(s,1H),3.97(s,2H),3.66(s,3H)
实施例65：5-溴-2,3-二氢-1H-吲哚-7-甲腈(39)
Figure PCTCN2016113838-appb-000111
在干燥的100mL圆底烧瓶中室温下依次加入7-氰基吲哚啉化合物38(600mg,4.161mmol),DCM(10mL),低温零度下，慢慢加入NBS(756mg,4.244mmol)。搅拌加热至25摄氏度，反应1小时。TLC板检测反应完毕后，过滤,用DCM萃取(20mL)，合并有机相。饱和碳酸氢钠水溶液(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物5-溴-2,3-二氢-1H-吲哚-7-甲腈39(900mg,棕色固体)，产率：96.9％
LCMS:m/z223.0，225.0(M+H)；RT＝4.96min(9min)。
5-(4,4,5,5-四甲基-[1,3,2]二氧硼杂环戊烷-2-基)-2,3-二氢-1H-吲哚-7-甲腈的合成(40)
Figure PCTCN2016113838-appb-000112
在干燥的50mL单口瓶中室温下依次加入化合物5-溴-2,3-二氢-1H-吲哚-7-甲腈39(700mg,3.14mmol),联硼酸频那醇酯(1595mg,6.28mmol)，Pd(dppf)Cl2(230mg,0.314mmol)，醋酸钾(617mg,6.28mmol)和1,4-二氧六环(16mL)，氮气置换3次。搅拌加热至110摄氏度，反应3小时。LCMS检测反应完毕后，过滤，滤液减压浓缩后用comiflash(EA/PE＝10％-30％)纯化所得残余物得到产物，得产物5-(4,4,5,5-四甲基-[1,3,2]二氧硼杂环戊烷-2-基)-2,3-二氢-1H-吲哚-7-甲腈3(700mg,黄色固体)，产率：82.5％,纯度约90％。
LCMS:m/z271.2(M+H)；RT＝4.86min(9min).
4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺(42)
Figure PCTCN2016113838-appb-000113
在干燥的50mL单口瓶中室温下依次加入1-甲基-1H-吡唑-5-胺(600mg,4.67mmol),THF(2mL)，降温至-78℃，缓慢滴加LiHDMS(11.7mL,11.7mmol)并搅拌30min。把4-氯-2-(甲基磺酰基)嘧啶(1.17g,6.07mmol)溶于13mLTHF中并滴加到反应液中，并在 -78℃搅拌30min后于室温下搅拌30min。LCMS检测反应完毕后，加入20mL水淬灭，并用EA萃取，减压浓缩后，粗产品用combiflash(EA/PE 0％-50％)纯化得到产物4-氯-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺(42)(740mg,黄色固体).
5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(41)
Figure PCTCN2016113838-appb-000114
在干燥的50mL圆底烧瓶中室温下依次加入5-(4,4,5,5-四甲基-[1,3,2]二氧硼杂环戊烷-2-基)-2,3-二氢-1H-吲哚-7-甲腈40(300mg,1.11mmol),1,4-二氧六环(5mL)和水(1mL)，化合物42(240mg,0.89mmol)，Pd(dppf)Cl2(81mg,0.111mmol),碳酸钾(184mg,1.33mmol)，氮气置换3次。升温至100摄氏度，搅拌1个小时。反应完毕后，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯至DCM:MeOH＝20:1)纯化所得残余物，得到5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈41(308mg,淡黄色固体)，产率：87.5％。
LCMS:m/z 318.2(M+H)；RT＝3.26min(9min).
1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A65)
Figure PCTCN2016113838-appb-000115
在干燥的50mL圆底烧瓶中室温下依次加入5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈41(250mg,0.788mmol),DMF(6mL)，2-氯吡啶-3-乙酸(162mg,0.945mmol)，EDCI(454mg,2.364mmol),HOBt(319mg,2.364mmol)，三乙胺(399mg,3.94mmol)，氮气置换3次。升温至35摄氏度，搅拌24-48个小时。反应完毕后，过滤，用EA萃取(40mL*2)，合并有机相。饱和食盐水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯至DCM:MeOH＝20:1)纯化所得残余物，再用制备色谱纯化，得到产物1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈A65(39mg,淡黄色固体)，产率：10.5％。
LCMS:m/z471.2(M+H)；RT＝3.36min(9min).
1H NMR(400MHz,dmso):δ9.47(s,1H),8.47(d,J＝5.2Hz,1H),8.37–8.19(m,3H),7.82(d,J＝6.1Hz,1H),7.49–7.37(m,2H),7.32(s,1H),6.22(s,1H),4.31(t,J＝8.1Hz,2H),4.09(s,2H),3.63(s,3H),3.23(t,J＝7.7Hz,2H).
实施例66：1-[2-(2-氯-苯基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A66)
Figure PCTCN2016113838-appb-000116
在干燥的50mL圆底烧瓶中室温下依次加入5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈41(100mg,0.315mmol),DMF(4mL),化合物43(119mg,0.63mmol)(该化合物的合成见GE053)，DIPEA(163mg,1.26mmol)氮气置换3次。升温至30摄氏度，搅拌18个小时。EA(50mL*2)萃取，饱和食盐水(10mL)洗涤后，干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯至DCM:MeOH＝20:1)纯化所得残余物，得到粗品用制备色谱柱纯化后，得到产物1-[2-(2-氯-苯基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈A66(49mg,淡黄色固体)，产率：33.1％。
LCMS:m/z470.2，472.2(M+H)；RT＝4.10min(9min).
1H NMR(400MHz,dmso):δ9.46(s,1H),8.47(d,J＝5.2Hz,1H),8.25(d,J＝4.8Hz,2H),7.52–7.39(m,2H),7.42–7.18(m,4H),6.22(d,J＝1.7Hz,1H),4.29(t,J＝8.2Hz,2H),4.05(s,2H),3.64(s,3H),3.22(t,J＝8.1Hz,2H).
采用实施例66类似的方法制备如下67-69化合物：
实施例67：1-[2-(2-氯-4-氟-苯基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基胺)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A67)
Figure PCTCN2016113838-appb-000117
LCMS:m/z488.2(M+H)；RT＝4.18min(9min).
1H NMR(400MHz,dmso):δ9.49(s,1H),8.50(d,J＝5.3Hz,1H),8.28(d,J＝4.5Hz,2H),7.54–7.40(m,3H),7.35(d,J＝1.8Hz,1H),7.25–7.17(m,1H),6.25(d,J＝1.7Hz,1H),4.32(t,J＝8.2Hz,2H),4.07(s,2H),3.67(s,3H),3.25(t,J＝8.2Hz,2H).
实施例68：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(四氢-吡喃-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A68)
Figure PCTCN2016113838-appb-000118
LCMS:m/z475.2(M+H)；RT＝3.31min(9min).
1H-NMR(DMSO-d6,400MHz):8.34(d,J＝4.0Hz,2H),8.28(d,J＝4.0Hz,2H),7.86(d,J＝4.0Hz,1H),7.44(br,1H),7.41(d,J＝4.0Hz,1H),7.25(s,1H),4.35-4.32(m,2H),4.12(s,2H),4.01-3.97(m,1H),3.87-3.83(m,2H),3.38(t,2H),3.25(t,2H),1.85-1.82(m,2H),1.52-1.50(m,2H).
实施例69：2-(2-氯苯基)-N-(2-氰基-4-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)苯基)乙酰胺化合物的合成(A69)
Figure PCTCN2016113838-appb-000119
LCMS:m/z448.2(M+H)；RT＝4.05min(9min).
1H NMR(dmso,400MHz)1H NMR(400MHz,dmso)δ10.57(s,1H),8.50(d,J＝2.0Hz,1H),8.37(d,J＝5.4Hz,2H),7.80(d,J＝8.7Hz,1H),7.54–7.35(m,3H),7.34–7.18(m,3H),4.00(s,1H),3.93(s,2H),3.85(d,J＝11.0Hz,2H),3.38(s,2H),1.83(d,J＝11.4Hz,2H),1.58–1.43(m,2H).
实施例70：4-溴-2-氟-6-碘-苯胺化合物的合成(45)
Figure PCTCN2016113838-appb-000120
在干燥的100mL单口瓶中室温下依次加入化合物44(3000mg,15.79mmol),Ag2SO4(5.4g,17.32mmol),I2(4.4g,17.32mmol)和EtOH(100mL)，室温搅拌6小时。LCMS检测反应完毕后，过滤并减压浓缩，加入乙酸乙酯(200mL)，分别用硫代硫酸钠饱和溶液(50mL×3)，饱和碳酸钠溶液(50mL×2)和水(50ML)洗涤，有机相用无水硫酸钠干燥，过滤滤液减压浓缩后用comiflash(EA/PE＝0％-100％)纯化所得残余物得到产物用comiflash(EA/PE＝0％-4％)纯化所得残余物得到产物4-溴-2-氟-6-碘-苯胺45(3.8g,紫色固体)，产率：76％。
LCMS:m/z315.9(M+H)；RT＝4.86min(9min).
2-氨基-5-溴-3-氟-苄腈化合物的合成(46)
Figure PCTCN2016113838-appb-000121
在干燥的50mL单口瓶中室温下依次加入化合物45(1500mg,4.75mmol),ZnCN2(279mg,2.37mmol)，Pd2(dpa)3(435mg,0.475mmol)，dppf(263mg,0.475mmol)和DMF(15mL),H2O(0.15mL)，氮气置换3次。加热至110摄氏度，反应1小时。LCMS检测反应完毕后，过滤，滤液减压浓缩后，用comiflash(EA/PE＝0％-20％)纯化所得残余物得到产物用comiflash(EA/PE＝0％-4％)纯化所得残余物得到产物2-氨基-5-溴-3-氟-苄腈46(700mg,黄色固体)，产率：68％
LCMS:m/z215(M+H)；RT＝3.90min(9min).
N-(4-溴-2-氨基-6-氟-苯基)-2-(2-氯苯基)-乙酰胺化合物的合成(47)
Figure PCTCN2016113838-appb-000122
在干燥的50mL单口瓶中室温下依次加入化合物46(270mg,1.26mmol),43(1429mg,7.56mmol)，吡啶(993mg,12.6mmol)和DMF(5mL)，室温下反应3小时。LCMS检测反应完毕后，加入水(30ML)淬灭反应，用EA(30mL×2)萃取，合 并有机相，用饱和盐水(30mL)洗涤，有机相减压浓缩后，用comiflash(MeOH/0.5％TFA水溶液＝10％-80％)纯化所得残余物得到产物N-(4-溴-2-氨基-6-氟-苯基)-2-(2-氯苯基)-乙酰胺47(165mg,白色固体)，产率：36％
LCMS:m/z367(M+H)；RT＝4.33min(9min).
2-(2-氯-苯基)-N-[2-氰基-6-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊-2-基)-苯基]乙酰胺化合物的合成(48)
Figure PCTCN2016113838-appb-000123
在干燥的50mL单口瓶中室温下依次加入化合物47(134mg,0.365mmol),联硼酸频那醇酯(278mg,1.094mmol)，Pd(dppf)Cl2(40mg,0.0548mmol)，醋酸钾(107mg,1.094mmol)和1,4-二氧六环(8mL)，氮气置换3次。搅拌加热至115摄氏度，反应5小时。LCMS检测反应完毕后，过滤，滤液减压浓缩用comiflash(EA/PE＝0％-80％)纯化所得残余物得到产物2-(2-氯-苯基)-N-[2-氰基-6-氟-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊-2-基)-苯基]乙酰胺48(45mg,黄色固体)，产率：30％
LCMS:m/z 333.1(M+H)；RT＝3.39min(9min).
2-(2-氯-苯基)-N-{2-氰基-6-氟-4-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-苯基}乙酰胺化合物的合成(A70)
Figure PCTCN2016113838-appb-000124
在干燥的50mL微波管中室温下依次加入48(15mg,0.109mmol),42(28mg,0.134mmol)，Pd(dppf)2Cl2(8mg,0.0109mmol),碳酸氢钠(18mg,0.218mmol)，1,4-二氧六环(2mL)和水(0.5mL)，氮气置换3次。加热至80摄氏度反应1小时。LCMS检测反应完毕后，过滤，滤液减压浓缩后，用prep-HPLC纯化所得残余物后得产物2-(2-氯-苯基)-N-{2-氰基-6-氟-4-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-苯基}乙酰胺A70(38mg,黄色固体)，产率：76％
LCMS:m/z462.2(M+H)；RT＝3.84min(9min).
1H NMR(dmso,400MHz)δ10.67(s,1H),9.59(s,1H),8.58(d,J＝5.2Hz,1H),8.42(s,1H),8.30(d,J＝10.8Hz,1H),7.58(d,J＝5.2Hz,1H),7.48–7.40(m,2H),7.36(d,J＝1.7Hz,1H),7.32–7.26(m,2H),6.26(d,J＝1.5Hz,1H),3.92(s,2H),3.67(s,3H).
实施例71：2-(2-氯苯基)-N-(2-氰基-5-氟-4-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)苯基)乙酰胺化合物的合成(A71)
Figure PCTCN2016113838-appb-000125
采用实施例70类似的方法制备。
LCMS:m/z 462.2(M+H)；RT＝4.24min(9min).
1H NMR(dmso,400MHz)1H NMR(400MHz,dmso)δ10.72(s,1H),9.58(s,1H),8.54(d,J＝5.2Hz,1H),8.39(d,J＝8.2Hz,1H),7.80(d,J＝13.3Hz,1H),7.48–7.38(m,2H),7.34(d,J＝1.8Hz,1H),7.32–7.27(m,2H),7.25(dd,J＝5.1,1.8Hz,1H),6.25(d,J＝1.7Hz,1H),3.97(s,2H),3.66(s,3H).
实施例72：1-[2-(2-氯苯基)-乙基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吲哚-7-甲腈(50)的合成
Figure PCTCN2016113838-appb-000126
在干燥的10mL微波管中室温下依次加入5-溴-1-[2-(2-氯苯基)-乙基]-1H-吲哚-7-甲腈(49)(147mg,0.41mmol),双(频哪醇合)二硼(208mg,0.82mmol)，Pd(dppf)Cl2(10mg,cat.)，醋酸钾(80mg,0.82mmol)和1,4-二氧六环(2mL)，氮气置换3次。微波加热至120摄氏度，反应2小时。LCMS检测反应完毕后，过滤除去催化剂，加入20mL水，用乙酸乙酯萃取(30mL×3)，合并有机相。饱和食盐水(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯:石油醚＝3:2)纯化所得残余物，得到产物1-[2-(2-氯苯基)-乙基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吲哚-7-甲腈(50)(128mg,浅黄色固体)，产率：76.6％.
LCMS:m/z408(M+H)；RT＝6.14min(9min).
1-[2-(2-氯-苯基)-乙基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-1H-吲哚-7-甲腈的合成(A72)
Figure PCTCN2016113838-appb-000127
在干燥的10mL微波管中室温下依次加入1-[2-(2-氯苯基)-乙基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吲哚-7-甲腈(50)(128mg,0.31mmol),2-(4-氯嘧啶)-3-(2-甲基-2H-吡唑)胺GE001-04(66mg,0.31mmol)，Pd(dppf)Cl2(10mg,cat.)，碳酸钾(85mg,0.62mmol),1,4-二氧六环(2mL)和水(0.5mL)，氮气置换3次。微波加热至100摄氏度，反应1小时。LCMS检测反应完毕后，过滤除去催化剂，加入20mL水，用乙酸乙酯萃取(30mL×3)，合并有机相。饱和食盐水(20mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(100％乙酸乙酯)，再用prep-HPLC以洗脱剂(乙腈/水含0.5％三氟乙酸＝50％)纯化所得残余物，得到产物1-[2-(2-氯-苯基)-乙基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-1H-吲哚-7-甲腈(A72)(29mg,苍白色固体)，产率：20.7％.
LCMS:m/z455(M+H)；RT＝4.658min(9min).
1H-NMR(DMSO-d6,400MHz):9.51(s,1H),8.88(s,1H),8.62(s,1H),8.52(d,J＝4Hz,1H),8.44(s,1H),7.57(d,J＝8.0Hz,1H),7.37-7.35(m,2H),7.20-7.08(m,3H),6.28(s,1H),4.89(t,2H),3.69(s,3H),3.32(t,2H).
采用与实施例72类似的方法制备73-94化合物：
实施例73：2-(2-氯苯基)-N-(2-氰基-4-(2-(吡啶-4-基氨基)嘧啶-4-基)苯基)乙酰胺的合成(A73)
Figure PCTCN2016113838-appb-000128
LCMS:m/z441.2(M+H)；RT＝2.92min(9min).
1H NMR(dmso,400MHz)1H NMR(400MHz,dmso)δ11.42(s,1H),10.66(s,1H),8.83(d,J＝5.3Hz,1H),8.67–8.55(m,3H),8.50(dd,J＝8.7,2.2Hz,1H),8.23(d,J＝5.6Hz,2H),7.95–7.83(m,2H),7.50–7.39(m,2H),7.35–7.26(m,2H),3.96(s,2H).
实施例74：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(吡啶-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A74)
Figure PCTCN2016113838-appb-000129
LCMS:m/z468.2(M+H)；RT＝2.69min(9min).
1H NMR(400MHz,dmso):δ11.42(s,1H),8.81(d,J＝5.3Hz,1H),8.60(d,J＝6.9Hz,2H),8.37(dd,J＝21.2,5.3Hz,3H),8.24(s,2H),7.87(t,J＝5.7Hz,2H),7.44(dd,J＝7.3,4.9Hz,1H),4.38(t,J＝8.1Hz,2H),4.14(s,2H),3.30(t,J＝8.0Hz,2H).
实施例75：1-[2-(2,5-二氯苯基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A75)
Figure PCTCN2016113838-appb-000130
LCMS:m/z504.2(M+H)；RT＝4.399min(9min).
1H NMR(400MHz,dmso):δ9.50(s,1H),8.50(d,J＝5.2Hz,1H),8.28(d,J＝4.5Hz,2H),7.67–7.44(m,3H),7.44–7.26(m,2H),6.26(d,J＝1.7Hz,1H),4.33(t,J＝8.2Hz,2H),4.10(s,2H),3.67(s,3H),3.26(t,J＝8.1Hz,2H).
实施例76：1-[2-(2-甲氧基-苯基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A76)
LCMS:m/z466.3(M+H)；RT＝3.96min(9min).
1H NMR(400MHz,dmso):δ9.50(s,1H),8.49(d,J＝5.2Hz,1H),8.26(d,J＝10.8Hz,2H),7.49(d,J＝5.3Hz,1H),7.36(d,J＝1.7Hz,1H),7.29–7.13(m,2H),6.98(d,J＝8.2Hz,1H),6.90(t,J＝7.4Hz,1H),6.25(s,1H),4.23(t,J＝8.2Hz,2H),3.85(s,2H),3.74(s,3H),3.67(s,3H),3.20(t,J＝8.1Hz,2H).
实施例77：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-甲基-吡啶-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A77)
Figure PCTCN2016113838-appb-000132
LCMS:m/z482.2(M+H)；RT＝2.81min(9min).
1H NMR(400MHz,dmso):δ11.31(s,1H),8.80(d,J＝5.4Hz,1H),8.39(ddd,J＝16.0,6.5,4.4Hz,4H),8.16(s,1H),7.98(s,1H),7.86(d,J＝5.5Hz,2H),7.44(dd,J＝7.5,4.8Hz,1H),4.38(t,J＝8.2Hz,2H),4.14(s,2H),3.28(t,J＝8.1Hz,2H),2.60(s,3H).
实施例78：1-(2-(2,3-二氯苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吲哚-7-甲腈化合物的合成(A78)
Figure PCTCN2016113838-appb-000133
LCMS:m/z504.1(M+H)；RT＝4.43min(9min).
1H NMR(dmso,400MHz)1H NMR(400MHz,dmso)δ9.48(s,1H),8.50(d,J＝5.2Hz,1H),8.28(d,J＝4.0Hz,2H),7.58(dd,J＝7.8,1.6Hz,1H),7.49(d,J＝5.3Hz,1H),7.42–7.31(m,3H),6.24(d,J＝1.6Hz,1H),4.33(t,J＝8.2Hz,2H),4.16(s,2H),3.66(s,3H),3.25(t,J＝8.1Hz,2H).
实施例79：1-(2-(2-氯-5-氟苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吲哚-7-甲腈化合物的合成(A79)
Figure PCTCN2016113838-appb-000134
LCMS:m/z488.1(M+H)；RT＝4.23min(9min).
1H NMR(dmso,400MHz)1H NMR(400MHz,dmso)δ9.49(s,1H),8.50(d,J＝5.3Hz,1H),8.28(d,J＝4.8Hz,2H),7.55–7.45(m,2H),7.39–7.27(m,2H),7.25–7.15(m,1H),6.25(d,J＝1.7Hz,1H),4.32(t,J＝8.2Hz,2H),4.09(s,2H),3.67(s,3H),3.25(t,J＝8.0Hz,2H).
实施例80：5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-1-(2-吡唑-1-基-乙酰基)-2,3-二氢-1H-吲哚-7-甲腈的合成(A80)
Figure PCTCN2016113838-appb-000135
LCMS:m/z426.2(M+H)；RT＝2.98min(9min).
1H NMR(400MHz,dmso):δ9.51(s,1H),8.51(d,J＝3.4Hz,1H),8.29(d,J＝6.5Hz,2H),7.70(s,1H),7.59–7.39(m,2H),7.35(s,1H),6.39–6.14(m,2H),5.37(s,2H),4.24(d,J＝7.9Hz,2H),3.67(d,J＝2.3Hz,3H),3.25(t,J＝7.8Hz,2H).
实施例81：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(4-氯-3-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A81)
Figure PCTCN2016113838-appb-000136
LCMS:m/z488(M+H)；RT＝4.24min(8min).
1H-NMR(DMSO,400MHz)δ9.48(s,1H),8.50(d,J＝5.2Hz,1H),8.27(d,J＝9.5Hz,2H),7.63–7.42(m,2H),7.42–7.24(m,2H),7.16(d,J＝8.2Hz,1H),6.24(s,1H),4.27(t,J＝8.2Hz,2H),4.02(s,2H),3.66(s,3H),3.22(t,J＝8.0Hz,2H).
实施例82：1-(2-(2-氯苯基)乙酰基)-5-(2-((四氢-2H-吡喃-4-基)氨基)嘧啶-4-基)吲哚-7-甲腈化合物的合成(A82)
Figure PCTCN2016113838-appb-000137
LCMS:m/z474.1(M+H)；RT＝4.48min(9min).
1H NMR(dmso,400MHz)δ8.39(d,J＝5.4Hz,1H),8.31(s,2H),7.57(s,1H),7.52–7.46(m,1H),7.45–7.39(m,1H),7.37–7.31(m,2H),7.28(d,J＝5.3Hz,1H),4.35(t,J＝8.2Hz,2H),4.11(s,2H),3.89(d,J＝11.3Hz,2H),3.41(s,2H),3.27(t,J＝8.1Hz,2H),1.86(d,J＝11.5Hz,2H),1.64–1.42(m,2H).
实施例83：5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-(2-(吡啶-3-基)乙酰基)二氢吲哚-7-腈
Figure PCTCN2016113838-appb-000138
LCMS:m/z 474.1(M+H)；m/z437.2(M+H)；RT＝2.36min(10min).
1H NMR(dmso,400MHz)δ9.53(s,1H),8.78(d,J＝4.3Hz,2H),8.55(d,J＝5.3Hz,1H),8.31(d,J＝16.0Hz,2H),8.28(d,J＝7.9Hz,1H),7.89(dd,J＝7.9,5.6Hz,1H),7.54(d,J＝5.3Hz,1H),7.39(d,J＝1.9Hz,1H),6.29(d,J＝1.8Hz,1H),4.37(d,J＝8.3Hz,2H),4.25(s,2H),3.71(s,3H),3.31(t,J＝8.2Hz,2H).
实施例84：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-(腈基)苯基)乙酰基)二氢吲哚-7-甲腈的合成(A84)
Figure PCTCN2016113838-appb-000139
在干燥的100mL圆底烧瓶中室温下依次加入化合物51(151.9mg,0.943mmol)，醋酸酐(96.5mg,0.945mml),DMF(1ml)，N2保护，30℃搅拌2小时。再加入化合物41(100mg,0.315mmol),N-吗啡啉(103mg,1.018mmol)，DMF(4ml)。氮气置换3次,室温搅拌反应24小时。LC/MS检测反应完毕后，通过制备分离纯化得到产物5-(2-(1-甲基-1H-吡唑-5- 基氨基)嘧啶-4-基)-1-(2-(2-(腈基)苯基)乙酰基)二氢吲哚-7-甲腈A84(54mg,淡黄色固体),收率Y:12％。
LCMS:m/z472(M+H)；RT＝3.36min(8min)
1H-NMR(DMSO,400MHz):δ9.48(s,1H),8.50(d,J＝5.2Hz,1H),8.27(d,J＝13.8Hz,2H),7.42(ddd,J＝27.5,26.0,3.5Hz,3H),6.99(d,J＝5.0Hz,2H),6.25(d,J＝1.7Hz,1H),4.27(t,J＝8.2Hz,2H),4.21(s,2H),3.67(s,3H),3.21(t,J＝8.0Hz,2H)。
实施例85：1-(2-(2-氯吡啶-3-基)乙酰基)-5-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈化合物的合成(A85)
Figure PCTCN2016113838-appb-000140
LCMS:m/z471.1(M+H)；RT＝3.52min(9min).
1H NMR(dmso,400MHz)1H NMR(400MHz,dmso)δ9.54(s,1H),8.46(d,J＝5.1Hz,1H),8.40–8.25(m,3H),7.94–7.81(m,2H),7.52(s,1H),7.47–7.39(m,1H),7.34(d,J＝5.3Hz,1H),4.35(t,J＝8.2Hz,2H),4.12(s,2H),3.79(s,3H),3.28(t,J＝8.2Hz,2H).
实施例86：1-(2-(2-溴苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吲哚-7-甲腈化合物的合成(A86)
Figure PCTCN2016113838-appb-000141
LCMS:m/z514.1(M+H)；RT＝4.25min(9min).
1H NMR(dmso,400MHz)1H NMR(400MHz,dmso)δ9.45(s,1H),8.46(d,J＝5.2Hz,1H),8.23(d,J＝5.5Hz,2H),7.58(d,J＝8.0Hz,1H),7.45(d,J＝5.3Hz,1H),7.39–7.26(m,3H),7.23–7.13(m,1H),6.22(d,J＝1.8Hz,1H),4.28(t,J＝8.2Hz,2H),4.03(s,2H),3.63(s,3H),3.21(t,J＝8.0Hz,2H).
实施例87：1-[3-(2-氯-苯基)-丙酰基]-5-[2-(2-甲基-2H-吡唑-3-基胺)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A87)
Figure PCTCN2016113838-appb-000142
LCMS:m/z484.2(M+H)；RT＝4.65min(9min).
1H NMR(400MHz,dmso):δ8.61(d,J＝5.5Hz,1H),8.03(s,1H),7.89(d,J＝1.3Hz,1H),7.77(d,J＝5.5Hz,1H),7.45–7.33(m,3H),7.30–7.05(m,3H),6.15(d,J＝2.0Hz,1H),3.65(t,J＝8.7Hz,2H),3.56(s,3H),3.13–2.97(m,6H).
实施例88：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(噻吩-2-基)乙酰基)二氢吲哚-7-甲腈的合成(A88)
Figure PCTCN2016113838-appb-000143
LCMS:m/z442(M+H)；RT＝3.878min(8min).
1H-NMR(DMSO,400MHz):δ9.48(s,1H),8.50(d,J＝5.2Hz,1H),8.27(d,J＝13.8Hz,2H),7.42(ddd,J＝27.5,26.0,3.5Hz,3H),7.04–6.92(m,2H),6.25(d,J＝1.7Hz,1H),4.27(t,J＝8.2Hz,2H),4.21(s,2H),3.67(s,3H),3.21(t,J＝8.0Hz,2H)
实施例89：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2,3-氟苯基)乙酰基)二氢吲哚-7-甲腈)的合成(A89)
Figure PCTCN2016113838-appb-000144
LCMS:m/z472(M+H)；RT＝4.468min(8min).
1H-NMR(DMSO,400MHz):δ9.48(s,1H),8.49(d,J＝5.3Hz,1H),8.27(d,J＝5.1Hz,2H),7.48(d,J＝5.3Hz,1H),7.34(d,J＝1.9Hz,2H),7.20–7.12(m,2H),6.24(d,J＝1.8Hz,1H),4.31(s,2H),4.09(s,2H),3.66(s,3H),3.24(s,2H),
实施例90：1-(2,2-二氟-2-苯基-乙酰基)-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A90)
Figure PCTCN2016113838-appb-000145
LCMS:m/z472.2(M+H)；RT＝4.25min(9min).
1H NMR(400MHz,dmso):δ9.51(s,1H),8.52(d,J＝5.2Hz,1H),8.35(d,J＝25.2Hz,2H),7.76–7.53(m,5H),7.51(d,J＝5.2Hz,1H),7.34(d,J＝1.9Hz,1H),6.25(d,J＝1.8Hz,1H),4.15(t,J＝7.8Hz,2H),3.66(s,3H),3.14(t,J＝7.9Hz,2H).
实施例91：5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-1-(2-苯基-丙酰基)-2,3-二氢-1H-吲哚-7-甲腈的合成(A91)
Figure PCTCN2016113838-appb-000146
LCMS:m/z450.2(M+H)；RT＝4.31min(9min).
1H NMR(400MHz,dmso)δ8.60(d,J＝5.5Hz,1H),7.97(s,1H),7.79(dd,J＝10.0,3.4Hz,2H),7.39(d,J＝1.9Hz,1H),7.26–7.13(m,3H),7.05–6.96(m,2H),6.16(d,J＝1.9Hz,1H),4.42(d,J＝6.9Hz,1H),3.65(t,J＝8.8Hz,2H),3.32(s,3H),3.05(t,J＝8.6Hz,2H),1.40(d,J＝6.9Hz,3H).
实施例92：1-[2-(3-氯-吡啶-4-基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A92)
Figure PCTCN2016113838-appb-000147
LCMS:m/z471.1(M+H)；RT＝3.47min(9min).
1H NMR(400MHz,dmso)δ9.46(s,1H),8.62(s,1H),8.49(dd,J＝5.0,3.2Hz,2H),8.28(d,J＝3.4Hz,2H),7.47(dd,J＝11.6,5.1Hz,2H),7.34(d,J＝1.8Hz,1H),6.24(d,J＝1.8Hz,1H),4.33(t,J＝8.2Hz,2H),4.16(s,2H),3.66(s,3H),3.26(s,2H).
实施例93：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2,6-二甲基吡啶-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A93)
Figure PCTCN2016113838-appb-000148
LCMS:m/z496.2(M+H)；RT＝2.86min(9min).
1H NMR(400MHz,dmso):δ10.00(s,1H),8.62(d,J＝5.2Hz,1H),8.36(d,J＝15.1Hz,3H),7.86(d,J＝6.2Hz,1H),7.67–7.21(m,4H),4.36(t,J＝8.1Hz,2H),4.12(s,2H),3.27(d,J＝7.8Hz,2H),2.35(s,6H).
实施例94：1-(2-(2-氟苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)吲哚-7-甲腈化合物的合成(A94)
Figure PCTCN2016113838-appb-000149
LCMS:m/z454.0(M+H)；RT＝4.05min(9min).
1H NMR(dmso,400MHz)δ9.51(s,1H),8.46(d,J＝5.1Hz,1H),8.29(s,2H),7.86(s,1H),7.52(s,1H),7.42–7.26(m,3H),7.23–7.09(m,2H),4.31(t,J＝8.2Hz,2H),4.02(s,2H),3.79(s,3H),3.26(t,J＝8.1Hz,2H).
实施例95：4-氯-N-(氧杂环丁烷-3-基)嘧啶-2-胺化合物的合成(54)
Figure PCTCN2016113838-appb-000150
在干燥的10mL单口瓶中室温下依次加入化合物52(2.0g,27.36mmol),53(4.08g,27.36mmol)，TEA(3.3g,32.83mmol)和乙醇(50mL)，升温至50℃并搅拌16小时。LCMS检测反应完毕后，减压浓缩后，粗产品溶于50mL EA中，并分别用水及饱和盐水洗涤，浓缩后用combiflash(EA/PE 0％-80％)纯化得到产物4-氯-N-(氧杂环丁烷-3-基)嘧啶-2-胺54(900mg,白色固体)，产率：17.8％。
LCMS:m/z186.5(M+H)；RT＝2.46min(9min).
5-(2-(氧杂环丁烷-3-基氨基)嘧啶-4-基)吲哚-7-甲腈化合物的合成(55)
Figure PCTCN2016113838-appb-000151
在干燥的50mL单口瓶中室温下依次加入54(400mg,2.16mmol),40(582mg,2.16mmol)，Pd(dppf)Cl2(158mg,0.216mmol),碳酸钾(596mg,4.31mmol)，1,4-二氧六环(6mL)和水(1.5mL)，氮气置换3次。加热至100摄氏度反应3个小时。LCMS检测反应完毕后，过滤，滤液减压浓缩，用combiflash(EA/PE 0％-100％)纯化所得残余物得到产物5-(2-(氧杂环丁烷-3-基氨基)嘧啶-4-基)吲哚-7-甲腈55(155mg,黄色固体)，产率：24.5％
LCMS:m/z294.1(M+H)；RT＝2.97min(9min).
1-(2-(2-氯吡啶-3-基)乙酰基)-5-(2-(氧杂环丁烷-3-基氨基)嘧啶-4-基)二氢吲哚-7-甲腈化合物的合成(A95)
Figure PCTCN2016113838-appb-000152
在干燥的50mL单口瓶中室温下依次加入化合物55(155mg,0.528mmol)，化合物56(363mg,2.11mmol),EDCI(607mg,3.17mmol),HOBt(428mg,3.17mmol),TEA(534mg,5.28mmol)和DMF(4mL)，40℃搅拌16小时。LCMS检测反应完毕后，用combiflash(MeOH/DCM 0％-5％)纯化得到产物1-(2-(2-氯吡啶-3-基)乙酰基)-5-(2-(氧杂环丁烷-3-基氨基)嘧啶-4-基)二氢吲哚-7-甲腈A95(20mg,黄色固体)，产率：8％。
LCMS:m/z447.3(M+H)；RT＝3.39min(9min).
1H NMR(dmso,400MHz)δ8.40–8.30(m,2H),8.27(d,J＝6.2Hz,2H),7.98(d,J＝6.0Hz,1H),7.85(dd,J＝7.5,1.8Hz,1H),7.43(dd,J＝7.5,4.8Hz,1H),7.26(d,J＝5.2Hz,1H),4.99(s,1H),4.77(t,J＝6.5Hz,2H),4.52(t,J＝6.2Hz,2H),4.34(t,J＝8.2Hz,2H),4.12(s,2H),3.26(s,2H).
实施例96：1-(2-(2-氯吡啶-3-基)乙酰基)-5-(2-((2-氯吡啶-4-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈化合物的合成(A96)
Figure PCTCN2016113838-appb-000153
采用实施例95类似的方法制备。
LCMS:m/z502.1(M+H)；RT＝4.11min(9min).
1H NMR(dmso,400MHz)δ10.44(s,1H),8.68(d,J＝5.3Hz,1H),8.43–8.26(m,3H),8.17(d,J＝5.7Hz,1H),8.07(d,J＝1.7Hz,1H),7.86(dd,J＝7.6,1.8Hz,1H),7.70–7.59(m,2H),7.43(dd,J＝7.5,4.8Hz,1H),4.37(t,J＝8.2Hz,2H),4.13(s,2H),3.29(t,J＝8.1Hz,2H).
实施例97：(2-氯苯基)-二氟-乙酸乙基酯(59)
Figure PCTCN2016113838-appb-000154
在干燥的100mL圆底烧瓶中室温下依次加入1-氯-2-碘苯57(906mg,3.8mmol),DMF(8mL),室温下,氮气保护下，慢慢加入铜粉(600mg,9.44mmol)，再加入1-溴-1,1-二氟-乙酸乙酯58(853mg,4.2mmol)，加完96度下搅拌反应18小时。TLC板检测反应完毕后,用EA萃取(100mL)，合并有机相。饱和碳酸氢钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚＝1/20)纯化所得残余物，得到(2-氯苯基)-二氟-乙酸乙基酯59(650mg,无色液体)，产率：72.9％
LCMS:m/z235.2(M+H)；RT＝5.24min(8min)。
(2-氯苯基)-二氟-乙酸(60)
Figure PCTCN2016113838-appb-000155
在干燥的50mL圆底烧瓶中室温下依次加入(2-氯苯基)-二氟-乙酸乙基酯59(3.2g,13.64mmol),MeOH(9mL)，THF(6mL)和水(6mL)，一水合氢氧化锂(2.28g,54.66mmol)。室温搅拌2个小时。反应完毕后，减压浓缩，用盐酸调节PH＝5-6，用EA萃取(100mL*4)，合并有机相。饱和碳酸氢钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到(2-氯苯基)-二氟-乙酸60(2.5g,白色固体)，产率：88.6％。
LCMS:m/z207.1(M+H)；RT＝0.64min(4min).
1-[2-(2-氯-苯基)-2,2-二氟-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2-，3-二氢-1H-吲哚-7-甲腈(A97)
Figure PCTCN2016113838-appb-000156
在干燥的50mL圆底烧瓶中室温下依次加入(2-氯苯基)-二氟-乙酸60(664mg,3.214mmol),DCM(20mL),DMF(0.1mL),草酰氯(4mL,25.2mmol)升温至40摄氏度，搅拌1个小时,减压蒸干，用DCM(20mL)稀释后，再次减压蒸干，剩余物，慢慢加入5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(170mg,0.536mmol)和三乙胺(489mg,4.824mmol)的DCM(30mL)和DMF(3mL)的混合溶剂中，氮气置换3次。升温至25摄氏度，搅拌24个小时。反应完毕后，蒸干溶剂，用EA萃取(50mL*3)，合并有机相。饱和食盐水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯/PE＝1/4,至乙酸乙酯)纯化所得残余物，再用制备色谱纯化，得到产物1-[2-(2-氯-苯基)-2,2-二氟-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2-，3-二氢-1H-吲哚-7-甲腈A97(44mg,淡黄色固体)，产率：16.2％。
LCMS:m/z506.2(M+H)；RT＝7.85min(15min).
1H NMR(400MHz,dmso):δ9.51(s,1H),8.53(d,J＝5.2Hz,1H),8.36(d,J＝ 15.9Hz,2H),7.86(d,J＝7.3Hz,1H),7.71–7.44(m,4H),7.35(d,J＝1.8Hz,1H),6.25(d,J＝1.7Hz,1H),4.13(t,J＝7.9Hz,2H),3.67(s,3H),3.24(t,J＝7.7Hz,2H).
采用实施例97类似方法制备如下98-100化合物：
实施例98：1-苯甲酰基-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吲哚-7-甲腈化合物的合成(A98)
Figure PCTCN2016113838-appb-000157
LCMS:m/z422.2(M+H)；RT＝3.91min(9min).
1H NMR(dmso,400MHz)δ8.50(d,J＝5.4Hz,1H),7.64–7.53(m,3H),7.51–7.42(m,4H),7.38(t,J＝7.3Hz,2H),7.31(s,1H),6.26(d,J＝2.0Hz,1H),3.68(s,3H),3.61(t,J＝8.8Hz,2H),2.97(t,J＝8.6Hz,2H).
实施例99：1-[2-(2-氟-苯基)-2,2-二氟-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2-，3-二氢-1H-吲哚-7-甲腈(A99)
Figure PCTCN2016113838-appb-000158
LCMS:m/z490.1(M+H)；RT＝7.58min(15min).
1H NMR(400MHz,dmso):δ9.52(s,1H),8.53(d,J＝5.2Hz,1H),8.37(d,J＝14.3Hz,2H),7.81–7.63(m,2H),7.52(d,J＝5.2Hz,1H),7.48–7.29(m,3H),6.26(d,J＝1.7Hz,1H),4.20(t,J＝7.7Hz,2H),3.67(s,3H),3.23(t,J＝7.8Hz,2H).
实施例100：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2,6-二氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A100)
Figure PCTCN2016113838-appb-000159
LCMS:m/z472(M+H)；RT＝7.071min(15min).
1H-NMR(DMSO,400MHz):δ9.46(s,1H),8.49(d,J＝5.3Hz,1H),8.28(s,2H),7.49(d,J＝5.2Hz,1H),7.34(d,J＝1.9Hz,1H),7.11(t,J＝7.8Hz,2H),6.24(d,J＝1.8Hz,1H),4.36(t,J＝8.1Hz,2H),4.03(s,2H),3.66(s,3H),
实施例101：2,6-二氟-4-硝基苯基乙酸的合成(62)
Figure PCTCN2016113838-appb-000160
在干燥的100mL圆底烧瓶中,室温下向化合物61(1.0g,5.71mmol)的DCM(8ml)溶液中加入Et3N(1.732g,17.13mmol)。零摄氏度缓慢滴加乙酰氯(896.68Mg，11.42mmol),室温下搅拌反应2小时。TLC检测反应完毕后，EA萃取三次(50ml*3),饱和食盐水(30ml)洗涤，分液，减压蒸馏浓缩所得有机相，用硅胶柱色谱法以洗脱剂体系(PE:EA＝4：6) 纯化，得到产物2,6-二氟-4-硝基苯基乙酸62(1.23g,淡黄色固体),收率Y:97％。
LCMS:m/z218(M+H)；RT＝3.738min(5min)
4-氨基-2,6-二氟苯乙酯的合成(63)
Figure PCTCN2016113838-appb-000161
在干燥的100mL圆底烧瓶中，室温下化合物62(1.23g,5.66mmol)溶解于Me(8ml)中。小心加入Pd/C(2.0g)，此反应液在氢气氛中室温搅拌反映14h。LC/MS，TLC检测反应完毕后，用硅藻土吸附抽滤除去过量的钯炭，滤液蒸干，再用EA溶解萃取三次(50ml*3),饱和食盐水(30ml)洗涤，分液，减压蒸馏浓缩所得有机相，用硅胶柱色谱法以洗脱剂体系(PE:EA＝3：7)纯化得到产物4-氨基-2,6-二氟苯乙酯63(700mg,淡黄色固体，Y:81.1％)
LCMS:m/z153(M+H)；RT＝3.256min(5min)
5-(2-(3,5-二氟-4-乙酰酯基苯基氨基)嘧啶-4-基)吲哚-7-甲腈(64)
Figure PCTCN2016113838-appb-000162
在干燥的25ml微波反应反应管中依次加入化合物63(320mg,1.247mmol),化合物65(282mg,1.496mmol),Pd(dba)3(171.3mmg,0.187mmol),Se2(CO3)(1.218g,3.741mmol),RuPhOS(174.56mg,0.3741mmol),1.4-二氧六环(8ml),120℃微波反应2小时。LC/MS检测反应完毕后，EA(50mL*3)萃取，饱和食盐水(30mL)洗涤后，干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯至DCM:(DCM:MeOH＝15:1)＝4：6)纯化所得残留物，得到产物5-(2-(3,5-二氟-4-乙酰酯基苯基氨基)嘧啶-4-基)吲哚-7-甲腈64(170mg,P：90％，黄色固体)。
LCMS:m/z408(M+H)；RT＝4.817min(10min)
5-(2-(3,5-二氟-4-乙酰酯基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A101)
Figure PCTCN2016113838-appb-000163
在干燥的100mL圆底烧瓶中室温下依次加入邻氟苯乙酸(590.2mg,3.383mmol)，化合物(COCl)2(5ml),DCM(30ml),DMF(0.5ml)室温搅拌10分钟，40℃搅拌回流反应1小时。将反应液蒸干，DCM溶解再蒸干两次，残留物用DCM(20ml)溶清得到邻氟苯乙酰氯二氯甲烷溶液备用。化合物64(120mg,0.295mmol)用DCM(20ml)溶清,依次加入Et3N(446mg),上述制得的邻氟苯乙酰氯二氯甲烷溶液(10ml)室温反应2小时LC/MS检测反应完毕后，通过制备分离纯化得到产物5-(2-(3,5-二氟-4-乙酰酯基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈A101(40mg,淡黄色固体),收率Y:25％。
LCMS:m/z544(M+H)；RT＝9.33min(15min)
1H-NMR(DMSO,400MHz)δ10.14(s,1H),8.62(d,J＝5.3Hz,1H),8.33(d,J＝9.4Hz,2H),7.70(d,J＝10.8Hz,2H),7.57(d,J＝5.3Hz,1H),7.34(d,J＝7.4Hz,2H),7.18(d,J＝7.9Hz,2H),4.32(t,J＝8.1Hz,2H),4.02(s,2H),
实施例102：5-(2-(3,5-二氟-4-羟基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A102)
Figure PCTCN2016113838-appb-000164
在干燥的100mL圆底烧瓶中室温下依次加入化合物A101(30mg,0.0552mmol)，碳酸钾(7.6mg,0.0552mml),H2O(1ml)，MeOH(9ml)室温搅拌40分钟。LC/MS检测反应完毕后，EA(10mL*3)萃取，饱和食盐水(10mL)洗涤后，干燥，过滤，滤液减压浓缩，得残留物粗产品，用DMF(1ml)溶清，通过制备分离得到5-(2-(3,5-二氟-4-羟基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈A102(15mg,淡黄色固体),收率Y:50％。
LCMS:m/z502(M+H)；RT＝8.125min(15min).
1H-NMR(DMSO,400MHz):δ9.75(s,1H),9.59(s,1H),8.55(d,J＝5.2Hz,1H),8.31(d,J＝8.9Hz,2H),7.49(t,J＝7.7Hz,3H),7.34(d,J＝7.4Hz,2H),7.18(d,J＝8.0Hz,2H),4.31(d,J＝8.2Hz,2H),4.02(s,2H),3.25(t,J＝8.1Hz,2H),
实施例103：2-(3-氯吡啶-2-基)乙腈的合成(66)
Figure PCTCN2016113838-appb-000165
在干燥的250mL圆底烧瓶中N2保护，零摄氏度下依次加入化合物67(2.3g,54mmol),THF(100ml),LiHDMS(100ml,100mmol)。乙腈(4.0g,28mmol)的四氢呋喃溶液50ml缓慢加入，氮气置换3次,室温下搅拌反应2小时。LC/MS检测反应完毕后，50ml冰水淬灭，EA(50mL*3)萃取，饱和食盐水(30mL)洗涤后，干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE:EA＝5:1)纯化所得残留物，得到2-(3-氯吡啶-2-基)乙腈66(6.0g,淡黄色固体),收率Y:100％，纯度85％，继续投下步反应。
LCMS:153(M+H)；RT＝4.25min(10min).
2-(3-氯吡啶-2-基)乙酸盐酸盐的合成(68)
Figure PCTCN2016113838-appb-000166
在干燥的250mL圆底烧瓶中室温下依次加入化合物66(4.0g,25.3mmol),浓盐酸(15ml,)加热反应液至90℃搅拌4小时。LC/MS检测反应完毕后，直接蒸干反应液得到2-(3-氯吡啶-2-基)乙酸盐酸盐68(6.7g,淡黄色固体),收率Y:100％。
LCMS:172(M+H)；RT＝1.81min(5min)
1-(2-(3-氯吡啶-2-基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A103)
Figure PCTCN2016113838-appb-000167
在干燥的100mL圆底烧瓶中室温下依次加入化合物41(80mg0.252mmol),化合物68(259.5mg,1.52mmol)，HATU(718.9mg,1.890mml),DIPEA(244.4mg,1.890mmol)，DMF(20ml)N2保护，室温搅拌72小时。LC/MS检测反应完毕后，EA(50mL*3)萃取，饱和食盐水(30mL)洗涤后，干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(DCM:(DCM:MeOH＝15:1)＝4:1)纯化所得残留物，再用乙醇重结晶得到产物5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(3-氯吡啶-2-基)乙酰基)二氢吲哚-7-甲腈A103(33mg，淡黄色固体),收率Y:23％。
LCMS:472(M+H)；RT＝6.128min(15min).
1H-NMR(DMSO,400MHz):δ9.47(s,1H),8.48(dd,J＝9.3,5.0Hz,2H),8.28(d,J＝6.6Hz,2H),7.99–7.83(m,1H),7.49(d,J＝5.2Hz,1H),7.42–7.22(m,2H),6.24(d,J＝1.5Hz,1H),4.42–4.14(m,4H),3.66(s,3H),3.24(d,J＝8.1Hz,2H).
采用实施例103类似方法制备如下104-121化合物：
实施例104：5-[2-(4-溴-2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-1-[2-(2-氟-苯基)-乙酰基]-2,3-二氢-1H-吲哚-7-甲腈(A104)
Figure PCTCN2016113838-appb-000168
LCMS:m/z532.0,534.0(M+H)；RT＝3.66min(10min).
1H NMR(400MHz,dmso):δ9.22(s,1H),8.63(s,1H),8.43(d,J＝5.5Hz,1H),8.09(s,1H),7.67–7.44(m,2H),7.39(d,J＝6.4Hz,1H),7.29–7.19(m,2H),6.23(s,2H),4.21(t,J＝6.4Hz,2H),3.65(s,2H),3.37(t,J＝6.2Hz,2H).
实施例105：叔丁基4-(4-(7-氰基-1-(2-(2-氟苯基)乙酰基)吲哚-5-基)嘧啶-2-基氨基)-1H-吡唑-1-羧酸叔丁酯化合物的合成(A105)
Figure PCTCN2016113838-appb-000169
LCMS:m/z540.1(M+H)；RT＝4.99min(9min).
1H NMR(dmso,400MHz)δ9.88(s,1H),8.56(d,J＝4.4Hz,1H),8.39(s,1H),8.28(s,2H),7.88(s,1H),7.44(d,J＝5.2Hz,1H),7.39–7.28(m,2H),7.23–7.12(m,2H),4.32(t,J＝8.2Hz,2H),4.02(s,2H),3.25(t,J＝8.2Hz,2H),1.56(s,9H).
实施例106：5-(2-(1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A106)
Figure PCTCN2016113838-appb-000170
在干燥的50mL单口瓶中室温下依次加入化合物5(65mg,0.120mmol)，TFA(250mg,2.19mmol)和DCM(10mL)，室温搅拌5小时。LCMS检测反应完毕后，饱和碳酸氢钠溶液淬灭，DCM萃取，依次用水，盐水洗涤，浓缩，粗产品用prep-HPLC纯化得到产物5-(2-(1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈GE109-12(30mg,黄色固体)，产率：57.7％。
LCMS:m/z440.1(M+H)；RT＝4.37min(9min).
1H NMR(400MHz,dmso)δ9.53(s,1H),8.47(d,J＝5.2Hz,1H),8.30(s,2H),7.77(s,2H),7.40–7.28(m,3H),7.28–6.98(m,3H),4.32(t,J＝8.2Hz,2H),4.03(s,2H),3.26(t,J＝8.2Hz,2H).
实施例107：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基胺)-吡啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A107)
Figure PCTCN2016113838-appb-000171
LCMS:m/z470.1(M+H)；RT＝4.49min(10min).
1H NMR(400MHz,dmso):δ8.82(s,1H),8.35(dd,J＝4.7,1.6Hz,1H),8.16(d,J＝5.3Hz,1H),7.96–7.73(m,3H),7.44(dd,J＝7.5,4.8Hz,1H),7.32(d,J＝1.6Hz,1H),7.11(d,J＝4.4Hz,1H),7.02(s,1H),6.26(d,J＝1.6Hz,1H),4.34(t,J＝8.1Hz,2H),4.12(s,2H),3.66(s,3H),3.26(t,J＝8.1Hz,2H).
实施例108：5-(2-(1-甲基-1H-吡唑-5-基氨基)吡啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A108)
Figure PCTCN2016113838-appb-000172
LCMS:m/z469(M+H)；RT＝3.573min(10min).
1H-NMR(DMSO,400MHz):δ9.08(s,1H),8.15(d,J＝5.6Hz,1H),7.89(d,J＝19.3Hz,2H),7.43(ddd,J＝16.8,9.4,5.6Hz,3H),7.32(dd,J＝5.8,3.5Hz,2H),7.19(s,1H),7.08(s,1H),6.30(s,1H),4.31(t,J＝8.2Hz,2H),4.08(s,2H),3.67(s,3H),3.24(t,J＝8.1Hz,2H)
实施例109：5-[2-(3-氟-4-甲氧基苯基氨基)-嘧啶-4-基]-1-[2-(2-氟-苯基)-乙酰基]-2,3-二氢-1H-吲哚-7-甲腈(A109)
Figure PCTCN2016113838-appb-000173
LCMS:m/z498.1(M+H)；RT＝5.00min(10min)
1H NMR(400MHz,dmso):δ9.69(s,1H),8.53(d,J＝5.2Hz,1H),8.32(d,J＝5.3Hz,2H),7.79(dd,J＝14.3,2.5Hz,1H),7.49–7.29(m,4H),7.19(d,J＝8.0Hz,2H),7.11(d,J＝9.5Hz,1H),4.32(t,J＝8.2Hz,2H),4.03(s,2H),3.78(s,3H),3.26(t,J＝8.5 Hz,2H).
实施例110：5-(2-(1-甲基-1H-吡唑-5-基氨基)吡啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A110)
Figure PCTCN2016113838-appb-000174
LCMS:(M+H)+/m/z＝453；RT＝3.421min(10min)
1H-NMR(DMSO,400MHz):δ8.80(s,1H),8.15(d,J＝5.3Hz,1H),7.85(d,J＝24.8Hz,2H),7.32(d,J＝1.6Hz,3H),7.18(d,J＝7.8Hz,2H),7.10(d,J＝5.2Hz,1H),7.01(s,1H),6.26(d,J＝1.4Hz,1H),4.29(s,2H),4.01(s,2H),3.66(s,3H),3.23(s,2H)
实施例111：5-[2-(3-氟-4-甲氧基苯基氨基)-嘧啶-4-基]-1-[2-(2-氟-苯基)-乙酰基]-2,3-二氢-1H-吲哚-7-甲腈(A111)
Figure PCTCN2016113838-appb-000175
LCMS:m/z498.1(M+H)；RT＝5.00min(10min).
1H NMR(400MHz,dmso):δ9.69(s,1H),8.53(d,J＝5.2Hz,1H),8.32(d,J＝5.3Hz,2H),7.79(dd,J＝14.3,2.5Hz,1H),7.49–7.29(m,4H),7.19(d,J＝8.0Hz,2H),7.11(d,J＝9.5Hz,1H),4.32(t,J＝8.2Hz,2H),4.03(s,2H),3.78(s,3H),3.26(t,J＝8.5Hz,2H).
实施例112：1-[2-(2,6-二氟-苯基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基胺)-吡啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A112)
Figure PCTCN2016113838-appb-000176
LCMS:m/z471.1(M+H)；RT＝3.74min(10min).
1H NMR(400MHz,dmso):δ8.81(s,1H),8.15(d,J＝5.4Hz,1H),7.86(d,J＝26.7Hz,2H),7.43–7.37(m,1H),7.32(d,J＝1.8Hz,1H),7.16–7.06(m,3H),7.02(s,1H),6.26(d,J＝1.8Hz,1H),4.35(t,J＝8.1Hz,2H),4.04(s,2H),3.66(s,3H),3.25(t,J＝8.0Hz,2H).
实施例113：5-(2-(3,5-二氟-4-甲氧基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A113)
Figure PCTCN2016113838-appb-000177
在干燥的50mL单口瓶中室温下依次加入化合物71(50mg,0.114mmol),化合物72(55mg,0.343mmol)、DCM(2mL)和DMSO(0.1mL)，90度搅拌16小时。LCMS检测反 应完毕后，粗产品用prep-HPLC纯化得到产物5-(2-(3,5-二氟-4-甲氧基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈A113(25mg,黄色固体)，产率：42.4％。
LCMS:m/z516.1(M+H)；RT＝5.32min(9min).
1H NMR(400MHz,dmso)δ9.97(s,1H),8.59(d,J＝5.3Hz,1H),8.32(d,J＝8.2Hz,2H),7.65–7.49(m,3H),7.41–7.27(m,2H),7.23–7.12(m,2H),4.32(t,J＝8.2Hz,2H),4.02(s,2H),3.83(s,3H),3.26(t,J＝7.5Hz,2H).
实施例114：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A114)
Figure PCTCN2016113838-appb-000178
LCMS:m/z472(M+H)；RT＝3.90min(8min).
1H-NMR(DMSO,400MHz):δ9.42(s,1H),8.46(d,J＝5.2Hz,1H),8.24(d,J＝6.0Hz,2H),7.50–7.17(m,5H),7.15(d,J＝7.8Hz,2H),6.21(d,J＝1.6Hz,1H),4.27(t,J＝8.2Hz,2H),3.98(s,2H),3.63(s,3H)。
实施例115：4-(4-(7-氰基-1-(2-(2-氟苯基)乙酰基)吲哚-5-基)嘧啶-2-基氨基)-N，N-二甲基苯甲酰化合物的合成(A115)
Figure PCTCN2016113838-appb-000179
LCMS:m/z521.2(M+H)；RT＝4.34min(9min).
1H NMR(400MHz,dmso)δ9.91(s,1H),8.57(d,J＝5.3Hz,1H),8.34(d,J＝4.8Hz,2H),7.83(d,J＝8.7Hz,2H),7.51(d,J＝5.3Hz,1H),7.40–7.28(m,4H),7.23–7.14(m,2H),4.32(t,J＝8.2Hz,2H),4.02(s,2H),3.26(t,J＝8.3Hz,2H),2.94(s,6H).
实施例116：5-(2-(4-甲氧基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A116)
Figure PCTCN2016113838-appb-000180
LCMS:m/z480.1(M+H)；RT＝4.92min(9min).
1H NMR(400MHz,dmso)δ9.47(s,1H),8.47(d,J＝5.2Hz,1H),8.30(d,J＝2.2Hz,2H),7.63(d,J＝9.0Hz,2H),7.41–7.29(m,3H),7.18(dd,J＝15.7,7.8Hz,2H),6.87(d,J＝9.1Hz,2H),4.31(t,J＝8.2Hz,2H),4.02(s,2H),3.70(s,3H),3.26(t,J＝8.1Hz,2H).
实施例117：5-(2-(4-氟-3-甲氧基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A117)
Figure PCTCN2016113838-appb-000181
LCMS:m/z 498.1(M+H)；RT＝5.057min(9min).
1H NMR(dmso,400MHz)δ9.71(s,1H),8.54(d,J＝5.2Hz,1H),8.34(s,2H),7.91(d,J＝7.5Hz,1H),7.46(d,J＝5.2Hz,1H),7.34(dt,J＝7.7,6.6Hz,2H),7.15(dq,J＝19.8,9.1Hz,4H),4.32(t,J＝8.1Hz,2H),4.02(s,2H),3.86(s,3H),3.24(t,J＝8.2Hz,2H).
实施例118：4-(4-(7-氰基-1-(2-(2-氟苯基)乙酰基)吲哚-5-基)嘧啶-2-基氨基)苯甲酸甲酯化合物的合成(A118)
Figure PCTCN2016113838-appb-000182
LCMS:m/z522.1(M+H)；RT＝5.28min(9min).
1H NMR(400MHz,dmso)δ10.14(s,1H),8.61(d,J＝5.3Hz,1H),8.35(d,J＝3.5Hz,2H),7.91(q,J＝9.0Hz,4H),7.57(d,J＝5.3Hz,1H),7.40–7.30(m,2H),7.23–7.14(m,2H),4.37–4.20(m,4H),4.03(s,2H),3.29–3.22(m,2H),1.28(t,J＝7.1Hz,3H).
实施例119：5-(2-(3-氰基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A119)
Figure PCTCN2016113838-appb-000183
LCMS:m/z475.1(M+H)；RT＝5.01min(9min).
1H NMR(400MHz,dmso)δ10.08(s,1H),8.61(d,J＝5.3Hz,1H),8.34(d,J＝3.9Hz,3H),7.99(d,J＝9.6Hz,1H),7.56(d,J＝5.3Hz,1H),7.50(t,J＝8.0Hz,1H),7.41–7.28(m,3H),7.24–7.14(m,2H),4.33(t,J＝8.2Hz,2H),4.02(s,2H),3.26(t,J＝6.2Hz,2H).
实施例120：4-(4-(7-氰基-1-(2-(2-氟苯基)乙酰基)吲哚-5-基)吡啶-2-基氨基)苯基)(吡咯烷-1-基)甲酮化合物的合成(A120)
Figure PCTCN2016113838-appb-000184
LCMS:m/z547.1(M+H)；RT＝4.54min(9min).
1H NMR(400MHz,dmso)δ9.92(s,1H),8.57(d,J＝5.3Hz,1H),8.35(d,J＝5.4Hz,2H),7.83(d,J＝8.7Hz,2H),7.50(dd,J＝9.4,7.0Hz,3H),7.39–7.27(m,2H),7.23 –7.14(m,2H),4.32(t,J＝8.2Hz,2H),4.02(s,2H),3.44(s,4H),3.29–3.21(m,2H),1.80(s,4H).
实施例121：5-(2-(5-氰基-1-甲基-1H-吡咯-3-基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A121)
Figure PCTCN2016113838-appb-000185
LCMS:m/z 478.0(M+H)；RT＝4.60min(9min).
1H NMR(dmso,400MHz)δ9.62(s,1H),8.48(d,J＝5.1Hz,1H),8.29(s,2H),7.46(d,J＝1.7Hz,1H),7.38–7.30(m,3H),7.22–7.15(m,2H),6.88(s,1H),4.32(t,J＝8.3Hz,2H),4.02(s,2H),3.73(s,3H),3.26(s,2H).
实施例122：1-[2-(2-氟-苯基)-乙酰基]-5-[2-(四氢呋喃-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A122)
Figure PCTCN2016113838-appb-000186
在干燥的5mL微波管中，室温下依次加入5-(2-溴-吡啶-4-基)-1-[2-(2-氟-苯基)-乙酰基]-2,3-二氢-1H-吲哚-7-甲腈1(125mg,0.286mmol),DCM(2mL)和DMSO(0.1mL),3-氨基四氢呋喃盐酸盐2(212mg,0.123.58mmol)和三乙胺(347mg,3.43mmol)。升温至45摄氏度，搅拌反应0.5小时，让DCM挥发干后，升温至90摄氏度，继续搅拌反应18h后，用制备色谱中性制备纯化，得到产物1-[2-(2-氟-苯基)-乙酰基]-5-[2-(四氢呋喃-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈GE148(62mg,淡黄色固体)，产率：49.2％。
LCMS:m/z444.1(M+H)；RT＝3.69min(10min).
1H NMR(400MHz,dmso):δ8.35(d,J＝5.1Hz,1H),8.26(s,2H),7.48(d,J＝6.2Hz,1H),7.40–7.27(m,2H),7.26–7.06(m,3H),4.44(s,1H),4.30(t,J＝8.2Hz,2H),4.01(s,2H),3.90(s,1H),3.82(dd,J＝15.2,7.6Hz,1H),3.71(dd,J＝13.8,8.0Hz,1H),3.54(dd,J＝8.8,4.3Hz,1H),3.23(t,J＝8.0Hz,2H),2.15(dd,J＝12.5,7.4Hz,1H),1.89(dd,J＝12.2,6.9Hz,1H).
采用与实施例122类似的方法制备如下123-127化合物：
实施例123：4-(4-{7-氰基-1-[2-(2-氟-苯基)-乙酰基]-2,3-二氢-1H-吲哚-5-基}-嘧啶-2-基氨基)-哌啶-1-羧酸叔丁基酯(A123)
Figure PCTCN2016113838-appb-000187
LCMS:m/z579.1(M+Na)；RT＝4.52min(10min).
1H NMR(400MHz,dmso):δ8.33(d,J＝5.0Hz,1H),8.25(s,2H),7.33(dt,J＝7.8,6.6Hz,2H),7.28–6.99(m,4H),4.30(t,J＝8.2Hz,2H),4.01(s,2H),3.99–3.72(m,3H),3.24(dd,J＝15.0,7.0Hz,2H),2.88(s,2H),1.84(d,J＝10.4Hz,2H),1.51–1.03(m, 11H).
实施例124：5-(2-(3-甲氧基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A124)
Figure PCTCN2016113838-appb-000188
LCMS:m/z 480.1(M+H)；RT＝5.068min(9min).
1H NMR(DMSO-d6,400MHz)δ9.76(s,1H),8.62(d,J＝5.2Hz,1H),8.42(d,J＝5.2Hz,2H),7.72(s,1H),7.54(d,J＝5.2Hz,1H),7.47–7.36(m,2H),7.36–7.19(m,4H),6.59(dd,J＝7.8,2.0Hz,1H),4.39(t,J＝8.3Hz,2H),4.09(s,2H),3.82(s,3H),3.32(t,J＝7.1Hz,2H).
实施例125：4-(4-(7-氰基-1-(2-(2-氟苯基)乙酰基)吲哚-5-基)嘧啶-2-基氨基)苯甲酰胺化合物的合成(A125)
Figure PCTCN2016113838-appb-000189
LCMS:m/z493.1(M+H)；RT＝4.01min(9min).
1H NMR(400MHz,dmso)δ9.97(s,1H),8.59(d,J＝5.3Hz,1H),8.35(d,J＝4.4Hz,2H),7.94–7.68(m,5H),7.53(d,J＝5.3Hz,1H),7.34(dt,J＝7.8,6.5Hz,2H),7.23–7.04(m,3H),4.33(t,J＝8.2Hz,2H),4.03(s,2H),3.28–3.22(m,2H).
实施例126：1-[2-(2-氯-苯基)-乙酰基]-5-[2-(2-氘代甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H--1H-吲哚-7-甲腈的合成(A126)
Figure PCTCN2016113838-appb-000190
1H-NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.49(d,J＝5.2Hz,1H),8.27(d,J＝4.3Hz,2H),7.54–7.43(m,2H),7.39(s,1H),7.36–7.19(m,3H),6.24(d,J＝1.8Hz,1H),4.31(t,J＝8.2Hz,2H),4.08(s,2H),3.27–3.19(m,2H).
LCMS:m/z473.1(M+H)；RT＝5.306min(10min)
实施例127：5-(2-(4-氰基苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A127)
Figure PCTCN2016113838-appb-000191
LCMS:m/z 475.0(M+H)；RT＝4.971min(9min).
1H NMR(dmso,400MHz)δ10.32(s,1H),8.69(d,J＝5.2Hz,1H),8.42(d,J＝5.3Hz,2H),8.06(d,J＝8.8Hz,2H),7.80(d,J＝8.8Hz,2H),7.67(d,J＝5.3Hz,1H),7.48–7.33(m,2H),7.29–7.14(m,2H),4.39(t,J＝8.2Hz,2H),4.09(s,2H),3.32(d,J＝5.3Hz,2H).
实施例128：1-[2-(2-氯-苯基)-乙酰基]-5-(4,4,5,5-四甲基-[1,3,2]二氧硼戊-2-基)-2,3-二氢-1H-吲哚-7-甲腈(73)
Figure PCTCN2016113838-appb-000192
在干燥的100mL圆底烧瓶中室温下依次加入5-(4,4,5,5-四甲基-[1,3,2]二氧硼杂环戊烷-2-基)-2,3-二氢-1H-吲哚-7-甲腈40(3.0g,11.11mmol),THF(80mL),室温下,氮气保护下，慢慢加入邻氯苯乙酸(3.409g,20mmol)，HATU(7.605g,20mmol)，再加入Et3N(2.473g,24.44mmol)，加完室温下搅拌反应48小时。TLC板检测反应完毕后,用EA萃取(100mL)，合并有机相。饱和碳酸氢钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物，用硅胶柱色谱法以洗脱剂体系(乙酸乙酯/石油醚＝1/5至乙酸乙酯/石油醚＝1/1)纯化所得残余物，得到(1-[2-(2-氯-苯基)-乙酰基]-5-(4,4,5,5-四甲基-[1,3,2]二氧硼戊-2-基)-2,3-二氢-1H-吲哚-7-甲腈3(1.0g,黄色固体)，产率：21.5％
LCMS:m/z423.1(M+H)；RT＝3.33min(5min)。
5-(2-溴-吡啶-4-基)-1-[2-(2-氯-苯基)-乙酰基]-2,3-二氢-1H-吲哚-7-甲腈(74)
Figure PCTCN2016113838-appb-000193
在干燥的50mL圆底烧瓶中室温下依次加入(1-[2-(2-氯-苯基)-乙酰基]-5-(4,4,5,5-四甲基-[1,3,2]二氧硼戊-2-基)-2,3-二氢-1H-吲哚-7-甲腈73(1.2g,2.839mmol),2,4-二溴嘧啶(675mg,2.839mmol)，Pd(dppf)Cl2(249mg,0.34mmol),碳酸氢钠(596mg,7.1mmol)，1,4-二氧六环(10mL)和水(3mL)，氮气置换3次。加热至78摄氏度反应2个小时。LCMS检测反应完毕后，过滤，滤液减压浓缩，用comiflash(EA/PE＝1/1，DCM/MeOH＝30/1)纯化所得残余物得到产物5-(2-溴-吡啶-4-基)-1-[2-(2-氯-苯基)-乙酰基]-2,3-二氢-1H-吲哚-7-甲腈74(840mg,黄色固体)，产率：65.6％
LCMS:m/z454.0(M+H)；RT＝4.96min(10min).
1-[2-(2-氯-苯基)-乙酰基]-5-[2-(2-氰基吡啶-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7甲腈(A128)
Figure PCTCN2016113838-appb-000194
在干燥的5mL微波管中，室温下依次加入5-(2-溴-吡啶-4-基)-1-[2-(2-氯-苯基)-乙酰基]-2,3-二氢-1H-吲哚-7-甲腈74(85mg,0.187mmol),DMF(1.5mL),Ruphos(13mg,0.028mmol),2-氰基-4-氨基吡啶75(45mg,0.374mmol)和Et3N(57mg,0.56mmol),Pd2(dba)3(26mg,0.028mmol)，氮气置换3次。升温至80摄氏度，在微波反应仪中搅拌反应80min。反应完毕后，过滤，用制备色谱纯化，得到1-[2-(2-氯-苯基)-乙酰基]-5-[2-(2-氰基吡啶-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7甲腈A128(23mg,淡黄色固体)，产率：25％。
LCMS:m/z492.1(M+H)；RT＝4.82min(10min).
1H NMR(400MHz,dmso):δ10.60(s,1H),8.71(d,J＝5.3Hz,1H),8.50(d,J＝5.8Hz,1H),8.38(dd,J＝14.1,4.3Hz,3H),7.96(dd,J＝5.7,2.0Hz,1H),7.70(d,J＝5.3Hz,1H),7.50–7.38(m,2H),7.36–7.24(m,2H),4.34(t,J＝8.2Hz,2H),4.09(s,2H),3.26(t,2H).
实施例129：1-[2-(2-氟-苯基)-乙酰基]-5-[2-(1-甲烷磺酰基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A129)
Figure PCTCN2016113838-appb-000195
在干燥的25mL圆底瓶中，室温下依次加入1-[2-(2-氟-苯基)-乙酰基]-5-[2-(1H-吡唑-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈A106(50mg,0.114mmol),DCM(5mL)和三乙胺(58mg,0.57mmol),滴加MsCl(40mg,0.342mmol)，氮气置换3次。升温至30摄氏度，搅拌反应3小时。反应完毕后，用MeOH(1mL)和水(0.5mL)淬灭后，减压浓缩，用制备色谱中性制备纯化，得到产物1-[2-(2-氟-苯基)-乙酰基]-5-[2-(1-甲烷磺酰基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈A129(33mg,淡黄色固体)，产率：55.9％。
LCMS:m/z518.0(M+H)；RT＝4.39min(10min).
1H NMR(400MHz,dmso):δ9.98(s,1H),8.59(d,J＝5.0Hz,1H),8.44(s,1H),8.31(s,2H),8.03(s,1H),7.48(d,J＝5.3Hz,1H),7.42–7.26(m,2H),7.25–7.09(m,2H),4.33(t,J＝8.2Hz,2H),4.02(s,2H),3.47(s,3H),3.26(dd,J＝10.5,5.8Hz,2H).
实施例130：5-(2-(1-甲氧基丙-2-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A130)
Figure PCTCN2016113838-appb-000196
LCMS:m/z 462.1(M+H)；RT＝4.535min(9min).
1H NMR(dmso,400MHz)δ8.39(d,J＝4.8Hz,1H),8.33(s,2H),7.56–7.44(m,2H),7.42–7.31(m,2H),7.24(d,J＝5.2Hz,1H),7.10(d,J＝8.1Hz,1H),4.38(t,J＝8.2Hz,2H),4.28(s,1H),4.15(s,2H),3.50–3.45(m,1H),3.35–3.25(m,6H),1.20(d,J＝6.4Hz,3H).
实施例131：5-(2-(1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A131)
Figure PCTCN2016113838-appb-000197
室温下依次加入化合物74(65mg,0.143mmol)、4-氨基吡唑(30mg,0.358mmol)于干燥的反应管中，加入2mL二氯甲烷和0.1mL二甲亚砜溶解后，缓慢加热至80℃，使溶剂慢慢挥发，继续在该温度下搅拌18小时。LCMS检测反应完毕后，用prep-HPLC 纯化得到产物5-(2-(1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈A131(8.9mg,绿色固体)，产率：13.7％。
LCMS:m/z 456.0(M+H)；RT＝4.012min(9min).
1H NMR(dmso,400MHz)δ12.56(s,1H),9.56(s,1H),8.53(d,J＝5.0Hz,1H),8.36(s,2H),7.97(s,1H),7.67(s,1H),7.55–7.46(m,2H),7.39(dt,J＝3.5,2.5Hz,3H),4.40(t,J＝8.2Hz,2H),4.16(s,2H),3.33(d,J＝8.4Hz,2H).
采用与实施例131类似的方法制备如下132-140化合物：
实施例132：5-(2-((1H-吡唑-3-基)氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A132)
Figure PCTCN2016113838-appb-000198
LCMS:t＝1.67min,ESI:[M+H]+m/z 456.
1H NMR(400MHz,DMSO)δ9.81(s,1H),8.51(d,J＝5.3Hz,1H),8.34(s,2H),7.62(s,1H),7.49(dd,J＝5.7,3.6Hz,1H),7.46–7.40(m,2H),7.35(dd,J＝5.7,3.6Hz,2H),6.58(s,1H),4.35(t,J＝8.1Hz,2H),4.11(s,2H),3.32–3.25(m,2H).
实施例133：5-(2-(2-羟基丙基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A133)
Figure PCTCN2016113838-appb-000199
LCMS:m/z 432.1(M+H)；RT＝4.171min(9min).
1H NMR(dmso,400MHz)δ8.38(d,J＝5.4Hz,1H),8.32(s,2H),7.46–7.29(m,3H),7.29(d,J＝5.1Hz,1H),7.25–7.16(m,2H),4.34(t,J＝8.2Hz,2H),4.05(s,2H),3.85–3.83(m,1H),3.27(t,J＝8.1Hz,3H),1.10(d,J＝6.2Hz,3H).
实施例134：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-氰基吡啶-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈化合物的合成(A134)
Figure PCTCN2016113838-appb-000200
LCMS:m/z493.0(M+H)；RT＝4.11min(10min).
1H NMR(dmso,400MHz)δ10.61(s,1H),8.72(d,J＝5.3Hz,1H),8.51(d,J＝5.8Hz,1H),8.45–8.28(m,4H),7.97(dd,J＝5.8,2.1Hz,1H),7.86(d,J＝7.7Hz,1H),7.71(d,J＝5.3Hz,1H),7.44(dd,J＝7.4,4.8Hz,1H),4.37(t,J＝8.3Hz,2H),4.14(s,2H),3.27(s,2H).
实施例135：5-(2-(1-乙酰胺基-1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A135)
Figure PCTCN2016113838-appb-000201
LCMS:m/z482.1(M+H)；RT＝4.6min(9min).
1H NMR(400MHz,dmso)δ9.97(s,1H),8.57(d,J＝12.7Hz,2H),8.31(s,2H),7.97(s,1H),7.47(d,J＝5.2Hz,1H),7.39–7.29(m,2H),7.18(dd,J＝15.9,8.3Hz,2H),4.37–4.26(m,2H),4.02(s,2H),3.28–3.20(m,2H),2.59(s,3H).
实施例136：5-(2-(1-异丙基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A136)
Figure PCTCN2016113838-appb-000202
LCMS:m/z 498.1(M+H)；RT＝4.595min(9min).
1H NMR(dmso,400MHz)δ9.38(s,1H),8.54(d,J＝5.3Hz,1H),8.33(s,2H),7.56–7.51(m,2H),7.48(t,J＝4.8Hz,2H),7.39(dd,J＝5.9,3.5Hz,2H),6.24(s,1H),4.60–4.55(m,1H),4.39(t,J＝8.2Hz,2H),4.15(s,2H),3.30(d,J＝8.2Hz,2H),1.37(d,J＝6.5Hz,6H).
实施例137：3-(4-{1-[2-(2-氯-苯基)-乙酰基]-7-氰基-2,3-二氢-1H-吲哚-5-基}-嘧啶-2-基氨基)-氮杂环丁烷-1-羧酸叔丁基酯(A137)
Figure PCTCN2016113838-appb-000203
LCMS:m/z 545.1(M+H)；RT＝5.018min(10min).
1H NMR(dmso,400MHz)δ8.36(d,J＝5.2Hz,1H),8.27(d,J＝6.6Hz,2H),7.89(d,J＝6.1Hz,1H),7.44(ddd,J＝17.5,7.5,4.7Hz,2H),7.37–7.24(m,3H),4.62(s,1H),4.31(t,J＝8.2Hz,2H),4.13(s,2H),4.08(s,2H),3.77(s,2H),3.25(dd,J＝14.1,6.0Hz,2H),1.36(s,9H).
实施例138：5-(2-(3-氯-1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A138)
Figure PCTCN2016113838-appb-000204
LCMS:m/z474.0(M+H)；RT＝4.19min(9min).
1H NMR(400MHz,dmso)δ12.88(s,1H),8.77(s,1H),8.43(d,J＝5.3Hz,1H),8.26(s,2H),7.97(s,1H),7.46–7.27(m,3H),7.23–7.08(m,2H),4.30(t,J＝8.2Hz,2H),4.01(s,2H),3.24(dd,J＝14.8,6.7Hz,2H).
实施例139：5-(2-(1-异丙基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A139)
Figure PCTCN2016113838-appb-000205
LCMS:m/z499.1(M+H)；RT＝3.88min(9min).
1H NMR(400MHz,dmso)δ9.30(s,1H),8.47(d,J＝5.2Hz,1H),8.34(dd,J＝4.8,1.9Hz,1H),8.26(s,2H),7.85(dd,J＝7.5,1.8Hz,1H),7.51–7.37(m,3H),6.17(d,J＝1.6Hz,1H),4.55–4.45(m,1H),4.34(t,J＝8.2Hz,2H),4.12(s,2H),3.26–3.20(m,2H),1.30(d,J＝6.6Hz,6H).
实施例140：5-(2-(3,5-二氟-4-甲氧基苯基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A140)
Figure PCTCN2016113838-appb-000206
LCMS:m/z533.1(M+H)；RT＝4.90min(9min).
1H NMR(400MHz,dmso)δ9.96(s,1H),8.59(d,J＝5.3Hz,1H),8.41–8.27(m,3H),7.86(dd,J＝7.5,1.8Hz,1H),7.59(d,J＝11.4Hz,2H),7.53(d,J＝5.3Hz,1H),7.43(dd,J＝7.5,4.8Hz,1H),4.36(t,J＝8.2Hz,2H),4.13(s,2H),3.83(s,3H),3.27(s,2H).
实施例141：1-(2-(2-氯吡啶-3-基)乙酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)二氢吲哚-7-甲腈化合物的合成(3)
Figure PCTCN2016113838-appb-000207
在干燥的100mL单口瓶中室温下依次加入化合物40(1.83g,6.77mmol),化合物2-氯吡啶-3-乙酸(1.86g,10.8mmol),HATU(5.6g,14.8mmol),TEA(1.6g,16.3mmol)和DMF(20mL)，室温搅拌16小时。LCMS检测反应完毕后，加入40mL水，并用EA萃取，最后用饱和盐水洗涤，分液，浓缩，粗产品用combiflash(EA/PE 0-70％)纯化得到产物1-(2-(2-氯吡啶-3-基)乙酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)二氢吲哚-7-甲腈76(2.2g,黄色固体)，产率：76.7％。
LCMS:m/z424.1(M+H)；RT＝3.06min(4min).
5-(2-溴吡啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈化合物的合成(77)
Figure PCTCN2016113838-appb-000208
在干燥的100mL单口瓶中室温下依次加入化合物76(1.98g,4.67mmol),化合物2,4-二溴嘧啶(1.45g,6.08mmol)，Pd(dppf)Cl2(342mg,0.467mmol),TEA(945m g,9.34mmol)和dioxane(40mL),H2O(10mL)，60度搅拌50min。LCMS检测反应完毕后，过滤，浓缩，粗产品用combiflash(EA/PE 0-100％)纯化得到产物5-(2-溴吡啶-4-基)-1-(2-(2-氯吡啶-3- 基)乙酰基)二氢吲哚-7-甲腈77(1.08g,黄色固体)，产率：51％。
LCMS:m/z454(M+H)；RT＝2.79min(4min).
5-(2-(1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈的合成(A141)
Figure PCTCN2016113838-appb-000209
在干燥的50mL单口瓶中室温下依次加入化合物77(75mg,0.165mmol),化合物78(91mg,0.495mmol)和DCM(2mL)，90度搅拌16小时。LCMS检测反应完毕后，粗产品用prep-HPLC纯化得到产物5-(2-(1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈A141(13mg,黄色固体)，产率：17.3％。
LCMS:m/z457(M+H)；RT＝3.33min(9min).
1H NMR(400MHz,dmso)δ12.49(s,1H),9.49(s,1H),8.47(d,J＝5.2Hz,1H),8.39–8.22(m,3H),7.97–7.81(m,2H),7.60(s,1H),7.43(dd,J＝7.5,4.8Hz,1H),7.32(d,J＝5.2Hz,1H),4.35(t,J＝8.2Hz,2H),4.13(s,2H),3.28–3.21(m,2H).
采用与实施例141类似的方法之别如下142-146化合物：
实施例142：5-(2-(1-羟基丙-2-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A142)
Figure PCTCN2016113838-appb-000210
LCMS:m/z 448.0(M+H)；RT＝3.854min(9min).
1H NMR(dmso,400MHz)δ8.39(d,J＝4.8Hz,1H),8.32(d,J＝3.3Hz,2H),7.55–7.50(m,1H),7.49–7.45(m,1H),7.38(dd,J＝5.5,3.7Hz,2H),7.23(d,J＝5.2Hz,1H),6.95(d,J＝7.4Hz,1H),4.72(t,J＝5.6Hz,1H),4.38(t,J＝8.2Hz,2H),4.14(s,2H),4.12–3.99(m,1H),3.57–3.50(m,1H),3.34(s,1H),3.30(d,J＝8.5Hz,2H),1.19(d,J＝6.6Hz,3H).
实施例143：1-[2-(2-氯-苯基)-乙酰基]-5-[2-(四氢呋喃-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A143)
Figure PCTCN2016113838-appb-000211
LCMS:m/z460.1(M+H)；RT＝3.75min(10min).
1H NMR(400MHz,dmso):δ8.35(d,J＝5.1Hz,1H),8.26(s,2H),7.46(t,J＝7.7Hz,2H),7.43–7.36(m,1H),7.36–7.24(m,2H),7.21(d,J＝5.2Hz,1H),4.43(s,1H),4.31(t,J＝8.2Hz,2H),4.07(s,2H),3.90(s,1H),3.85–3.78(m,1H),3.75–3.67(m,1H),3.54(dd,J＝8.7,4.1Hz,1H),3.24(t,J＝8.1Hz,2H),2.14(s,1H),1.88(d,J＝5.5Hz,1H).
实施例144：5-(2-(1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2,6-二氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A144)
Figure PCTCN2016113838-appb-000212
LCMS:m/z 458.1(M+H)；RT＝3.502min(9min).
1H NMR(dmso,400MHz)δ12.57(s,1H),9.56(s,1H),8.54(d,J＝5.1Hz,1H),8.37(d,J＝5.2Hz,2H),7.97(s,1H),7.67(s,1H),7.47(dd,J＝15.1,6.8Hz,1H),7.39(d,J＝5.2Hz,1H),7.19(t,J＝7.8Hz,2H),4.44(t,J＝8.1Hz,2H),4.12(s,2H),3.34(d,J＝8.7Hz,2H).
实施例145：5-(2-(4-(甲基磺酰基)苯基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A145)
Figure PCTCN2016113838-appb-000213
LCMS:m/z 528.1(M+H)；RT＝4.105min(9min).
1H NMR(dmso,400MHz)δ10.32(s,1H),8.70(d,J＝5.3Hz,1H),8.43(d,J＝3.1Hz,2H),8.11(d,J＝8.9Hz,2H),7.90(d,J＝8.8Hz,2H),7.67(d,J＝5.3Hz,1H),7.46–7.37(m,2H),7.30–7.20(m,2H),4.40(t,J＝8.2Hz,2H),4.10(s,2H),3.34(d,J＝8.1Hz,2H),3.20(s,3H).
实施例146：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(吡啶-3-基)乙酰基)二氢吲哚-7-甲腈(A146)
Figure PCTCN2016113838-appb-000214
LCMS:m/z437.2(M+H)；RT＝2.36min(10min).
1H NMR(400MHz,dmso)δ9.53(s,1H),8.78(d,J＝4.3Hz,2H),8.55(d,J＝5.3Hz,1H),8.31(d,J＝16.0Hz,2H),8.28(d,J＝7.9Hz,1H),7.89(dd,J＝7.9,5.6Hz,1H),7.54(d,J＝5.3Hz,1H),7.39(d,J＝1.9Hz,1H),6.29(d,J＝1.8Hz,1H),4.37(d,J＝8.3Hz,2H),4.25(s,2H),3.71(s,3H),3.31(t,J＝8.2Hz,2H).
实施例147：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-环丙基吡啶-3-基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A147)
Figure PCTCN2016113838-appb-000215
在干燥的50mL单口瓶中室温下依次加入化合物80(90mg,0.508mmol)，Ac2O(49mg,0.476mmol),DMF(1mL)于60℃下搅拌1h，加入A8(50mg,0.158mmol),NMP(55mg,0.54mmol)，50℃搅拌1.5小时。LCMS检测反应完毕后，用combiflash(MeOH/DCM 0％-3％)纯化得到产物5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-环丙基吡啶-3-基)乙酰基)二氢吲哚-7-甲腈A147(7mg,白色固体)，产率：10％。
LCMS:m/z477.2(M+H)；RT＝2.22min(9min).
1H NMR(dmso,400MHz)δ9.46(s,1H),8.49(d,J＝5.2Hz,1H),8.33–8.23(m,3H),7.53(dd,J＝7.7,1.6Hz,1H),7.49(d,J＝5.3Hz,1H),7.34(d,J＝1.9Hz,1H),7.09(dd,J＝7.6,4.8Hz,1H),6.24(d,J＝1.8Hz,1H),4.31(t,J＝8.2Hz,2H),4.14(s,2H),3.66(s,3H),3.24(t,J＝8.1Hz,2H),2.17–2.09(m,1H),0.96–0.84(m,4H).
采用与实施例147类似的方法制备如下148-151化合物：
实施例148：4-(4-(1-(2-(2-氯吡啶-3-基)乙酰基)-7-氰基吲哚-5-基)嘧啶-2-基氨基)-N，N-二甲基苯甲酰胺化合物的合成(A148)
Figure PCTCN2016113838-appb-000216
LCMS:m/z538.1(M+H)；RT＝3.45min(9min).
1H NMR(400MHz,dmso)δ9.91(s,1H),8.57(d,J＝5.2Hz,1H),8.35(dd,J＝6.4,2.1Hz,3H),7.85(dd,J＝14.0,5.3Hz,3H),7.51(d,J＝5.3Hz,1H),7.43(dd,J＝7.5,4.8Hz,1H),7.36(d,J＝8.6Hz,2H),4.36(t,J＝8.3Hz,2H),4.13(s,2H),3.27(s,2H),2.94(s,6H).
实施例149：1-(2-(2-氯苯基)乙酰基)-5-(2-(哒嗪-4-基氨基)嘧啶-4-基)二氢吲哚-7-腈的合成(A149)
Figure PCTCN2016113838-appb-000217
LCMS:t＝1.58min,ESI:[M+H]+m/z 468.
1H NMR(400MHz,DMSO-d6)δ9.92(d,J＝7.8Hz,1H),9.57(d,J＝20.8Hz,2H),9.10(d,J＝5.4Hz,1H),8.75(d,J＝2.9Hz,1H),8.60(d,J＝14.9Hz,2H),8.38(d,J＝5.4Hz,1H),7.50(dd,J＝5.7,3.6Hz,1H),7.44(dd,J＝5.6,3.7Hz,1H),7.39–7.33(m,2H),7.27(dd,J＝8.2,2.6Hz,1H),4.39(t,J＝8.1Hz,2H),4.14(s,2H),3.36–3.30(m,2H).
实施例150：4-((4-(7-氰基-1-(2-(2-氟苯基)乙酰基)二氢吲哚-5-基)嘧啶-2-基)氨基)-N-甲基苯甲酰胺的合成(A150)
Figure PCTCN2016113838-appb-000218
LCMS:m/z507(M+H)；RT＝1.67min.
1H-NMR(DMSO,400MHz):δ10.00(s,1H),8.62(d,J＝5.2Hz,1H),8.38(d,J＝3.9Hz,2H),8.28(d,J＝4.5Hz,1H),7.88(d,J＝8.9Hz,2H),7.80(d,J＝8.8Hz,2H),7.57(s,1H),7.39(s,2H),7.31–7.13(m,2H),4.35(s,3H),4.06(s,3H),3.30(t,J＝8.2Hz,3H),2.77(d,J＝4.5Hz,3H).
实施例151：1-(2-(2-氯苯基)乙酰基)-5-(2-((3-氰基-4-氟苯基)氨基)嘧啶-4-基)二氢 吲哚-7-甲腈的合成(A151)
Figure PCTCN2016113838-appb-000219
LCMS:t＝1.86min,ESI:[M+H]+m/z 493.
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.63(d,J＝5.3Hz,1H),8.49–8.23(m,2H),8.03(dd,J＝8.2,3.8Hz,1H),7.59(d,J＝5.3Hz,1H),7.51(t,J＝9.1Hz,1H),7.38(dd,J＝16.2,9.2Hz,1H),7.29–7.15(m,1H),4.36(t,J＝8.2Hz,2H),4.06(s,2H),3.31–3.14(m,2H).
实施例152：1-[2-(2-氯-苯基)-乙酰基]-5-(2-氟吡啶-4-基)-2,3-二氢-1H-吲哚-7-甲腈(82)
Figure PCTCN2016113838-appb-000220
在干燥的50mL圆底烧瓶中室温下依次加入(1-[2-(2-氯-苯基)-乙酰基]-5-(4,4,5,5-四甲基-[1,3,2]二氧硼戊-2-基)-2,3-二氢-1H-吲哚-7-甲腈73(850g,2.01mmol),2-氟-4溴吡啶81(531mg,3.01mmol)，Pd(dppf)Cl2(147mg,0.201mmol),碳酸氢钠(591mg,7.04mmol)，1,4-二氧六环(6mL)和水(1.5mL)，氮气置换3次。加热至70摄氏度反应1个小时。LCMS检测反应完毕后，过滤，滤液减压浓缩，用comiflash(EA/PE＝1/2，EA/PE＝3/1)纯化所得残余物得到产物1-[2-(2-氯-苯基)-乙酰基]-5-(2-氟吡啶-4-基)-2,3-二氢-1H-吲哚-7-甲腈82(540mg,黄色固体)，产率：68.6％
LCMS:m/z392.0(M+H)；RT＝4.18min(10min).
1-[2-(2-氯-苯基)-乙酰基]-5-[2-(1H-吡唑-4-基氨基)-吡啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈(A152)
Figure PCTCN2016113838-appb-000221
在干燥的5mL微波管中，室温下依次加入82(120mg,0.306mmol),DCM(2mL)和DMSO(0.2mL),1-Boc-4-氨基-吡唑(168mg,0.918mmol)。升温至60摄氏度，搅拌反应0.5小时，让DCM挥发干后，升温至105摄氏度，继续搅拌反应18h后，用制备色谱中性制备纯化，得到产物1-[2-(2-氯-苯基)-乙酰基]-5-[2-(1H-吡唑-4-基氨基)-吡啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈A152(20mg,黄色固体)，产率：14.3％。
LCMS:m/z455.1(M+H)；RT＝2.79min(10min).
1H NMR(400MHz,dmso):δ12.42(s,1H),8.73(s,1H),8.12(d,J＝5.3Hz,1H),7.92(s,1H),7.82(d,J＝29.8Hz,2H),7.50(s,1H),7.48–7.38(m,2H),7.32(dd,J＝5.5,3.8Hz,2H),6.92(d,J＝5.4Hz,1H),6.86(s,1H),4.30(t,J＝8.2Hz,2H),4.07(s,2H),3.24(dd,J＝13.9,5.6Hz,2H).
采用与实施例152类似的方法制备如下153-171化合物：
实施例153：5-(2-(1H-吡唑-5-基氨基)吡啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A153)
Figure PCTCN2016113838-appb-000222
LCMS:m/z 455.0(M+H)；RT＝2.951min(9min).
1H NMR(dmso,400MHz)δ12.17(s,1H),9.30(s,1H),8.21(d,J＝5.3Hz,1H),7.93(s,1H),7.84(s,1H),7.64(d,J＝24.8Hz,2H),7.53(dd,J＝5.6,3.8Hz,1H),7.49–7.45(m,1H),7.41–7.35(m,2H),7.09(d,J＝4.8Hz,1H),6.34(s,1H),4.37(t,J＝8.1Hz,2H),4.14(s,2H),3.30(d,J＝8.0Hz,2H).
实施例154：5-(2-(1H-吡唑-4-基氨基)吡啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A154)
Figure PCTCN2016113838-appb-000223
LCMS:m/z439.1(M+H)；RT＝2.66min(9min).
1H NMR(400MHz,dmso)δ12.43(s,1H),8.74(s,1H),8.12(d,J＝5.4Hz,1H),7.93(s,1H),7.85(s,1H),7.78(s,1H),7.50(s,1H),7.39–7.28(m,2H),7.23–7.12(m,2H),6.91(d,J＝5.5Hz,1H),6.86(s,1H),4.29(t,J＝8.1Hz,2H),4.01(s,2H),3.22(t,J＝8.1Hz,2H).
实施例155：4-(4-{7-氰基-1-[2-(2-氟-苯基)-乙酰基]-2,3-二氢-1H-吲哚-5-基}-嘧啶-2-基氨基)-2-氟-N，N-二甲基苯甲酰胺(A155)
Figure PCTCN2016113838-appb-000224
LCMS:m/z539.0(M+H)；RT＝4.107min(10min).
1H NMR(400MHz,dmso):δ10.10(s,1H),8.61(d,J＝5.2Hz,1H),8.34(d,J＝9.7Hz,2H),7.90(d,J＝13.2Hz,1H),7.55(d,J＝5.8Hz,2H),7.32(dd,J＝20.4,7.8Hz,3H),7.18(d,J＝7.7Hz,2H),4.32(t,J＝8.2Hz,2H),4.02(s,2H),3.25(d,J＝8.2Hz,2H),2.96(s,3H),2.86(s,3H).
实施例156：4-(4-(1-(2-(2-氯吡啶-3-基)乙酰基)-7-氰基吲哚-5-基)嘧啶-2-基氨基)苯甲酰胺化合物的合成(A156)
Figure PCTCN2016113838-appb-000225
LCMS:m/z510.0(M+H)；RT＝3.23min(9min).
1H NMR(400MHz,dmso)δ9.96(s,1H),8.58(d,J＝5.3Hz,1H),8.38–8.28(m,3H),7.91–7.74(m,6H),7.52(d,J＝5.3Hz,1H),7.42(dd,J＝7.5,4.8Hz,1H),7.13(s, 1H),4.35(t,J＝8.3Hz,2H),4.12(s,2H),3.26(s,2H).
实施例157：3-(2-(2-氟苯基)乙酰基)-6-(2-(哒嗪-4-基氨基)嘧啶-4-基)-2,3-二氢-1H-茚-4-腈的合成(A157)
Figure PCTCN2016113838-appb-000226
LCMS:t＝1.88min,ESI:[M+H]+m/z 468.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.55(d,J＝5.3Hz,1H),8.35(d,J＝3.4Hz,2H),7.86–7.74(m,2H),7.49(d,J＝5.3Hz,1H),7.44–7.32(m,2H),7.19(dt,J＝17.8,9.4Hz,4H),4.35(t,J＝8.2Hz,2H),4.05(s,2H),3.29(dd,J＝10.8,6.1Hz,2H).
实施例158：1-(2-(2-氯苯基)乙酰基)-5-(2-((4-氟苯基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈的合成(A158)
Figure PCTCN2016113838-appb-000227
LCMS:t＝1.93min,ESI:[M+H]+m/z 484.
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.55(d,J＝5.2Hz,1H),8.35(d,J＝3.0Hz,2H),7.79(dd,J＝9.0,5.0Hz,2H),7.54–7.47(m,2H),7.46–7.40(m,1H),7.35(dd,J＝5.7,3.5Hz,2H),7.16(t,J＝8.9Hz,2H),4.36(t,J＝8.2Hz,2H),4.12(s,2H),3.30(t,J＝7.6Hz,2H).
实施例159：4-(4-((4-(7-(氰基-1-(2-(2-氟苯基)乙酰基)二氢吲哚-5-基)嘧啶-2-基)氨基)苯甲酰基)哌嗪-1-甲酸叔丁酯的合成(159)
Figure PCTCN2016113838-appb-000228
LCMS:m/z661(M+H)；RT＝1.85min.
1H-NMR:(DMSO,400MHz)δ9.97(s,1H),8.61(d,J＝5.3Hz,1H),8.38(d,J＝4.9Hz,2H),7.88(d,J＝8.6Hz,2H),7.55(d,J＝5.3Hz,1H),7.40(d,J＝8.6Hz,3H),7.21(d,J＝7.9Hz,2H),4.34(d,J＝8.2Hz,2H),4.05(s,2H),3.48(s,3H),3.37(d,J＝7.0Hz,3H),3.29(d,J＝9.0Hz,3H),1.41(s,8H).
实施例160：1-(2-(2-氟苯基)乙酰基)-5-(2-((4-(哌嗪-1-羰基)苯基)氨基)嘧啶-4-基)二氢吲哚-7-腈的合成(A160)
Figure PCTCN2016113838-appb-000229
LCMS:m/z563(M-100+H)；RT＝1.58min.
1H-NMR:(400MHz,DMSO)δ9.94(s,2H),8.60(d,J＝5.2Hz,1H),8.38(d,J＝ 4.1Hz,2H),7.86(d,J＝8.8Hz,2H),7.54(d,J＝5.3Hz,1H),7.37(t,J＝8.2Hz,2H),7.21(dd,J＝16.3,8.5Hz,1H),4.35(t,J＝8.0Hz,2H),4.05(s,2H),2.67(s,4H).
实施例161：1-[2-(2-氟-苯基)-乙酰基]-5-{2-[4-(3-羟基-吡咯烷-1-羰基)-苯基氨基]-嘧啶-4-基}-2,3-二氢-1H-吲哚-7-甲腈(A161)
Figure PCTCN2016113838-appb-000230
LCMS:m/z563.2(M+H)；RT＝3.62min(10min).
1H NMR(400MHz,dmso):δ9.93(s,1H),8.57(d,J＝5.3Hz,1H),8.35(d,J＝5.8Hz,2H),7.84(d,J＝8.7Hz,2H),7.50(dd,J＝12.5,6.7Hz,3H),7.34(dt,J＝7.6,6.5Hz,2H),7.24–7.10(m,2H),4.92(d,J＝31.5Hz,1H),4.32(t,J＝8.2Hz,2H),4.20(s,1H),4.02(s,2H),3.71–3.39(m,4H),3.25(s,2H),1.94–1.74(m,2H).
实施例162：4-(4-(7-氰基-1-(2-(2-氟苯基)乙酰基)吲哚-5-基)嘧啶-2-基氨基)-2,5-二氟-N，N-二甲基苯甲酰胺的合成(A162)
Figure PCTCN2016113838-appb-000231
LCMS:m/z 557.1(M+H)；RT＝4.220min(9min).
1H NMR(dmso,400MHz)δ9.58(s,1H),8.66(d,J＝5.3Hz,1H),8.41(d,J＝10.8Hz,2H),8.13(dd,J＝11.6,6.5Hz,1H),7.65(d,J＝5.3Hz,1H),7.45–7.34(m,3H),7.29–7.20(m,2H),4.39(t,J＝8.2Hz,2H),4.09(s,2H),3.30(d,J＝8.1Hz,2H),3.04(s,3H),2.95(s,3H)..
实施例163：4-(4-(1-(2-(2-氯吡啶-3-基)乙酰基)-7-氰基吲哚-5-基)吡啶-2-基氨基)-2-氟苯甲酰胺的合成(A163)
Figure PCTCN2016113838-appb-000232
LCMS:m/z 528.1(M+H)；RT＝3.407min(9min).
1H NMR(dmso,400MHz)δ10.26(s,1H),8.71(d,J＝5.3Hz,1H),8.42(dd,J＝6.9,4.0Hz,3H),7.99–7.91(m,2H),7.73(d,J＝8.7Hz,1H),7.67–7.61(m,2H),7.51(dd,J＝7.4,4.8Hz,2H),7.45(s,1H),4.44(t,J＝8.2Hz,2H),4.21(s,2H),3.34(s,2H).
实施例164：4-(4-{7-氰基-1-[2-(2-氟-苯基)-乙酰基]-2,3-二氢-1H-吲哚-5-基}-嘧啶-2-基氨基)-2-氟-苯甲酰胺(A164)
Figure PCTCN2016113838-appb-000233
LCMS:m/z511.1(M+H)；RT＝3.89min(10min).
1H NMR(400MHz,dmso):δ10.16(s,1H),8.61(d,J＝5.3Hz,1H),8.33(d,J＝8.2Hz,2H),7.88(dd,J＝14.5,1.8Hz,1H),7.65(t,J＝8.7Hz,1H),7.60–7.47(m,2H),7.47–7.23(m,4H),7.18(t,J＝8.6Hz,2H),4.31(t,J＝8.2Hz,2H),4.01(s,2H),3.24(d,J＝8.4Hz,2H).
实施例165：5-(2-((2,4-二氟苯基)氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-腈的合成(A165)
Figure PCTCN2016113838-appb-000234
LCMS:t＝1.92min,ESI:[M+H]+m/z 486.
1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),9.23(s,1H),8.48(d,J＝5.3Hz,1H),8.29(d,J＝4.9Hz,2H),8.13(s,1H),7.71(dd,J＝15.4,9.1Hz,2H),7.47(d,J＝5.3Hz,1H),7.21(d,J＝8.0Hz,3H),7.09–7.01(m,1H),4.33(t,J＝8.4Hz,4H),4.04(s,2H),3.92(s,1H),3.26(t,J＝8.7Hz,3H).
实施例166：5-(2-((4-氟-3-甲基苯基)氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A166)
Figure PCTCN2016113838-appb-000235
LCMS:m/z482(M+H)；RT＝1.96min.
1H-NMR(DMSO,400MHz):δ9.67(s,1H),8.55(d,J＝5.2Hz,1H),8.36(d,J＝8.1Hz,2H),7.78(d,J＝6.5Hz,1H),7.52(d,J＝4.1Hz,1H),7.48(d,J＝5.2Hz,1H),7.43–7.30(m,2H),7.28–7.15(m,2H),7.08(t,J＝9.2Hz,1H),4.35(t,J＝8.2Hz,2H),4.05(s,2H),3.31–3.25(m,2H),2.25(s,3H).
实施例167：5-((4-(7-氰基-1-(2-(2-氟苯基)乙酰基)二氢吲哚-5-基)嘧啶-2-基)氨基)-N，N-二甲基吡啶酰胺的合成(A167)
Figure PCTCN2016113838-appb-000236
LCMS:t＝1.83min,ESI:[M+H]+m/z 522.
1H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.94(d,J＝2.2Hz,1H),8.64(d,J＝5.3Hz,1H),8.36(dd,J＝10.8,4.5Hz,3H),7.64–7.53(m,2H),7.38(t,J＝7.4Hz,2H),7.27–7.15(m,2H),4.35(t,J＝8.1Hz,2H),4.06(s,2H),3.29(t,J＝6.1Hz,2H),3.04(s,3H),3.00(s,3H).
实施例168：5-(2-((3,4-二氟苯基)氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-腈的合成(A168)
Figure PCTCN2016113838-appb-000237
LCMS:t＝1.95min,ESI:[M+H]+m/z 486.
1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.60(d,J＝5.3Hz,1H),8.36(d,J＝6.2Hz,2H),8.03(ddd,J＝14.0,7.4,2.5Hz,1H),7.55(d,J＝5.3Hz,1H),7.49(d,J＝9.3Hz,1H),7.42–7.33(m,3H),7.26–7.17(m,2H),4.35(t,J＝8.3Hz,2H),4.05(s,2H),3.31–3.26(m,2H).
实施例169：1-(2-(2-氟苯基)乙酰基)-5-(2-((5-氟吡啶-2-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈的合成(A169)
Figure PCTCN2016113838-appb-000238
LCMS:t＝1.65min,ESI:[M+H]+m/z 469.
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.62(d,J＝5.3Hz,1H),8.38(d,J＝5.3Hz,2H),8.34–8.26(m,2H),7.82–7.70(m,1H),7.60(d,J＝5.2Hz,1H),7.44–7.29(m,2H),7.29–7.15(m,2H),4.35(t,J＝8.3Hz,2H),4.05(s,2H),3.32–3.26(m,2H).
实施例170：1-(2-(2-氟苯基)乙酰基)-5-(2-((1-(2-羟丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)二氢吲哚-7-腈合成(A170)
Figure PCTCN2016113838-appb-000239
LCMS:t＝1.76min,ESI:[M+H]+m/z 498.
1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.49(s,1H),8.33(d,J＝8.1Hz,2H),7.96(s,1H),7.55(s,1H),7.38(dd,J＝13.1,6.3Hz,3H),7.29–7.15(m,2H),4.91(s,1H),4.35(t,J＝8.2Hz,2H),4.05(s,2H),3.98(s,3H),3.29(t,J＝7.6Hz,2H),1.04(d,J＝5.4Hz,3H).
实施例171：1-(2-(2-氟苯基)乙酰基)-5-(2-((1-(2-羟丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)二氢吲哚-7-腈合成(A171)
Figure PCTCN2016113838-appb-000240
LCMS:t＝1.74min,ESI:[M+H]+m/z 498.
1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.49(s,1H),8.33(d,J＝8.1Hz,2H),7.96(s,1H),7.55(s,1H),7.38(dd,J＝13.1,6.3Hz,3H),7.29–7.15(m,2H),4.91(s,1H),4.35(t,J＝8.2Hz,2H),4.05(s,2H),3.98(s,3H),3.29(t,J＝7.6Hz,2H),1.04(d,J＝5.4Hz,3H).
实施例172：1-[2-(2-氯-苯基)-乙酰基]-5-[2-(1H-吡唑-4-基氨基)-嘧啶-4-基]-2,3- 二氢-1H-吲哚-7-甲酸酰胺(A172)
Figure PCTCN2016113838-appb-000241
在干燥的50mL反应瓶中，室温下依次加入1(50mg,0.11mmol),DCM(14mL)和水(0.8mL),TFA(4.56g,40mmol)。升温至50摄氏度，搅拌反应18小时，用制备色谱中性制备纯化，得到产物1-[2-(2-氯-苯基)-乙酰基]-5-[2-(1H-吡唑-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲酸酰胺A172(6.5mg,黄色固体)，产率：12.5％
LCMS:m/z474.1(M+H)；RT＝3.45min(10min).
1H NMR(400MHz,dmso):δ12.47(s,1H),9.45(s,1H),8.42(d,J＝5.2Hz,1H),8.06(s,2H),7.91(s,1H),7.59(s,2H),7.45–7.33(m,2H),7.31–7.16(m,3H),7.08(s,1H),4.22(t,J＝7.8Hz,2H),3.94(s,2H),3.16(t,J＝7.6Hz,2H).
采用与实施例172类似的方法制备如下173-化合物：
实施例173：1-[2-(2-氯-苯基)-乙酰基]-5-[2-(1H-吡唑-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-羧酸(A173)
Figure PCTCN2016113838-appb-000242
LCMS:m/z475.0(M+H)；RT＝3.64min(10min).
1H NMR(400MHz,dmso):δ12.52(s,2H),9.46(s,1H),8.42(d,J＝5.0Hz,1H),8.13(d,J＝30.3Hz,2H),7.74(s,2H),7.37(dd,J＝12.1,7.4Hz,2H),7.30–7.09(m,3H),4.25(s,2H),3.98(s,2H),3.19(s,2H).
实施例174：4-((4-(1-(2-(2-氯苯基)乙酰基)-7-氰基二氢吲哚-5-基)嘧啶-2-基)氨基)苯甲酸合成(A174)
Figure PCTCN2016113838-appb-000243
LCMS:t＝1.55min,ESI:[M+H]+m/z 494.
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.63(d,J＝5.2Hz,1H),8.39(d,J＝4.1Hz,2H),8.29(d,J＝9.3Hz,1H),8.23–8.17(m,1H),7.89(s,3H),7.57(d,J＝5.3Hz,1H),7.45–7.28(m,2H),7.27–7.15(m,2H),4.35(t,J＝8.1Hz,3H),4.06(s,2H),3.55–3.10(m,17H),2.10–1.86(m,1H),0.85(s,1H).
实施例175：1-(2-(2-氟苯基)乙酰基)-5-(2-((4-(4-甲基哌嗪-1-羰基)苯基)氨基)嘧啶-4-基)二氢吲哚-7-腈的合成(A175)
Figure PCTCN2016113838-appb-000244
LCMS:t＝1.87min,ESI:[M+H]+m/z 576.
1H NMR(400MHz,DMSO-d6)δ9.84–9.64(m,1H),8.62(d,J＝5.2Hz,1H),8.38(d,J＝7.7Hz,2H),7.92(d,J＝8.7Hz,2H),7.57(d,J＝5.2Hz,1H),7.46(d,J＝8.6Hz,3H),7.42–7.32(m,2H),7.21(d,J＝7.9Hz,3H),4.36(s,2H),4.06(s,3H),3.29(d,J＝7.8Hz,4H),3.13–3.05(m,2H),2.83(s,4H),2.67(s,1H).
实施例176：4-((4-(7-氰基-1-(2-(2-氟苯基)乙酰基)二氢吲哚-5-基)嘧啶-2-基)氨基)哌啶-1-甲酸苄酯的合成(A176)
Figure PCTCN2016113838-appb-000245
LCMS:t＝2.18min,ESI:[M+H]+m/z 591.
1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.28(s,2H),7.37(d,J＝5.9Hz,5H),7.29(d,J＝8.0Hz,1H),7.26–7.17(m,3H),5.09(s,2H),4.33(t,J＝8.3Hz,2H),4.04(s,2H),3.98(d,J＝13.2Hz,2H),3.30(s,1H),3.26(t,J＝8.2Hz,2H),3.13–2.89(m,3H),1.90(d,J＝9.8Hz,2H),1.50–1.32(m,2H).
实施例177：5-(2-(1-氰基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A177)
Figure PCTCN2016113838-appb-000246
LCMS:m/z 465.1(M+H)；RT＝4.119min(9min).
1H NMR(dmso,400MHz)δ10.72(s,1H),8.67(d,J＝5.3Hz,1H),8.60(d,J＝2.9Hz,1H),8.41(d,J＝2.1Hz,2H),7.67(d,J＝5.3Hz,1H),7.47–7.38(m,2H),7.32–7.24(m,2H),7.22(d,J＝2.9Hz,1H),4.41(t,J＝8.2Hz,2H),4.11(s,2H),3.36–3.31(m,2H).
实施例178：1-[2-(2-氟-苯基)-乙酰基]-5-[2-(2-甲基-2H-[1,2,3]三唑-4-基氨基)-嘧啶-4-基]-6-氧代-2,3-二氢-1H-吲哚-7-腈的合成(A178)
Figure PCTCN2016113838-appb-000247
LCMS:m/z 455.1(M+H)；RT＝4.809min(10min).
1H NMR(dmso,400MHz)δ10.31(s,1H),8.57(d,J＝5.2Hz,1H),8.34(s,2H),8.01(s,1H),7.51(d,J＝5.3Hz,1H),7.44-7.30(m,2H),7.28–7.13(m,2H),4.34(t,J＝8.2Hz,2H),4.07(s,3H),4.05(s,2H),3.28d,J＝8.1Hz,2H).
实施例179：1-[2-(2-氟-苯基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-羧酸酰胺(A179)
Figure PCTCN2016113838-appb-000248
LCMS:m/z472.1(M+H)；RT＝4.43min(10min).
1H NMR(400MHz,dmso):δ9.44(s,1H),8.45(d,J＝5.3Hz,1H),8.03(s,2H),7.49(s,1H),7.42-7.21(m,4H),7.21-6.99(m,3H),6.26(d,J＝1.6Hz,1H),4.22(t,J＝7.9Hz,2H),3.87(s,2H),3.64-3.58(m,3H),3.15(t,J＝7.8Hz,2H).
实施例180：1-[2-(2-氟-苯基)-乙酰基]-5-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-羧酸(A180)
Figure PCTCN2016113838-appb-000249
LCMS:m/z473.1(M+H)；RT＝4.64min(10min).
1H NMR(400MHz,dmso):δ12.55(s,1H),9.44(s,1H),8.44(d,J＝5.2Hz,1H),8.12(d,J＝11.4Hz,2H),7.40(d,J＝5.3Hz,1H),7.30(q,J＝6.5Hz,3H),7.21–7.07(m,2H),6.23(d,J＝1.5Hz,1H),4.26(t,J＝8.1Hz,2H),3.92(s,2H),3.66(s,3H),3.20(t,J＝7.9Hz,2H).
实施例181：1-(5-溴-7-甲氧基吲哚-1-基)-2-(2-氯苯基)乙酮化合物的合成(84)
Figure PCTCN2016113838-appb-000250
在干燥的50mL单口瓶中室温下依次加入化合物83(310mg,1.36mmol),邻氯苯乙酸(927mg,5.44mmol)，HATU(2.07g,5.44mmol),TEA(826mg,8.16mmol)和DMF(3mL)，室温下反应16小时。LCMS检测反应完毕后，加入水(10ML)淬灭反应，用EA萃取，合并有机相，用饱和盐水洗涤，有机相减压浓缩后，用comiflash(EA/PE＝0％-30％)纯化所得残余物得到产物1-(5-溴-7-甲氧基吲哚-1-基)-2-(2-氯苯基)乙酮84(500mg,黄色固体)，产率：96.7％
LCMS:m/z380.8(M+H)；RT＝6.10min(9min).
(2-氯苯基)-1-(7-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吲哚-1-基)乙酮化合物的合成(85)
Figure PCTCN2016113838-appb-000251
在干燥的50mL单口瓶中室温下依次加入化合物84(120mg,0.315mmol),联硼酸频那醇酯(160mg,0.63mmol)，Pd(dppf)Cl2(23mg,0.0315mmol)，醋酸钾(62mg,0.63mmol)和1,4-二氧六环(2mL)，氮气置换3次。搅拌加热至110摄氏度，反应3小时。LCMS检测反应完毕后，过滤，滤液减压浓缩用comiflash(EA/PE＝0％-20％)纯化所得残余物得到产物(2-氯苯基)-1-(7-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吲哚-1-基)乙酮85(110mg,黄色固体)，产率：81.5％
LCMS:m/z 428.1(M+H)；RT＝6.19min(9min).
1-(5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-7-甲氧基吲哚-1-基)-2-(2-氯苯基)乙酮化合物的合成(A181)
Figure PCTCN2016113838-appb-000252
在干燥的50mL微波管中室温下依次加入85(50mg,0.117mmol),86(32mg,0.152mmol)，Pd(dppf)2Cl2(9mg,0.0117mmol),碳酸钾(32mg,0.234mmol)，1,4-二氧六环(1mL)和水(0.25mL)，氮气置换3次。加热至90摄氏度反应1小时。LCMS检测反应完毕后，过滤，滤液减压浓缩后，用prep-HPLC纯化所得残余物后得产物1-(5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-7-甲氧基吲哚-1-基)-2-(2-氯苯基)乙酮A182(25mg,黄色固体)，产率：45％
LCMS:m/z475.1(M+H)；RT＝5.44min(9min).
1H NMR(dmso,400MHz)δ9.45(s,1H),8.47(d,J＝5.3Hz,1H),7.69(s,2H),7.45(d,J＝5.3Hz,1H),7.41–7.30(m,3H),7.29–7.21(m,2H),6.28(d,J＝1.7Hz,1H),4.12(t,J＝7.5Hz,2H),3.88(s,2H),3.86(s,3H),3.67(s,3H),3.01(t,J＝7.4Hz,2H).
采用与实施例181类似的方法制备如下182-197化合物。
实施例182：1-(2-(2-氟苯基)乙酰基)-5-(2-(((1s，3s)-3-羟基环丁基)氨基)嘧啶-4-基)二氢吲哚-7-腈的合成(A182)
Figure PCTCN2016113838-appb-000253
LCMS:t＝1.76min,ESI:[M+H]+m/z 444.
1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.28(s,2H),7.57(d,J＝6.4Hz,1H),7.38(s,2H),7.25–7.16(m,3H),4.99(s,1H),4.33(t,J＝8.0Hz,2H),4.04(s,2H),3.30(s,2H),3.30–3.23(m,2H),2.21(s,4H).
实施例183：1-(2-(2-氟苯基)乙酰基)-5-(2-(((1r，3r)-3-羟基环丁基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈的合成(A183)
Figure PCTCN2016113838-appb-000254
LCMS:t＝1.78min,ESI:[M+H]+m/z 444.
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.27(s,2H),7.50(d,J＝7.2Hz,1H),7.38(s,2H),7.21(dd,J＝14.5,7.0Hz,3H),5.05(d,J＝5.9Hz,1H),4.33(t,J＝8.3Hz,2H),4.04(s,2H),3.87(s,2H),3.29–3.23(m,3H),2.60(s,2H),1.84(s,2H).
实施例184：5-(2-((1-(二甲基氨基)丙-2-基)氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-腈的合成(A184)
Figure PCTCN2016113838-appb-000255
LCMS:t＝1.88min,ESI:[M+H]+m/z 459.
1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝4.9Hz,1H),8.29(s,2H),7.38(t,J＝7.7Hz,2H),7.25–7.16(m,3H),6.99(d,J＝7.9Hz,1H),4.33(t,J＝8.3Hz,2H),4.16(s, 1H),4.04(s,2H),3.25(t,J＝8.2Hz,2H),2.37(dd,J＝19.1,12.2Hz,2H),2.17(s,6H),1.16(d,J＝8.0Hz,3H).
实施例185：5-(2-(2-羟基丙基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈的合成(A185)
Figure PCTCN2016113838-appb-000256
LCMS:m/z 449.1(M+H)；RT＝4.164min(9min).
1H NMR(dmso,400MHz)δ8.32(dd,J＝13.3,11.2Hz,4H),7.85(dd,J＝7.5,1.7Hz,1H),7.42(dd,J＝7.5,4.8Hz,1H),7.28(s,1H),7.24(d,J＝5.4Hz,1H),4.34(t,J＝8.2Hz,2H),4.11(s,2H),4.04–3.99(m,1H),3.81(s,1H),3.25(t,J＝8.1Hz,4H),1.06(d,J＝6.2Hz,3H).
实施例186：5-(2-(2-(磺酰胺基)乙基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A186)
Figure PCTCN2016113838-appb-000257
LCMS:m/z 481.1(M+H)；RT＝4.822min(9min).
1H NMR(dmso,400MHz)δ8.51–8.30(m,3H),7.54–7.32(m,4H),7.29–7.17(m,2H),6.99(s,2H),4.37(t,J＝8.2Hz,2H),4.08(s,2H),3.79(s,2H),3.30(t,J＝8.0Hz,4H).
实施例187：5-(2-(2-(甲基磺酰基)乙基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-腈化合物的合成(A187)
Figure PCTCN2016113838-appb-000258
LCMS:m/z497.1(M+H)；RT＝4.41min(9min).
1H NMR(400MHz,dmso)δ8.43–8.24(m,4H),7.85(dd,J＝7.6,1.9Hz,1H),7.51–7.38(m,2H),7.29(d,J＝5.3Hz,1H),4.34(t,J＝8.3Hz,2H),4.11(s,2H),3.74(s,2H),3.38(t,J＝6.7Hz,2H),3.25(t,J＝8.2Hz,2H),3.00(s,3H).
实施例188：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-甲基-2H-[1,2,3]三唑-4-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-腈(A188)
Figure PCTCN2016113838-appb-000259
LCMS:m/z472.0(M+H)；RT＝4.87min(10min).
1H NMR(400MHz,dmso)δ10.28(s,1H),8.53(d,J＝5.2Hz,1H),8.40-8.25(m,3H),7.97(s,1H),7.85(dd,J＝7.5,1.9Hz,1H),7.51–7.38(m,2H),4.35(t,J＝8.2Hz,2H),4.12(s,2H),4.03(s,3H),3.27(d,J＝8.3Hz,2H).
实施例189：5-(2-(2-(磺酰胺基)乙基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈的合成(A189)
Figure PCTCN2016113838-appb-000260
LCMS:m/z 498.0(M+H)；RT＝4.204min(9min).
1H NMR(dmso,400MHz)δ8.51–8.38(m,3H),8.35(s,1H),7.92(dd,J＝7.6,1.9Hz,1H),7.50(dd,J＝7.5,4.8Hz,1H),7.41(s,1H),7.35(d,J＝5.2Hz,1H),6.99(s,2H),4.41(t,J＝8.1Hz,2H),4.19(s,2H),3.80(s,2H),3.32(t,J＝8.1Hz,4H).
实施例190：5-(2-(1-羟甲基环丙基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈化合物的合成(A190)
Figure PCTCN2016113838-appb-000261
LCMS:m/z444.1(M+H)；RT＝4.83min(9min).
1H NMR(dmso,400MHz)δ8.36(s,1H),8.28(d,J＝5.7Hz,2H),7.41–7.24(m,3H),7.23–7.09(m,2H),4.30(t,J＝8.2Hz,3H),4.01(s,2H),3.54(s,2H),3.23(t,J＝8.2Hz,2H),0.80(t,J＝5.7Hz,2H),0.69(s,2H).
实施例191：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲酰胺(A191)
Figure PCTCN2016113838-appb-000262
LCMS:m/z488.1(M+H)；RT＝4.14min(9min).
1H NMR(400MHz,dmso)δ9.44(s,1H),8.46(d,J＝5.3Hz,1H),8.05(d,J＝2.8Hz,2H),7.51(s,1H),7.44–7.34(m,3H),7.33(d,J＝1.9Hz,1H),7.30–7.19(m,2H),7.08(s,1H),6.26(d,J＝1.8Hz,1H),4.22(t,J＝7.9Hz,2H),3.94(s,2H),3.67(s,3H),3.15(t,J＝7.8Hz,2H).
实施例192：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-羧酸的合成(A192)
Figure PCTCN2016113838-appb-000263
LCMS:m/z489.1(M+H)；RT＝4.06min(9min).
1H NMR(400MHz,dmso)δ12.56(s,1H),9.44(s,1H),8.45(d,J＝5.3Hz,1H),8.12(d,J＝11.1Hz,2H),7.44–7.39(m,2H),7.38–7.34(m,1H),7.32(d,J＝1.9Hz,1H),7.30–7.24(m,2H),6.23(d,J＝1.8Hz,1H),4.27(t,J＝8.1Hz,2H),4.00(s,2H),3.66(s,3H),3.21(t,J＝8.2Hz,2H).
实施例193：5-(2-(2-(磺酰胺基)乙基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A193)
Figure PCTCN2016113838-appb-000264
LCMS:m/z 497.1(M+H)；RT＝5.012min(9min).
1H NMR(dmso,400MHz)δ8.44(s,1H),8.33(s,2H),7.54–7.46(m,2H),7.43–7.31(m,4H),6.98(s,2H),4.38(t,J＝8.2Hz,2H),4.15(s,2H),3.79(s,2H),3.31(t,J＝7.4Hz,4H).
实施例194：5-(2-(1-甲基-1H-吡唑-5-基氨基)-5-氟吡啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A194)
Figure PCTCN2016113838-appb-000265
LCMS:m/z 472.1(M+H)；RT＝5.513min(9min).
1H NMR(dmso,400MHz)δ9.56(s,1H),8.60(d,J＝3.6Hz,1H),8.11(s,2H),7.41–7.25(m,3H),7.22–7.13(m,2H),6.22(d,J＝1.8Hz,1H),4.31(t,J＝8.3Hz,2H),4.02(s,2H),3.66(s,3H),3.25(t,J＝8.3Hz,2H).
实施例195：4-(4-((4-(7-(氰基-1-(2-(2-氟苯基)乙酰基)二氢吲哚-5-基)嘧啶-2-基)氨基)哌啶-1-羧酸叔丁酯的合成(A195)
Figure PCTCN2016113838-appb-000266
LCMS:t＝2.13min,ESI:m/z 523,567.
1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝4.9Hz,1H),8.29(s,2H),7.38(t,J＝7.7Hz,2H),7.25–7.16(m,3H),6.99(d,J＝7.9Hz,1H),4.33(t,J＝8.3Hz,2H),4.16(s,1H),4.04(s,2H),3.25(t,J＝8.2Hz,2H),2.37(dd,J＝19.1,12.2Hz,2H),2.17(s,6H),1.16(d,J＝8.0Hz,3H).
实施例196：1-(2-(2-氟苯基)乙酰基)-5-(2-((1-(哌啶-4-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)腈的合成(A196)
Figure PCTCN2016113838-appb-000267
LCMS:t＝1.50min,ESI:[M+H]+m/z 523.
1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.50(s,1H),8.34(s,2H),8.02(s,1H),7.53(s,1H),7.38(dd,J＝11.4,6.4Hz,3H),7.28–7.17(m,2H),4.35(t,J＝8.3Hz,2H),4.21–4.11(m,1H),4.05(s,2H),3.32–3.28(m,2H),3.04(d,J＝13.0Hz,2H),2.58(t,J＝11.8Hz,2H),1.98(dt,J＝19.6,10.6Hz,2H),1.81–1.70(m,2H).
实施例197：1-(2-环己基乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈的合成(A197)
Figure PCTCN2016113838-appb-000268
LCMS:t＝2.07min,ESI:[M+H]+m/z 442.
1H NMR(400MHz,DMSO-d6)δ8.66(d,J＝5.4Hz,1H),8.08(d,J＝1.6Hz,1H),7.95(s,1H),7.82(d,J＝5.5Hz,1H),7.61(s,1H),7.44(d,J＝1.9Hz,1H),6.21(d,J＝1.9Hz,1H),3.74–3.63(m,5H),3.10(t,J＝8.5Hz,2H),2.56(d,J＝6.8Hz,2H),1.86–1.76(m,1H),1.74–1.55(m,5H),1.27–1.06(m,3H),0.92(dd,J＝22.8,10.8Hz,2H).
实施例198：4-(叔丁基-二甲基-硅烷基氧基)-1,2,3,4-四氢-喹啉化合物的合成(2)
Figure PCTCN2016113838-appb-000269
在干燥的100mL单口瓶中室温下依次加入化合物87(800mg,5.36mmol),DCM(12mL),冷却至0度后缓慢添加TBSCl(1212mg,8.04mmol)，和咪唑(922mg,9.112mmol)于室温搅拌4小时。LCMS检测反应完毕后，加入0.2mL水淬灭，加入乙酸乙酯(20mL)，分别用饱和碳酸钠溶液和盐水洗涤，有机相用无水硫酸钠干燥，过滤滤液减压浓缩后得到粗产物粗产品用comiflash(EA/PE＝2％-10％)纯化得到产物4-(叔丁基-二甲基-硅烷基氧基)-1,2,3,4-四氢-喹啉88(1.2g,无色液体)，产率：88％。
LCMS:m/z264.1(M+H)；RT＝8.35min(10min).
6-溴-4-(叔丁基-二甲基-硅烷基氧基)-1,2,3,4-四氢-喹啉化合物的合成(89)
Figure PCTCN2016113838-appb-000270
在干燥的100mL单口瓶中室温下依次加入化合物88(300mg,1.138mmol),DCM(10mL),冷却至0度后缓慢添加NBS(202mg,1.138mmol),于0度搅拌1小时,于10度搅拌1小时。LCMS检测反应完毕后，加入0.2mL水淬灭，加入乙酸乙酯(20mL)，分别用饱和碳酸钠溶液和盐水洗涤，有机相用无水硫酸钠干燥，过滤滤液减压浓缩后得到粗产物粗产品用comiflash(EA/PE＝1％-13％)纯化得到产物6-溴-4-(叔丁基-二甲基-硅烷基氧基)-1,2,3,4-四氢-喹啉89(250mg,无色液体)，产率：64％
LCMS:m/z343.1(M+H)；RT＝7.6min(10min).
1-[6-溴-4-(叔丁基-二甲基-硅烷基氧基)-3,4-二氢-2H-喹啉-1-基]-2-(2-氯-苯基)-乙酮的合成(90)
Figure PCTCN2016113838-appb-000271
在干燥的50mL单口瓶中室温下依次加入化合物89(230mg,0.672mmol),2-氯苯乙酸(252mg,1.478mmol)，HATU(613mg,1.613mmol),TEA(191mg,1.882mmol)和DMF(3mL)，室温下反应16小时。LCMS检测反应完毕后，加入水(10ML)淬灭反应，用EA萃取，合并有机相，用饱和盐水洗涤，有机相减压浓缩后，用comiflash(EA/PE＝10％-50％)纯化所得残余物得到产物1-[6-溴-4-(叔丁基-二甲基-硅烷基氧基)-3,4-二氢-2H-喹啉-1-基]-2-(2-氯-苯基)-乙酮90(500mg,无色液体)，产率：66％
LCMS:m/z495.1(M+H)；RT＝6.8min(10min).
[4-(叔丁基-二甲基-硅烷氧基)-6-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-3,4-二氢-2H-喹啉-1-基]-2-(2-氯-苯基)-乙酮化合物的合成(91)
Figure PCTCN2016113838-appb-000272
在干燥的50mL单口瓶中室温下依次加入化合物90(180mg,0.364mmol),联硼酸频那醇酯(184mg,0.728mmol)，Pd(dppf)Cl2(40mg,0.0546mmol)，醋酸钾(72mg,0.728mmol)和1,4-二氧六环(4mL)，氮气置换3次。搅拌加热至110摄氏度，反应2小时。LCMS检测反应完毕后，过滤，滤液减压浓缩用comiflash(EA/PE＝10％-50％)纯化所得残余物得到产物1-[4-(叔丁基-二甲基-硅烷氧基)-6-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-3,4-二氢-2H-喹啉-1-基]-2-(2-氯-苯基)-乙酮91(110mg,无色液体)，产率：87％
LCMS:m/z 500.1(M+H)；RT＝7.5min(10min).
{4-(叔丁基-二甲基-硅烷基氧基)-6-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-3,4-二氢-2H-喹啉-1-基}-2-(2-氯-苯基)-乙酮(92)
Figure PCTCN2016113838-appb-000273
在干燥的50mL微波管中室温下依次加入91(100mg,0.2mmol),86(51mg,0.24mmol)，Pd(dppf)2Cl2(22mg,0.03mmol),碳酸钾(61mg,0.44mmol)，1,4-二氧六环(3mL)和水(0.5mL)，氮气置换3次。加热至105摄氏度反应2小时。LCMS检测反应完毕后，过滤，滤液减压浓缩后，用prep-HPLC纯化所得残余物后得产物1-{4-(叔丁基-二甲基-硅烷基氧基)-6-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-3,4-二氢-2H-喹啉-1-基}-2-(2-氯-苯基)-乙酮92(95mg,黄色液体)，产率：86％
LCMS:m/z548.2(M+H)；RT＝7.18min(10min).
2-(2-氯-苯基)-1-{4-羟基-6-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-3,4-二氢-2H-喹啉-1-基}-乙酮化合物的合成(A198)
Figure PCTCN2016113838-appb-000274
在干燥的50mL微波管中室温下依次加入92(100mg,0.183mmol),Bu4NF(1mL,1mol/L)溶液,THF(2mL)。室温搅拌反应18小时。LCMS检测反应完毕后，过滤，滤液减压浓缩后，用prep-HPLC纯化所得残余物后得产物2-(2-氯-苯基)-1-{4-羟基-6-[2-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-3,4-二氢-2H--喹啉-1-基}-乙酮A198(20mg,黄色固体)，产率：23.2％
LCMS:m/z475.1(M+H)；RT＝4.85min(10min).
1H NMR(dmso,400MHz)δ9.48(s,1H),8.50(d,J＝5.3Hz,1H),8.26(d,J＝1.8Hz,1H),7.98(dd,J＝8.7,2.0Hz,1H),7.78(s,1H),7.47–7.24(m,5H),6.30(d,J＝1.8Hz,1H),4.70–4.63(m,1H),4.10–4.00(m,3H),3.71(s,3H),3.67(s,1H),2.23–2.11(m,1H),1.84(d,J＝7.1Hz,1H).
实施例199：5-[5-氯-2-(2-甲基-2H-吡唑-3-基胺)-吡啶-4-基]-1-[2-(2-氯-吡啶-3- 基)-乙酰基]--6-氧代-2,3-二氢-1H-吲哚-7-腈的合成(A199)
Figure PCTCN2016113838-appb-000275
LCMS:m/z 504.2,505.2(M+H)；RT＝5.043min(10min).
1H NMR(dmso,400MHz)δ9.07(s,1H),8.37(dd,J＝4.7,1.8Hz,1H),8.26(s,1H),7.89(dd,J＝7.5,1.8Hz,1H),7.72(s,1H),7.67(d,J＝1.4Hz,1H),7.46(dd,J＝7.5,4.7Hz,1H),7.36(d,J＝1.9Hz,1H),6.81(s,1H),6.27(d,J＝1.8Hz,1H),4.37(t,J＝8.1Hz,2H),4.15(s,2H),3.68(s,3H),3.27(t,J＝8.0Hz,2H).
实施例200：5-(2-(1-甲基-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲酰胺的合成(A200)
Figure PCTCN2016113838-appb-000276
LCMS:m/z489.1(M+H)；RT＝3.86min(9min).
1H NMR(400MHz,dmso)δ9.43(s,1H),8.46(d,J＝5.3Hz,1H),8.29(dd,J＝4.7,1.8Hz,1H),8.05(s,2H),7.83(dd,J＝7.5,1.9Hz,1H),7.51(s,1H),7.42–7.35(m,2H),7.32(d,J＝1.8Hz,1H),7.08(s,1H),6.25(d,J＝1.7Hz,1H),4.25(t,J＝8.0Hz,2H),3.98(s,2H),3.67(s,3H),3.17(t,J＝7.8Hz,2H).
实施例201：1-(2-(2-氟苯基)乙酰基)-5-(2-((4-(哌嗪-1-基磺酰基)苯基)氨基)嘧啶-4-基)二氢吲哚-7-腈的合成(A201)
Figure PCTCN2016113838-appb-000277
LCMS:t＝2.00min,ESI:[M+H]+m/z 598.
1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO)δ8.42(d,J＝5.2Hz,1H),8.32(s,1H),8.28(s,1H),7.36(d,J＝8.6Hz,3H),7.30(d,J＝5.2Hz,1H),7.21(d,J＝8.0Hz,2H),6.62(d,J＝8.6Hz,2H),6.09(s,2H),4.32(t,J＝8.2Hz,2H),4.04(s,2H),3.91(s,4H),3.25(t,J＝8.1Hz,2H),2.88(s,4H).
实施例202：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-羟基-2-甲基-丙基氨基)-嘧啶-4-基]-1H-吲哚-7-甲腈(A202)
Figure PCTCN2016113838-appb-000278
LCMS:m/z463.1(M+H)；RT＝4.52min(10min).
1H NMR(400MHz,dmso)δ8.43–8.20(m,4H),7.85(dd,J＝7.5,1.8Hz,1H),7.43(dd,J＝7.5,4.8Hz,1H),7.24(d,J＝5.7Hz,1H),7.11(s,1H),4.34(t,J＝8.2Hz,2H),4.12(s,2H),3.35(s,3H),3.26(t,J＝8.1Hz,2H),1.11(s,6H).
实施例203：5-(2-(1-甲基-1H-吡唑-5-基氨基)-5-氟吡啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈的合成(A203)
Figure PCTCN2016113838-appb-000279
LCMS:m/z 489.0(M+H)；RT＝4.955min(9min).
1H NMR(dmso,400MHz)δ9.64(s,1H),8.67(d,J＝3.5Hz,1H),8.41(dd,J＝4.8,1.9Hz,1H),8.19(d,J＝4.6Hz,2H),7.93(dd,J＝7.6,1.8Hz,1H),7.50(dd,J＝7.5,4.8Hz,1H),7.40(d,J＝1.9Hz,1H),6.30(d,J＝1.9Hz,1H),4.42(t,J＝8.2Hz,2H),4.20(s,2H),3.73(s,3H),3.35(t,J＝8.1Hz,2H).
实施例204：5-(2-(1-甲基-1H-吡唑-5-基氨基)-5-(三氟甲基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-腈化合物的合成(A204)
Figure PCTCN2016113838-appb-000280
LCMS:m/z539.0(M+H)；RT＝5.62min(9min).
1H NMR(dmso,400MHz)δ10.22(s,1H),8.85(s,1H),8.34(dd,J＝4.8,1.9Hz,1H),7.85(dd,J＝7.5,1.9Hz,1H),7.68(d,J＝17.6Hz,2H),7.43(dd,J＝7.5,4.8Hz,1H),7.34(s,1H),6.22(d,J＝1.8Hz,1H),4.34(t,J＝8.2Hz,2H),4.12(s,2H),3.66(s,3H),3.24(t,J＝8.3Hz,2H).
实施例205：1-(5-溴-7-硝基二氢吲哚-1-基)-2-(2-氟苯基)乙-1-酮的合成(94)
Figure PCTCN2016113838-appb-000281
0℃搅拌下向化合物93(1.0g,4.1mmol)和邻氟苯乙酸(950mg,6.2mmol)的甲苯溶液中缓慢滴加SOCl2(9.6g,80.4mmol)，将反应置于75℃下反应过夜。用水淬灭反应，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，旋干。将所得粗产品用柱层析进行分离(PE:EA＝3:1)得到目标化合物(820mg,2.16mmol,红棕色固体)，产率为53％。
LCMS:t＝2.21min,ESI:[M+H]+m/z 379.
1-(7-氨基-5-溴二氢吲哚-1-基)-2-(2-氟苯基)乙-1-酮的合成(95)
Figure PCTCN2016113838-appb-000282
搅拌下向化合物94(100mg,0.26mmol)的乙醇溶液中缓慢加入SnCl2(251mg,1.32mmol)，将反应置于75℃下反应过夜。用饱和碳酸氢钠水溶液淬灭反应，乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤，旋干。将所得粗产品用柱层析进行分离(PE:EA＝3:1)得到目标化合物95(70mg,0.2mmol,黄色固体)，产率为77％。
LCMS:t＝2.00min,ESI:[M+H]+m/z 349.
1H NMR(400MHz,DMSO-d6)δ8.66(d,J＝5.4Hz,1H),8.08(d,J＝1.6Hz,1H),7.95(s,1H),7.82(d,J＝5.5Hz,1H),7.61(s,1H),7.44(d,J＝1.9Hz,1H),6.21(d,J＝ 1.9Hz,1H),3.74–3.63(m,5H),3.10(t,J＝8.5Hz,2H),2.56(d,J＝6.8Hz,2H),1.86–1.76(m,1H),1.74–1.55(m,5H),1.27–1.06(m,3H),0.92(dd,J＝22.8,10.8Hz,2H).
1-(7-氨基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)-2-(2-氟苯基)乙-1-酮的合成(96)
Figure PCTCN2016113838-appb-000283
在干燥的25mL圆底烧瓶中依次加入化合物95(182mg,0.52mmol)，B2Pin2(199mg,0.78mmol)，KOAc(153mg,1.56mmol),Pd(dppf)2Cl2(38mg,0.05mmol)，DMSO(3.0mL)，氮气置换3次，将反应体系置于90℃油浴中反应0.5h。反应完毕后，用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将所得粗产品用柱层析进行分离(PE:EA＝2:1)得到目标化合物96(265mg,0.52mmol,白色固体)，产率为99％。
LCMS:t＝1.93min,ESI:[M+H]+m/z 396.
1-(7-氨基-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-1-基)-2-(2-氟苯基)-1-酮的合成(A205)
Figure PCTCN2016113838-appb-000284
在干燥的25mL圆底烧瓶中依次加入化合物96(215mg,0.54mmol)，86(227mg,1.08mmol)，NaHCO3(181mg,2.16mmol),Pd(dppf)2Cl2(59mg,0.08mmol)，1,4-dioxane(2.0mL)，H2O(0.5mL)，氮气置换3次，将反应体系置于70℃油浴中反应2h。反应完毕后，用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将所得粗产品用HPLC进行分离得到目标化合物A205(84mg,0.19mmol,白色固体)，产率为35％。
LCMS:t＝1.65min,ESI:[M+H]+m/z 444.
1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.45(d,J＝5.2Hz,1H),7.39–7.28(m,5H),7.25–7.16(m,3H),6.29(d,J＝1.6Hz,1H),5.42(s,2H),4.20(t,J＝7.8Hz,2H),4.03(s,2H),3.70(s,3H),3.09(t,J＝7.6Hz,2H).
采用与实施例205类似的方法制备如下206-224化合物：
实施例206：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-羟基-1-甲基-乙基氨基)-嘧啶-4-基]-1H-吲哚-7-腈化合物的合成(A206)
Figure PCTCN2016113838-appb-000285
LCMS:m/z449.0(M+H)；RT＝4.20min(10min).
1H NMR(dmso,400MHz)δ8.50–8.12(m,4H),7.88(d,J＝7.7Hz,1H),7.46(dd,J＝7.5,4.8Hz,1H),7.24(s,1H),7.10(s,1H),4.37(t,J＝8.1Hz,2H),4.15(s,2H),3.57–3.54(m,3H),3.28(t,J＝8.0Hz,2H),1.15(d,J＝6.6Hz,3H).
实施例207：1-(2-(2-氯-3-氟苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶 -4-基)二氢吲哚-7-甲腈(A207)
Figure PCTCN2016113838-appb-000286
1H NMR(400MHz,CDCl3)δ8.46(d,J＝5.3Hz,1H),8.15(s,1H),8.09(s,1H),7.52(d,J＝1.7Hz,1H),7.39(s,1H),7.26–7.23(m,2H),7.17(d,J＝5.4Hz,1H),7.13-7.09(m,1H),6.36(d,J＝1.7Hz,1H),4.24(t,J＝8.2Hz,2H),4.07(s,2H),3.82(s,3H),3.25(t,J＝8.2Hz,2H).
LC-MS:t＝1.69min,MS:[M+H]+m/z 488.1.
实施例208：1-(2-(2,6-二氯苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-腈(A208)
Figure PCTCN2016113838-appb-000287
1H NMR(500MHz,CDCl3)δ8.45(d,J＝5.4Hz,1H),8.15(s,1H),8.11(s,1H),7.52(d,J＝1.8Hz,1H),7.37(s,1H),7.35(s,1H),7.21(d,J＝7.9Hz,1H),7.18(d,J＝5.4Hz,1H),6.36(d,J＝1.7Hz,1H),4.35(t,J＝8.2Hz,2H),4.25(s,2H),3.83(s,3H),3.32(t,J＝8.0Hz,2H).
LC-MS:t＝1.73min,MS:[M+H]+m/z 504.1.
实施例209：1-(2-(2-氯-6-氟苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A209)
Figure PCTCN2016113838-appb-000288
1H NMR(400MHz,CDCl3)δ8.45(d,J＝5.3Hz,1H),8.14(s,1H),8.09(s,1H),7.51(d,J＝1.9Hz,1H),7.25-7.22(m,2H),7.16(d,J＝5.3Hz,1H),7.07–6.98(m,1H),6.35(d,J＝1.9Hz,1H),4.31(t,J＝8.2Hz,2H),4.07(s,2H),3.82(s,3H),3.30(t,J＝8.2Hz,2H).
LC-MS:t＝1.69min,MS:[M+H]+m/z 488.1.
实施例210：5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-(2-苯基乙酰基)二氢吲哚-7-甲腈(A210)
Figure PCTCN2016113838-appb-000289
1H NMR(400MHz,CDCl3)δ8.42(d,J＝5.6Hz,1H),8.15(s,1H),8.05(s,1H),7.53(d,J＝2.0Hz,1H),7.38-7.36(m,4H),7.31-7.30(m,1H),7.21(d,J＝5.5Hz,1H),6.38(d,J＝2.0Hz,1H),4.15(t,J＝8.2Hz,2H),3.95(s,2H),3.84(s,3H),3.17(t,J＝8.2Hz,2H).
LC-MS:t＝1.62min,MS:[SM+H]+m/z 426.2.
实施例211：1-(2-(4-氯苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A211)
Figure PCTCN2016113838-appb-000290
1H NMR(400MHz,CDCl3)δ8.46(d,J＝5.4Hz,1H),8.15(s,1H),8.06(s,1H),7.51(d,J＝1.9Hz,1H),7.36–7.28(m,4H),7.17(d,J＝5.4Hz,1H),6.36(d,J＝1.9Hz,1H),4.16(t,J＝8.2Hz,2H),3.82(s,3H),3.20(t,J＝8.2Hz,2H).
LC-MS:t＝1.70min,MS:[SM+H]+m/z 470.1.
实施例212：1-(2-(3-氯苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A212)
Figure PCTCN2016113838-appb-000291
1H NMR(400MHz,CDCl3)δ8.47(d,J＝5.3Hz,1H),8.15(s,1H),8.07(s,1H),7.51(d,J＝1.8Hz,1H),7.36(s,1H),7.33–7.27(m,3H),7.15(d,J＝5.3Hz,1H),7.00(s,1H),6.34(d,J＝1.8Hz,1H),4.17(t,J＝8.2Hz,2H),3.91(s,2H),3.81(s,3H),3.20(t,J＝8.1Hz,2H).
LC-MS:t＝1.69min,MS:[SM+H]+m/z 470.1.
实施例213：5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-(2-(邻甲苯基)乙酰基)二氢吲哚-7-甲腈(A213)
Figure PCTCN2016113838-appb-000292
1H NMR(400MHz,CDCl3)δ8.38(d,J＝5.9Hz,1H),8.15(s,1H),8.07(s,1H),7.56(d,J＝1.7Hz,1H),7.27-7.25(m,1H),7.23-7.19(m,4H),6.42(d,J＝1.8Hz,1H),4.14(t,J＝8.2Hz,2H),3.93(s,2H),3.87(s,3H),3.21(t,J＝8.1Hz,2H),2.38(s,3H).
LC-MS:t＝1.68min,MS:[SM+H]+m/z 450.1
实施例214：1-(2-(3,4-二氯苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A214)
Figure PCTCN2016113838-appb-000293
1H NMR(400MHz,DMSO-D6)δ8.53(d,J＝5.2Hz,1H),8.32(s,1H),8.30(s,1H),7.63(d,J＝8.3Hz,1H),7.60(d,J＝2.0Hz,1H),7.52(d,J＝5.3Hz,1H),7.37(d,J＝1.9Hz,1H),7.32(dd,J＝8.3,2.0Hz,1H),6.27(d,J＝1.7Hz,1H),4.30(t,J＝8.1Hz,2H),4.05(s,2H),3.69(s,3H),3.25(t,J＝8.1Hz,2H).
LC-MS:t＝1.76min,MS:[SM+H]+m/z 504.0.
实施例215：1-((2-氯苄基)磺酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A215)
Figure PCTCN2016113838-appb-000294
1H NMR(400MHz,CDCl3)δ8.45(d,J＝5.3Hz,1H),8.13(s,1H),8.04(s,1H),7.66-7.63(m,1H),7.52(d,J＝1.9Hz,1H),7.45-7.41(m,1H),7.39–7.31(m,2H),7.18 (d,J＝5.4Hz,1H),6.38(d,J＝1.9Hz,1H),5.03(s,2H),3.84(s,3H),3.71(t,J＝8.1Hz,2H),3.07(t,J＝8.1Hz,2H).
LC-MS:t＝1.71min,MS:[SM+H]+m/z 506.0.
实施例216：5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-(2-(2-(三氟甲基)苯基)乙酰基)二氢吲哚-7-甲腈(A216)
Figure PCTCN2016113838-appb-000295
1H NMR(400MHz,CD3OD)δ8.48(d,J＝5.3Hz,1H),8.32(s,1H),8.28(s,1H),7.74(d,J＝8.1Hz,1H),7.63(t,J＝7.9Hz,1H),7.56–7.46(m,3H),7.43(d,J＝5.4Hz,1H),6.42(t,J＝2.0Hz,1H),4.36(t,J＝8.2Hz,2H),4.20(s,2H),3.79(s,3H),3.32(m,3H).
LC-MS:t＝1.72min,MS:[SM+H]+m/z 504.1.
实施例217：1-(2-(2-氟-3-(三氟甲基)苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-腈(A217)
Figure PCTCN2016113838-appb-000296
1H NMR(400MHz,CDCl3)δ8.44(d,J＝5.5Hz,1H),8.16(s,1H),8.10(s,1H),7.70(t,J＝7.1Hz,1H),7.62–7.48(m,2H),7.30-7.27(m,1H),7.21(d,J＝5.5Hz,1H),6.39(d,J＝1.9Hz,1H),4.30(t,J＝8.2Hz,2H),4.00(s,2H),3.85(s,3H),3.29(t,J＝8.3Hz,2H).
LC-MS:t＝1.74min,MS:[SM+H]+m/z 522.2.
实施例218：1-(2-(6-氯吡啶-3-基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A218)
Figure PCTCN2016113838-appb-000297
1H NMR(400MHz,CDCl3)δ8.50(d,J＝5.3Hz,1H),8.33(d,J＝2.1Hz,1H),8.16(s,1H),8.10(s,1H),7.79(dd,J＝8.3,2.5Hz,1H),7.56(d,J＝2.0Hz,1H),7.36(d,J＝8.2Hz,1H),7.17(d,J＝5.3Hz,1H),6.39(d,J＝2.0Hz,1H),4.25(t,J＝8.2Hz,2H),3.91(s,2H),3.85(s,3H),3.27(t,J＝8.3Hz,2H).
LC-MS:t＝1.55min,MS:[SM+H]+m/z 471.2.
实施例219：5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-(2-(嘧啶-5-基)乙酰基)二氢吲哚-7-甲腈(A219)
Figure PCTCN2016113838-appb-000298
LC-MS:t＝1.34min,MS:[SM+H]+m/z 438.2.
实施例220:5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-(2-(全氟苯基)乙酰基)二氢吲哚-7-甲腈(A220)
Figure PCTCN2016113838-appb-000299
1H NMR(400MHz,CDCl3)δ8.39(d,J＝5.6Hz,1H),8.09(s,1H),8.02(s,1H),7.53(d,J＝2.0Hz,1H),6.39(d,J＝1.9Hz,1H),5.35-5.33(m,1H),4.40(t,J＝8.0Hz,2H),3.92(s,2H),3.85(s,3H),3.34(t,J＝8.1Hz,2H).
LC-MS:t＝1.74min,MS:[SM+H]+m/z 527.1.
实施例221:1-(2-(2,5-二氟苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-腈(A221)
Figure PCTCN2016113838-appb-000300
1H NMR(400MHz,CDCl3)δ8.42(d,J＝5.6Hz,1H),8.15(s,1H),8.09(s,1H),7.54(d,J＝2.0Hz,1H),7.23(d,J＝5.7Hz,1H),7.20-7.14(m,1H),7.10-7.02(m,1H),7.01-6.94(m,1H),6.40(d,J＝1.9Hz,1H),4.26(t,J＝8.2Hz,2H),3.92(s,2H),3.86(s,3H),3.27(t,J＝8.2Hz,2H).
LC-MS:t＝1.71min,MS:[SM+H]+m/z 472.2.
实施例222：5-(2-((2-氰基乙基)氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈(A222)
Figure PCTCN2016113838-appb-000301
1H NMR(400MHz,DMSO-D6)δ8.40(d,J＝5.0Hz,1H),8.30(s,1H),7.65-7.58(m,1H),7.42–7.32(m,2H),7.29(d,J＝5.2Hz,1H),7.25–7.15(m,2H),4.33(t,J＝8.2Hz,2H),4.04(s,2H),3.65-3.55(m,2H),3.26(t,J＝8.1Hz,2H),2.85-2.75(m,2H).
LCMS:t＝1.63min,MS:[M+H]+m/z 427.3.
实施例223：1-(2-(2-氟苯基)乙酰基)-5-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A223)
Figure PCTCN2016113838-appb-000302
1H NMR(400MHz,CDCl3)δ8.38(s,1H),8.18(s,1H),8.12(s,1H),7.88(s,1H),7.66(s,1H),7.45(t,J＝7.4Hz,1H),7.32-7.27(m,1H),7.15(dd,J＝7.6Hz,1H),7.09(ddt,J＝9.1Hz,1H),7.04(d,J＝5.3Hz,1H),4.55-4.45(m,6.7Hz,1H),4.23(t,J＝8.1Hz,2H),3.96(s,2H),3.24(t,J＝8.1Hz,2H),1.55(s,3H),1.53(s,3H).
LCMS:t＝1.72min,MS:[M+H]+m/z 482.3.
实施例224：1-(2-(2-氟苯基)乙酰基)-5-(2-((2-甲基吡啶-4-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈(A224)
Figure PCTCN2016113838-appb-000303
1H NMR(400MHz,DMSO-D6)δ11.34(s,1H),8.82(d,J＝5.3Hz,1H),8.50(d,J＝7.0Hz,1H),8.43(s,1H),8.40(s,1H),8.18(s,1H),8.02(s,1H),7.88(d,J＝5.3Hz,1H),7.42-7.32(m,2H),7.26–7.17(m,2H),4.37(t,J＝8.2Hz,2H),4.06(s,2H),3.30(t,J＝8.3Hz,2H),2.63(s,3H).
LCMS:t＝1.59min,MS:[M+H]+m/z 461.1.
实施例225：(6-氯-嘧啶-4-基)-(2-甲基-2H-吡唑-3-基)-胺的合成(99)
Figure PCTCN2016113838-appb-000304
在干燥的50mL单口瓶中室温下依次加入化合物97(391mg,4.027mmol),98(400mg,2.685mmol)，Pd2(dba)3(246mg,0.2685mmol),RuPhos(125mg,0.2685mmol)，TEA(326mg,3.222mmol)和DMF(5mL)，升温至90℃并,微波搅拌反应2小时。LCMS检测反应完毕后，粗产品溶于50mL EA中，并分别用水及饱和盐水洗涤，浓缩后用combiflash(EA/PE 1/5-4/1)纯化得到产物(6-氯-嘧啶-4-基)-(2-甲基-2H-吡唑-3-基)-胺99(170mg,黄色固体)，产率：30.2％。
LCMS:m/z210.0(M+H)；RT＝1.48min(10min).
[2-(2-氯-吡啶-3-基)-乙酰基]-5-[6-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-腈的合成(A225)
Figure PCTCN2016113838-appb-000305
在干燥的50mL单口瓶中室温下依次加入99(70mg,0.334mmol),100(311mg,0.7346mmol)，Pd(dppf)Cl2(32mg,0.0434mmol),NaHCO3(70mg,0.835mmol)，1,4-二氧六环(3mL)和水(0.8mL)，氮气置换3次。加热至88摄氏度反应2.5个小时。LCMS检测反应完毕后，过滤，滤液减压浓缩，过柱纯化得到粗品，再送用prep-HPLC纯化所得残余物，中性制备得到产物1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[6-(2-甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-腈A225(28mg,黄色固体)，产率：17.8％.
LCMS:m/z471.0(M+H)；RT＝4.31min(10min).
1H NMR(dmso,400MHz)δ9.51(s,1H),8.67(s,1H),8.37(dd,J＝4.7,1.8Hz,1H),8.20(d,J＝18.5Hz,2H),7.88(dd,J＝7.6,1.8Hz,1H),7.60–7.35(m,2H),7.20(s,1H),6.34(d,J＝1.9Hz,1H),4.37(t,J＝8.2Hz,2H),4.15(s,2H),3.70(s,3H),3.28(d,J＝8.1Hz,2H).
实施例226：(2-氯-5-甲基嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈化合物的合成(102)
Figure PCTCN2016113838-appb-000306
在干燥的50mL单口瓶中室温下依次加入化合物100(236mg,0.558mmol),101(100mg,0.614mmol),Pd(dppf)Cl2(40mg,0.0558mmol)NaHCO3(94mg,1.12mmol)和dioxane(3mL),H2O(0.75mL)，氮气置换三次，升温至73℃并搅拌 1.5小时。LCMS检测反应完毕后，过滤减压浓缩后，粗产品用combiflash(EA/PE0％-80％)纯化得到产物(2-氯-5-甲基嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈102(110mg,黄色固体)，产率：55％。
LCMS:m/z424.0(M+H)；RT＝5.15min(9min).
5-(2-(1-甲基-1H-吡唑-5-基氨基)-5-甲基嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-腈化合物的合成(A226)
Figure PCTCN2016113838-appb-000307
在干燥的50mL单口瓶中室温下依次加入102(90mg,0.212mmol),97(29mg,0.299mmol)，Pd2(dba)3(20mg,0.0218mmol),RuPhos(27mg,0.0579mmol),TEA(23mg,0.0227mmol)，DMF(2mL)，氮气置换3次。加热至90摄氏度反应1.5小时。LCMS检测反应完毕后，过滤，滤液减压浓缩，用prep-HPLC纯化所得残余物得到产物5-(2-(1-甲基-1H-吡唑-5-基氨基)-5-甲基嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-腈A226(3mg,黄色固体)，产率：1％
LCMS:m/z485.0(M+H)；RT＝4.61min(9min).
1H NMR(dmso,400MHz)δ9.37(s,1H),8.43–8.31(m,2H),7.92–7.84(m,2H),7.82(s,1H),7.46(dd,J＝7.4,4.7Hz,1H),7.32(d,J＝1.9Hz,1H),6.23(d,J＝1.8Hz,1H),4.37(t,J＝8.2Hz,2H),4.15(s,2H),3.68(s,3H),3.28(t,J＝7.9Hz,2H),2.23(s,3H).
采用与实施例226类似的方法制备227-237化合物：
实施例227：5-(2-(3-氯-1-甲基-1H-吡唑-4-基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)腈化合物的合成(A227)
Figure PCTCN2016113838-appb-000308
1H NMR(400MHz,dmso)δ8.83(s,1H),8.42(d,J＝5.2Hz,1H),8.36–8.31(m,1H),8.28(s,2H),7.94(s,1H),7.85(d,J＝6.2Hz,1H),7.48–7.34(m,2H),4.34(t,J＝8.2Hz,2H),4.11(s,2H),3.78(s,3H),3.26(t,J＝8.0Hz,2H).
LCMS:m/z505.1(M+H)；RT＝4.74min(9min).
实施例228：5-(2-(1-羟基丙烷-2-基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A228)
Figure PCTCN2016113838-appb-000309
1H NMR(dmso,400MHz)δ8.31(d,J＝5.2Hz,1H),8.25(d,J＝2.3Hz,2H),7.32(dt,J＝7.8,6.6Hz,2H),7.22–7.11(m,3H),6.88(d,J＝8.1Hz,1H),4.65(t,J＝5.7Hz,1H),4.29(t,J＝8.2Hz,2H),4.01(s,1H),4.00(s,2H),3.50–3.42(m,1H),3.23(dd,J＝17.1,8.9Hz,3H),1.11(d,J＝6.5Hz,3H).
LCMS:m/z 432.1(M+H)；RT＝4.063min(9min).
实施例229：1-[2-(2-氟-苯基)-乙酰基]-5-[2-(2-甲磺酰基-乙基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-甲腈的合成(A229)
Figure PCTCN2016113838-appb-000310
1H NMR(dmso,400MHz)δ8.38(d,J＝5.1Hz,1H),8.28(s,2H),7.49(s,1H),7.38–7.22(m,3H),7.22–7.10(m,2H),4.30(s,2H),4.00(s,2H),3.75(s,2H),3.38(t,J＝6.3Hz,2H),3.22(t,J＝8.1Hz,2H),3.00(s,3H).
LCMS:m/z480.1(M+H)；RT＝4.31min(10min).
实施例230：5-(2-(2-羟基丙基氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A230)
Figure PCTCN2016113838-appb-000311
1H NMR(dmso,400MHz)δ8.38(d,J＝5.4Hz,1H),8.32(s,2H),7.46–7.29(m,3H),7.29(d,J＝5.1Hz,1H),7.25–7.16(m,2H),4.34(t,J＝8.2Hz,2H),4.05(s,2H),3.85–3.83(m,1H),3.27(t,J＝8.1Hz,3H),1.10(d,J＝6.2Hz,3H).
LCMS:m/z 432.1(M+H)；RT＝4.171min(9min).
实施例231：1-[2-(2-氯吡啶-3-基)-乙酰基]-5-{2-[1-(2,2,2-三氟-乙基)-1H-吡唑-4-基氨基]-嘧啶-4-基}-2,3-二氢-1H-吲哚-7-甲腈的合成(A231)
Figure PCTCN2016113838-appb-000312
1H-NMR(500MHz,DMSO-d6)δ9.69(s,1H),8.53(s,1H),8.38(dd,J＝4.8,1.9Hz,1H),8.36(d,J＝10.8Hz,2H),8.13(s,1H),7.89(dd,J＝7.6,1.8Hz,1H),7.69(s,1H),7.47(dd,J＝7.4,4.8Hz,1H),7.42(d,J＝5.2Hz,1H),5.12(d,J＝9.2Hz,2H),4.39(t,J＝8.2Hz,2H),4.16(s,2H),3.31(t,J＝8.2Hz,2H).
LCMS:m/z 539.0(M+H)；RT＝5.45min(10min)
实施例232：1-[2-(2氟-苯基)-乙酰基]-5-{2-[1-(2,2,2-三氟-乙基)-1H-吡唑-4-基氨基]-嘧啶-4-基}-2,3-二氢-1H-吲哚-7-甲腈的合成(A232)
Figure PCTCN2016113838-appb-000313
1H-NMR(500MHz,DMSO-d6)δ9.69(s,1H),8.54(s,1H),8.34(s,2H),8.13(s,1H),7.68(s,1H),7.47–7.32(m,3H),7.21(dd,J＝16.7,9.3Hz,2H),5.12(d,J＝9.3Hz,2H),4.35(t,J＝8.2Hz,2H),4.05(s,2H),3.29(t,J＝8.1Hz,2H).
LCMS:m/z 522.1(M+H)；RT＝6.00min(10min)
实施例233：1-[2-(2-氯-苯基)-乙酰基]-5-{2-[1-(2,2,2-三氟-乙基)-1H-吡唑-4-基氨基]-嘧啶-4-基}-2,3-二氢-1H-吲哚-7-甲腈的合成(A233)
Figure PCTCN2016113838-appb-000314
1H-NMR(500MHz,DMSO-d6)δ9.68(s,1H),8.52(d,J＝4.9Hz,1H),8.33(s,2H),8.12(s,1H),7.68(s,1H),7.48(dd,J＝5.6,3.7Hz,1H),7.44–7.36(m,2H),7.34(dd,J＝5.8,3.5Hz,2H),5.12(d,J＝9.0Hz,2H),4.35(t,J＝8.2Hz,2H),4.11(s,2H),3.28(d,J＝8.0Hz,2H).
LCMS:m/z 538.1(M+H)；RT＝5.77min(10min)
实施例234：5-(2-(1-氘甲基-1H-吡唑-3-基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈的合成(A234)
Figure PCTCN2016113838-appb-000315
1H-NMR(500MHz,DMSO-d6)δ9.77(s,1H),8.47(d,J＝5.2Hz,1H),8.38–8.25(m,3H),7.85(dd,J＝7.5,1.9Hz,1H),7.56(d,J＝2.1Hz,1H),7.47–7.35(m,2H),6.57(d,J＝2.2Hz,1H),4.35(t,J＝8.2Hz,2H),4.12(s,2H),3.27(t,J＝8.1Hz,2H).
LCMS:m/z474.0(M+H)；RT＝4.48min(10min)
实施例235：5-(2-(1-(2,2,2-三氟乙基)-1H-吡唑-3-基氨基)嘧啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7甲腈的合成(A235)
Figure PCTCN2016113838-appb-000316
1H-NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.49(d,J＝5.2Hz,1H),8.38–8.20(m,3H),7.86(dd,J＝7.6,1.9Hz,1H),7.74(d,J＝2.3Hz,1H),7.48–7.35(m,2H),6.75(d,J＝2.4Hz,1H),4.99(q,J＝9.0Hz,2H),4.35(t,J＝8.3Hz,2H),4.12(s,2H),3.27(d,J＝8.0Hz,2H).
LCMS:m/z539.0(M+H)；RT＝5.11min(10min)
实施例236：5-(2-(1-(2,2,2-三氟乙基)-1H-吡唑-3-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-腈的合成(A236)
Figure PCTCN2016113838-appb-000317
1H-NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.49(d,J＝5.2Hz,1H),8.31(s,2H),7.74(d,J＝2.4Hz,1H),7.49–7.37(m,3H),7.34–7.25(m,2H),6.76(d,J＝2.4Hz,1H),4.99(q,J＝9.1Hz,2H),4.32(t,J＝8.2Hz,2H),4.08(s,2H),3.25(d,J＝8.3Hz,2H).
LCMS:m/z538.0(M+H)；RT＝5.72min(10min)
实施例237：5-(2-(1-氘甲基-1H-吡唑-3-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-甲腈的合成(A237)
Figure PCTCN2016113838-appb-000318
1H-NMR(500MHz,DMSO-d6)9.76(s,1H),8.47(d,J＝5.2Hz,1H),8.30(s,2H),7.56(d,J＝2.1Hz,1H),7.49–7.36(m,3H),7.35–7.28(m,2H),6.57(d,J＝2.1Hz,1H),4.32(t,J＝8.2Hz,2H),4.08(s,2H),3.26(t,J＝8.1Hz,2H).
LCMS:m/z473.1(M+H)；RT＝5.16min(10min)
实施例238：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2,5-二甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-1,3-二氢-1H-吲哚-7-甲腈的合成(A238)
Figure PCTCN2016113838-appb-000319
在干燥的25mL单口瓶中室温下依次加入化合物77(60mg,0.132mmol),化合103(29mg,0.264mmol),DMF(2mL),Pd2(dba)3(12mg,0.0132mmol),RuPhosor xantPhos(0.0132mmol),90度搅拌80min。LCMS检测反应完毕后，粗产品用prep-HPLC纯化得到产物1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2,5-二甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-1,3-二氢-1H-吲哚-7-甲腈A238(4.2mg,黄色固体)，产率：6.56％。
1H-NMR(500MHz,DMSO-d6)δ9.47(s,1H),8.49(d,J＝5.2Hz,1H),8.39–8.17(m,3H),7.85(d,J＝7.6Hz,1H),7.54–7.39(m,2H),6.06(s,1H),4.35(t,J＝8.1Hz,2H),4.12(s,2H),3.59(s,3H),3.27(t,J＝8.0Hz,2H),2.10(s,3H).
LCMS:m/z485.1(M+H)；RT＝4.57min(10min)
实施例239：1-(2,2,2-三氟乙基)-5-硝基-1H-吡唑的合成(106)
Figure PCTCN2016113838-appb-000320
在干燥的50mL单口瓶中室温下依次加入化合物104(10g,88.4mmol),化合物105(41g,176.9mmol),碳酸钾(31g,221mmol)和DMF(100mL)，室温搅拌4小时。LCMS检测反应完毕后，加入水，并用EA萃取，有机相用饱和盐水洗涤，旋干后粗产品用combiflash(EA/PE 0-50％)纯化得到产物1-(2,2,2-三氟乙基)-5-硝基-1H-吡唑4(900mg,黄色液体)，产率：5％。
LCMS:m/z196.0(M+H)；RT＝5.05min(10min)
1-(2,2,2-三氟乙基)-1H-吡唑-5-胺的合成(107)
Figure PCTCN2016113838-appb-000321
在干燥的50mL单口瓶中室温下依次加入化合物106(900mg,4.6mmol),Pd/C(90mg),MeOH(10mL)，氢气置换3次，室温搅拌16小时。LCMS检测反应完毕后，过滤浓缩得到粗产物1-(2,2,2-三氟乙基)-1H-吡唑-5-胺107(650mg,黄色液体)，产率：85％。
LCMS:m/z166.1(M+H)；RT＝1.06min(10min)
5-(2-(1-(2,2,2-三氟乙基)-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基) 二氢吲哚-7-腈的合成(A239)
Figure PCTCN2016113838-appb-000322
在干燥的25mL单口瓶中室温下依次加入化合物74(80mg,0.176mmol),化合107(88mg,0.529mmol),Pd2(dba)3(16mg,0.0176mmol),Ruphos(16mg,0.0352mmol),TEA(18mg,0.176mmol)和DMF(1mL)，氮气置换3次，100度搅拌2小时。LCMS检测反应完毕后，粗品用prep-HPLC纯化5-(2-(1-(2,2,2-三氟乙基)-1H-吡唑-5-基氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-腈A239(17mg,黄色固体)，产率：18％。
1H-NMR(500MHz,DMSO-d6)δ9.77(s,1H),8.54(d,J＝5.2Hz,1H),8.30(d,J＝2.4Hz,2H),7.60–7.37(m,4H),7.35–7.27(m,2H),6.49(d,J＝1.6Hz,1H),5.12(dd,J＝18.1,8.9Hz,2H),4.32(t,J＝8.2Hz,2H),4.08(s,2H),3.26(t,J＝8.1Hz,2H).
LCMS:m/z538.0(M+H)；RT＝5.84min(10min)
实施例240：二氢吲哚-2-基甲醇的合成(109)
Figure PCTCN2016113838-appb-000323
0℃搅拌下向化合物108(1.0g,6.1mmol)的THF溶液中缓慢滴加BH3 .THF(12.2mol,1M in THF)，将反应置于70℃下反应4h。将反应冷却至室温后置于0℃下向内依次加入MeOH(5.0mL)和浓HCl(1.5mL)，将反应体系在70℃下反应1h后将反应液浓缩，用NaOH(8M)溶液碱化至pH为8，加水稀释，用乙酸乙酯萃取，合并有机相并用无水硫酸钠干燥，过滤，旋干。将所得粗产品用柱层析进行分离(PE:EA＝10:1)得到目标化合物109(913mg,6.1mmol,黄色液体)，产率为99％。
LCMS:t＝0.61min,ESI:[M+H]+m/z150.
2-(((叔丁基二甲基甲硅烷基)氧基)甲基)二氢吲哚的合成(110)
Figure PCTCN2016113838-appb-000324
搅拌下向化合物109(913mg,6.1mmol)的DCM溶液中依次缓慢加入Imid(625mg,9.19mmol)和TBSCl(1.38g,9.19mmol)，将反应置于室温下反应2h。过滤，将滤液旋干，将所得粗产品用柱层析进行分离(PE:EA＝10:1)得到目标化合物110(648mg,2.46mmol,无色油状液体)，产率为40％。
5-溴-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)二氢吲哚的合成(111)
Figure PCTCN2016113838-appb-000325
在干燥的25mL圆底烧瓶中依次加入化合物110(277mg,1.04mmol)，CH3CN(5.0mL)，-40℃下向内缓慢加入NBS(186mg,1.04mmol)。反应5min后，将反应用饱和NaHCO3溶液淬灭，乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将所得粗产品用柱层析进行分离(PE:EA＝10:1)得到目标 化合物111(320mg,0.94mmol,无色液体)，产率为90％。
LCMS:t＝2.70min,ESI:[M+H]+m/z342.
1-(5-溴-2-(((叔丁基二甲基甲硅烷基)氧基)甲基)二氢吲哚-1-基)-2-(2-氯苯基)乙-1-酮的合成(113)
Figure PCTCN2016113838-appb-000326
在25mL茄型瓶中依次加入化合物111(320mg,0.94mmol),112(239mg,1.4mmol),HATU(532mg,1.5mmol),DMF(5.0mL),DIPEA(364mg,2.8mmol)，将反应置于室温下反应过夜。旋干反应液，乙酸乙酯萃取，将有机相用饱和食盐水洗涤，硫酸钠干燥，过滤，旋干。将所得粗产品用柱层析(石油醚:乙酸乙酯＝10:1)分离得到目标化合物113(354mg,0.72mmol,白色固体)，产率为76％。
LCMS:t＝2.86min,ESI:[M+H]+m/z 494.
1-(2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)二氢吲哚-1-基)-2-(2-氯苯基)乙-1-酮的合成(114)
Figure PCTCN2016113838-appb-000327
在干燥的25mL圆底烧瓶中依次加入化合物113(296mg,0.6mmol)，B2Pin2(229mg,0.9mmol)，KOAc(176mg,1.8mmol),Pd(dppf)2Cl2(44mg,0.06mmol)，DMSO(3.0mL)，氮气置换3次，将反应体系置于90℃油浴中反应0.5h。反应完毕后，用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将所得粗产品用柱层析进行分离(PE:EA＝10:1)得到目标化合物114(319mg,0.59mmol,白色固体)，产率为98％。
LCMS:t＝2.96min,ESI:[M+H]+m/z542.
1-(2-(((叔丁基二甲基甲硅烷基)氧基)甲基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-2-(2-氯苯基)乙-1-酮的合成(115)
Figure PCTCN2016113838-appb-000328
在25mL圆底烧瓶中依次加入化合物114(46mg,0.085mmol)，86(27mg,0.13mmol)，NaHCO3(29mg,0.34mmol),Pd(dppf)Cl2(9mg,0.013mmol)，1,4-dioxane(0.8mL)，H2O(0.2mL)，氮气置换3次，将反应体系置于70℃油浴中反应2h。反应完毕后，用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将所得粗产品用柱层析进行分离得到目标化合物115(35mg,0.059mmol,白色固体)，产率为67％。
LCMS:t＝2.58min,ESI:[M+H]+m/z589.
(2-氯苯基)-1-(2-(羟甲基)-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚 -1-基)乙-1-酮的合成(A240)
Figure PCTCN2016113838-appb-000329
在干燥的25mL圆底烧瓶中加入化合物9(30mg,0.05mmol)和THF(1.0mL)，0℃搅拌下向反应体系中加入TBAF(0.1mL,1.0M in THF)并在该温度下反应3h。LCMS显示反应完全，用乙酸乙酯萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将所得粗产品用HPLC进行分离得到目标化合物(14mg,0.029mmol,白色固体)，产率为53％。
1H NMR(600MHz,CDCl3)δ8.42(d,J＝4.3Hz,1H),8.21(s,1H),7.92(s,1H),7.86(s,1H),7.50(d,J＝1.8Hz,1H),7.46–7.38(m,1H),7.34(s,1H),7.27(s,1H),7.16(d,J＝5.3Hz,1H),6.83(s,1H),6.35(d,J＝1.7Hz,1H),5.10(s,2H),4.77(s,2H),4.16(d,J＝12.9Hz,2H),3.78(d,J＝16.7Hz,2H),3.76(s,1H),3.42(dd,J＝16.0,9.1Hz,1H),2.97(s,2H).
LCMS:t＝1.78min,ESI:[M+H]+m/z475.
实施例241：1-(2-(2-氯苯基)乙酰基)-5-(2-((1,3-二甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈的合成(A241)
Figure PCTCN2016113838-appb-000330
采用与实施例240类似的方法制备。
1H NMR(500MHz,DMSO)δ9.46(s,1H),8.52(d,J＝5.2Hz,1H),8.32(d,J＝10.5Hz,2H),7.50(dd,J＝12.5,4.4Hz,2H),7.45–7.41(m,1H),7.35(dd,J＝5.8,3.5Hz,2H),6.07(s,1H),4.35(t,J＝8.3Hz,2H),4.11(s,2H),3.61(s,3H),3.28(t,J＝8.0Hz,2H),2.12(s,3H).
LCMS:t＝1.92min,ESI:[M+H]+m/z 484.
实施例242：4-碘-5-甲基-N-(1-甲基-1H-吡唑-5-基)吡啶-2-胺的合成
Figure PCTCN2016113838-appb-000331
在干燥的5mL微波管中依次加入化合物97(160mg,1.7mmol)，化合物116(200mg,0.85mmol)，tBuOK(14mg,0.015mmol)和DMSO(0.3mL)，将反应体系置于70℃下反应3h。LCMS监测反应完全，用水淬灭反应，二氯甲烷萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将粗产品用柱层析(PE:EA＝2:1)进行纯化得化合物117(132mg,0.42mmol,黄色固体)，产率为45％。
1-(2-(2-氯吡啶-3-基)乙酰基)-5-(5-甲基-2-((1-甲基-1H-吡唑-5-基)氨基)吡啶-4-基)-7-甲腈的合成(A242)
Figure PCTCN2016113838-appb-000332
在干燥的25mL圆底烧瓶中依次加入化合物116(75mg,0.24mmol)，化合物100(152mg,0.36mmol)，Pd(dppf)Cl2(26mg,0.036mmol)，NaHCO3(84mg,0.96mmol)，1,4-dioxane(1.0mL)和H2O(0.2mL)，氮气置换3次，将反应体系置于70℃油浴中反应1h。LCMS监测反应完全后，用二氯甲烷萃取，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将粗产品用HPLC进行纯化得目标化合物A242(50mg,0.10mmol,黄色固体)，产率为43％。
1H NMR(400MHz,DMSO)δ8.70(s,1H),8.37(dd,J＝4.8,1.9Hz,1H),8.04(s,1H),7.89(dd,J＝7.6,1.8Hz,1H),7.64(s,1H),7.56(s,1H),7.46(dd,J＝7.5,4.8Hz,1H),7.31(d,J＝1.8Hz,1H),6.64(s,1H),6.22(d,J＝1.8Hz,1H),4.35(t,J＝8.1Hz,2H),4.14(s,2H),3.66(s,3H),3.26(t,J＝7.9Hz,2H),2.11(s,3H).
LCMS:t＝1.84min,ESI:[M+H]+m/z 484.
采用与实施例242类似的方法制备243-化合物：
实施例243：5-(2-((1H-吡唑-5-基)氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A243)
Figure PCTCN2016113838-appb-000333
1H NMR(400MHz,DMSO)δ9.95(s,1H),8.52(d,J＝5.1Hz,1H),8.35(d,J＝3.1Hz,2H),7.65(s,1H),7.46(d,J＝5.2Hz,1H),7.37(dd,J＝16.3,9.3Hz,2H),7.28–7.13(m,2H),6.56(s,1H),4.34(t,J＝8.1Hz,2H),4.05(s,2H),3.28(t,J＝8.0Hz,2H).
实施例244：4-(1-(2-(2-氯吡啶-3-基)乙基)-1H-吡咯并[2,3-b]吡啶-5-基)-N-(1-甲基-1H-吡唑-5-基)吡啶-2-基)嘧啶-2-胺的合成(A244)
Figure PCTCN2016113838-appb-000334
1H NMR(400MHz,CDCl3)δ9.02(s,1H),8.57(s,1H),8.33(s,1H),8.26(d,J＝2.9Hz,1H),7.59(s,1H),7.41(d,J＝5.9Hz,1H),7.23(dd,J＝7.5,1.8Hz,1H),7.07(d,J＝3.5Hz,1H),7.04(dd,J＝7.4,4.9Hz,1H),6.53(d,J＝3.4Hz,1H),5.34(m,1H),4.64(t,J＝6.9Hz,2H),3.92(s,3H),3.33(t,J＝6.8Hz,2H).
实施例245：2-(3-氯苯基)-N-(5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)吡啶-2-基)的合成(A245)
Figure PCTCN2016113838-appb-000335
1H NMR(400MHz,CDCl3)δ8.83(s,1H),8.39(d,J＝5.6Hz,1H),8.25(s,1H),8.01(s,1H),7.42(d,J＝2.0Hz,1H),7.27(m,3H),7.18(m,1H),7.09(d,J＝5.2,1H),6.83(s,1H),6.27(d,J＝2.0Hz,1H),3.74(s,3H),3.69(s,2H).
实施例246：1-乙酰基-5-(2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈的合成(A246)
Figure PCTCN2016113838-appb-000336
1H NMR(500MHz,DMSO)δ9.50(s,1H),8.53(d,J＝5.2Hz,1H),8.30(d,J＝17.3Hz,2H),7.52(d,J＝5.2Hz,1H),7.37(d,J＝1.8Hz,1H),6.28(d,J＝1.6Hz,1H),4.23(t,J＝8.2Hz,2H),3.70(s,3H),3.23(t,J＝8.2Hz,2H),2.28(s,3H).
实施例247：5-(2-((1H-吡唑-4-基)氨基)吡啶-4-基)-1-(2-(2-氯吡啶-3-基)乙酰基)二氢吲哚-7-甲腈(A247)
Figure PCTCN2016113838-appb-000337
1H-NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.74(s,1H),8.34(dd,J＝4.8,1.9Hz,1H),8.12(d,J＝5.4Hz,1H),8.01–7.81(m,3H),7.79(d,J＝1.7Hz,1H),7.56–7.39(m,2H),6.96–6.82(m,2H),4.33(t,J＝8.2Hz,2H),4.11(s,2H),3.27–3.22(m,2H).
实施例248：1-(2-(2-氯苯基)乙酰基)-5-(5-氟-2-((1-甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈的合成(A248)
Figure PCTCN2016113838-appb-000338
1H-NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.63(d,J＝3.5Hz,1H),8.14(d,J＝3.5Hz,2H),7.50–7.41(m,2H),7.35(dd,J＝5.7,3.4Hz,3H),6.25(d,J＝1.8Hz,1H),4.35(t,J＝8.1Hz,2H),4.12(s,2H),3.69(s,3H),3.29(t,J＝8.1Hz,2H).
实施例249：1-[2-(2-氯-吡啶-3-基)-乙酰基]-5-[2-(2-氘代甲基-2H-吡唑-3-基氨基)-嘧啶-4-基]-2,3-二氢-1H-吲哚-7-腈的合成(A249)
Figure PCTCN2016113838-appb-000339
1H-NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.50(d,J＝5.3Hz,1H),8.37–8.19(m,3H),7.90–7.82(m,1H),7.49(d,J＝5.2Hz,1H),7.43(dd,J＝7.5,4.7Hz,1H),7.34(s,1H),6.24(s,1H),4.35(t,J＝8.2Hz,2H),4.12(s,2H),3.26(t,J＝8.1Hz,2H).
LCMS:m/z474.2(M+H)；RT＝4.55min(10min)
实施例250：5-(2-((1-乙酰基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1-(2-(2-氯苯基)乙酰基)二氢吲哚-7-腈的合成(A250)
Figure PCTCN2016113838-appb-000340
1H NMR(500MHz,DMSO)δ10.01(s,1H),8.63(s,1H),8.58(s,1H),8.35(s,1H), 7.99(s,1H),7.50(dd,J＝10.6,4.4Hz,1H),7.48–7.40(m,1H),7.35(dd,J＝5.8,3.5Hz,1H),4.37(t,J＝8.2Hz,2H),4.12(s,2H),3.33–3.26(m,2H),2.62(s,3H).
LCMS:t＝2.07min,ESI:[M+H]+m/z 498.
实施例251：1-(2-(2-氯苯基)乙酰基)-5-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)二氢吲哚-7-甲腈的合成(A251)
Figure PCTCN2016113838-appb-000341
1H NMR(500MHz,DMSO)δ8.83(s,1H),8.16(d,J＝5.4Hz,1H),7.96(s,1H),7.89(s,1H),7.82(s,1H),7.44(s,1H),7.39–7.33(m,1H),6.96(d,J＝5.8Hz,1H),6.90(s,1H),4.34(t,J＝8.2Hz,1H),4.11(s,1H),3.81(s,1H),3.26(d,J＝8.2Hz,1H).
LCMS:t＝2.00min,ESI:[M+H]+m/z 469.
实施例252：5-(2-((1,3-二甲基-1H-吡唑-5-基)氨基)嘧啶-4-基)-1-(2-(2-氟苯基)乙酰基)二氢吲哚-7-甲腈的合成(A252)
Figure PCTCN2016113838-appb-000342
1H NMR(400MHz,dmso)δ9.38(s,1H),8.45(d,J＝5.1Hz,1H),8.25(d,J＝8.3Hz,1H),7.44(d,J＝5.1Hz,1H),7.36–7.25(m,1H),7.21–7.10(m,1H),6.00(s,1H),4.28(t,J＝8.2Hz,1H),3.98(s,1H),3.54(s,1H),3.25–3.17(m,1H),2.06(s,1H).
LCMS:t＝1.96min,ESI:[M+H]+m/z468.
对比例C1：4-(6-氨基吡啶-3-基)-N-(1-甲基-1H-吡唑-5-基)嘧啶-2-胺的合成
Figure PCTCN2016113838-appb-000343
在25mL圆底烧瓶中依次加入A15(180mg,0.58mmol)，氢氧化钠(116mg，2.91mmol)，甲醇(5mL)和水(2mL)。80℃搅拌反应6h,TLC检测反应完全.反应液冷却到室温,减压浓缩.粗产品用硅胶柱层析纯化(二氯甲烷:甲醇＝5:1)得到黄色固体化合物C1(124mg,产率：80％)。
1HNMR(400MHz,CDCl3-d)δ8.75(d,1H,J＝1.6Hz)，8.38(d,1H,J＝5.2Hz)，8.10(dd,1H,J＝2.4Hz,8.8Hz)，7.49(d,1H,J＝2.0Hz)，7.10(d,1H,J＝5.6Hz)，6.83(s,1H)，6.56(d,1H,J＝8.8Hz)，6.34(d,1H,J＝1.6Hz)，4.81(s,2H)，3.80(s,3H)。
LCMS:m/z 268.2(M+H)+；RT＝0.648min。
对比例C2：4-(6-氨基吡啶-3-基)嘧啶-2-胺的制备：
Figure PCTCN2016113838-appb-000344
在干燥的50mL三口瓶中依次加入化合物C2-1(200mg，1.45mmol)，C2-2(188mg，1.45mmol)，[1,1’-双(二苯基膦基)二茂铁]二氯化钯(110mg，0.15mmol)，碳酸钾(300mg，2.17mmol)，1,4-二氧六环(8mL)和水(2mL)。氮气保护下加热到100摄氏度，反应3个小时。反应完毕后，倒入30mL水中，用乙酸乙酯(30mL×2)萃取，合并有机相。有机相依次用饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用Flash纯化(二氯甲烷：甲醇＝30：1～10:1)，得到产物C2(120mg，淡黄色固体)，产率：30％.
1HNMR(400MHz,MeOD-d4)δ8.76(d,1H,J＝1.6Hz)，8.59(dd,1H,J＝2.0Hz,9.2Hz)，8.31(d,1H,J＝6.4Hz)，7.36(d,1H,J＝6.4Hz)，7.09(d,1H,J＝9.2Hz)。
LCMS:m/z188.1(M+H)；RT＝0.29min(2min).
测试例1：本发明化合物对ERK激酶活性的测定
材料与仪器
ERK2enzyme(PV3595,Invitrogen)
Figure PCTCN2016113838-appb-000345
Kinase Assay Kit-Ser/Thr 3Peptide(PV3176)
Synergy 2Microplate Reader(BioTec)
ProxiPlate-384Plus F,Black 384-shallow well Microplate(Cat.6008269,PerkinElmer)
试验方法：
Z′-LYTETMSer/Thr 3Peptide Substrate，Phospho-peptide，5X Kinase Buffer，ATP，Development Reagent A，Development Buffer，Stop Reagent所有试剂平衡至室温准备加样。
检测化合物对ERK激酶活影响的筛选浓度从1μM(0.2μM)开始3倍梯度稀释，8个浓度，每个浓度取复孔，使用4％的DMSO作为共溶剂。反应完成后，向所有反应孔中加入5μl经Development Buffe稀释的Development Reagent A，室温反应1h后，向所有反应孔中加入5μl Stop Reagent终止反应，用Synergy 2Microplate Reader检测荧光信号(激发光波长为400nm，发射光波长为460nm、528nm)。
通过全活性孔和背景信号孔计算出每个孔的抑制率。实验平行重复两次。IC50值可通过一系列不同浓度下，受试化合物对于激酶的抑制数值进行计算。
表1本发明化合物对不同激酶活性的抑制率
化合物 ERK2(nM) 化合物 ERK2(nM) 化合物 ERK2(nM)
A1 B A32 B A57 D
A2 B A33 B A58 A
A3 A A34 B A59 B
A4 B A35 A A60 C
A5 B A36 B A61 C
A7 B A37 B A62 D
A9 B A38 C A63 B
A10 B A39 A A64 D
A11 C A40 B A65 A
A13 C A41 A A66 A
A14 B A42 B A67 A
A17 B A43 D A68 A
A18 B A44 B A69 A
A20 B A45 B A70 A
A21 B A46 C A71 A
A22 B A47 B A72 C
A23 C A48 B A73 A
A24 C A49 A A74 A
A25 B A50 C A75 A
A26 B A51 B A76 A
A27 B A52 B A77 A
A28 A A53 B A78 A
A29 B A54 C A79 A
A30 B A55 B A80 B
A31 A A56 A A81 B
A82 A A115 B A148 A
A83 B A116 B A149 D
A84 A A117 B A150 A
A85 A A118 B A151 B
A86 A A119 B A152 B
A87 C A120 B A153 B
A88 A A121 B A154 A
A89 A A122 A A155 B
A90 B A123 B A156 A
A91 D A124 B A157 B
A92 A A125 A A158 B
A93 B A126 A A159 B
A94 B A127 B A160 B
A95 A A128 B A161 A
A96 A A129 B A162 A
A97 A A130 A A163 A
A98 D A131 A A164 B
A99 B A132 A A165 B
A100 A A133 A A166 B
A101 B A134 A A167 A
A102 B A135 B A168 B
A103 A A136 B A169 B
A104 D A137 B A170 A
A105 A A138 A A171 A
A106 B A139 B A172 A
A107 A A140 B A173 A
A108 A A141 A A174 A
A109 C A142 A A175 B
A110 A A143 A A176 B
A111 B A144 A A177 A
A112 A A145 B A178 A
A113 B A146 B A179 A
A114 A A147 B A180 B
A181 C A204 A A227 A
A182 B A205 B A228 A
A183 A A206 A A229 B
A184 C A207 A A230 A
A185 A A208 A A231 A
A186 B A209 A A232 A
A187 B A210 A A233 A
A188 A A211 B A234 B
A189 A A212 B A235 A
A190 A A213 A A236 B
A191 A A214 B A237 A
A192 A A215 C A238 A
A193 A A216 A A239 A
A194 A A217 B A240 A
A195 B A218 C A241 A
A196 A A219 C A242 A
A197 D A220 C A243 A
A198 B A221 A A244 D
A199 A A222 B A245 B
A200 A A223 A A246 D
A201 C A224 B A247 A
A202 B A225 A A248 A
A203 A A226 A A249 A
A250 A A251 A A252 A
其中，A表示IC50≤10nM；B表示10nM<IC50≤100nM；C表示100nM<IC50≤1000nM；D表示IC50>1000nM。
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 (16)

  1. 一种式I化合物、其立体异构体、外消旋体、或其药学上可接受的盐：
    Figure PCTCN2016113838-appb-100001
    式中，X1、X2、X3、X4、X5和X6各自独立地选自：取代或未取代的CR5或N，其中，所述的“取代”指具有选自A组的一个或多个(如1、2、3或4个)取代基：-CN、-NH2、-CONH2、或-CON-(C1-C3烷基)；
    其中，R5选自下组：H、D、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、-OH、氰基、-CON(C1-C4烷基)2、-CONH2、卤素、-CF3、氨基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷基羰基、取代或未取代的C1-C8烷氧基羰基、取代或未取代的C1-C8羧基、取代或未取代的C1-C8酯基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的芳基、和取代或未取代的杂芳基；
    R1选自下组：H、取代或未取代的芳基乙酰基；
    R2选自下组：取代或未取代的C1-C10烷基、取代或未取代的5-8元芳基、取代或未取代的5-8元杂芳基、取代或未取代的3-8元环烷基、和取代或未取代的3-8元杂环基；或者R1和R2与相邻的N原子共同形成取代或未取代的5-8元杂环基；
    R3选自下组：H、取代或未取代的C1-C8烷基、-OH、氰基、卤素、C1-C8亚烷基羟基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的3-8元芳基、和取代或未取代的3-8元杂芳基；
    或者，R3和X4以及相邻的C和N原子共同形成取代或未取代的4-8元环，其中所述的环含有至少1个N杂原子并且总共含有1-3个选自O、S和N的杂原子，并且所述环为饱和或不饱和环；
    R4选自H、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、-CO(CR6R7)mR8、-SO2(CR6R7)mR8、-CONR9(CR6R7)mR8、-COO(CR6R7)mR8、氨基、C1-C8羧基；其中，m为0、1、2或3；
    各R6和R7各自独立地选自下组：H、D、取代或未取代的C1-C8烷基、C1-C8亚烷基羟基、取代或未取代的C1-C8烷氧基和卤素，或者R6与R7相连形成取代或未被取代的3至6元环；
    各R8选自下组：H、取代或未取代的C1-C8烷基、取代或未取代的5-8元芳基、取代或未取代的5-8元杂芳基、取代或未取代的3-8元环烷基、和取代或未取代的3-8元杂环基；
    各R9选自下组：H、取代或未取代的C1-C8烷基；
    其中，所述R1、R2、R3、R4、R5、R6、R7、R8、R9中，所述的“取代”指具有选自B组的一个或多个(如1、2、3、4或5个)取代基：D、卤素、-OH、-CN、、-CD3、 -COOH、-NH2、-NO2、C1-C4烷基、C1-C4卤代烷基、-C1-C4烷基-O-R11、C1-C8烷氧基、C1-C8烷胺基、(C1-C6烷基)COO-、C1-C6烷氧基羰基、取代或未取代的5-8元杂芳基羰基、N(R11R12)CO-、取代或未取代的C3-C6杂环基羰基、取代或未取代的C1-C4烷基磺酰基、C1-C4羟基烷基、C1-C4烷基氨基、氨基磺酰基、哌嗪磺酰基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、苄氧酰基、苄氧羰基；其中，R11、R12各自独立地选自：C1-C3烷基和H，其中，所述的“取代”指具有选自C组的一个或多个(如1、2、3个)取代基：C1-C6烷氧羰基、C1-C4烷基、C1-C4烷氧基、-OH、-NH2、Boc。
  2. 如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，其特征在于，R2为取代或未取代的4-6元饱和或不饱和的杂环基，其中所述的取代指具有一个或多个(如1-3个)选自下组的取代基：卤素、C1-C3烷基、-OH、氨基、氰基、CF3-、CF3CH2-、CD3-、C1-C8烷氧基、C1-C8烷胺基、C1-C4烷氧基羰基、C1-C4烷基磺酰基、C1-C4羟基烷基、苄氧羰基、(C1-C3烷基)2NCO-、未取代的哌啶基、或被一个或多个(如1-3个)C1-C4烷氧羰基取代的哌啶基。
  3. 如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，其特征在于，R4为-CO(CR6R7)mR8，且R8选自：H、取代或未取代的5-8元芳基、取代或未取代的5-8元杂芳基、取代或未取代的3-8元环烷基、和取代或未取代的3-8元杂环基，其中所述的取代指具有一个或多个(如1-5个)选自下组的取代基：卤素、C1-C3烷基、-OH、氨基、氰基、-CF3、C1-C8烷氧基、C1-C8烷胺基、C3-C8环烷基。
  4. 如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，其特征在于，R8选自下组：H、取代或取代基的苯基、取代或未取代的吡啶基、取代或未取代的吡唑基、取代或未取代的咪唑基、取代或未取代的噻吩基、取代或未取代的嘧啶基、或取代或未取代的环己基。
  5. 如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，其特征在于，所述式I化合物如下式Ia所示：
    Figure PCTCN2016113838-appb-100002
    其中，X1、X2、X3、X4、X5、X6各自独立地选自取代或未取代的CR5或N，，其中，所述的“取代”指具有选自A组的一个或多个(如1、2、3或4个)取代基：-CN、-NH2、-CONH2、或-CON-(C1-C3烷基)；
    R3选自下组：H、取代或未取代的C1-C8烷基、-OH、氰基、卤素、C1-C8亚烷基羟基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的3-8元芳基、和取代或未取代的3-8元杂芳基；
    R2、R4、R5的定义与权利要求1相同。
  6. 如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受 的盐，其特征在于，所述式Ia化合物如下式所示：
    Figure PCTCN2016113838-appb-100003
    其中，R3选自下组：H、取代或未取代的C1-C8烷基、-OH、氰基、卤素、C1-C8亚烷基羟基、取代或未取代的3-8元环烷基、取代或未取代的3-8元杂环基、取代或未取代的3-8元芳基、和取代或未取代的3-8元杂芳基；
    R2、R4、R5的定义与权利要求1相同。
  7. 如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，其特征在于，R2选自下组：
    Figure PCTCN2016113838-appb-100004
    其中，各Ra独立地选自：H、卤素、C1-C4烷氧基羰基、C1-C3烷基、-OH、氰基、氨基、-COOH、CF3-、CF3CH2-、CD3-、C1-C8烷胺基、C1-C4烷氧基羰基、C1-C4烷基磺酰基、C1-C4羟基烷基、苄氧羰基、取代或未取代的哌啶基、C1-C4烷氧基、取代或未取代的氨基羰基、取代或未取代的哌嗪基羰基、取代或未取代的四氢吡咯羰基、取代或未取代的哌嗪磺酰基、取代或未取代的C1-C4烷基羧基；其中，所述的取代基为具有一个或多个(如1-3个)选自下组的取代基：C1-C3烷基、C1-C4烷氧羰基、C1-C4烷氧基，其中，n为0、1、2或3。
  8. 如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，其特征在于，所述式I化合物如下式Ib所示：
    Figure PCTCN2016113838-appb-100005
    其中，
    X1、X2、X3、X5、X6各自独立地选自取代或未取代的CR5或N；
    p为0、1、2、3或4；
    q为1、2、3、4或5；
    且p+q≤5；
    Y和Z各自独立地选自-CRcRd、O、S、-NRc；其中各Rc、Rd各自独立地选自：H、取代或未取代的C1-C8烷基、-OH、氨基、卤素、氰基、取代或未取代的C1-C8亚烷基羟基、取代或未取代的C1-C8烷氧基、取代或未取代的胺基C1-C8烷基-、取代或未取代的C1-C8烷胺基，或者-CRcRd为-C(＝O)-；
    R2、R4、R5的定义与权利要求1相同。
  9. 如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐，其特征在于，在所述Ib化合物中，R2选自下组：
    Figure PCTCN2016113838-appb-100006
    其中，各Ra各自独立地选自：H、卤素、C1-C4烷氧基羰基、C1-C3烷基、-OH、氰基、氨基、-COOH、CF3-、CF3CH2-、CD3-、C1-C8烷胺基、C1-C4烷氧基羰基、C1-C4烷基磺酰基、C1-C4羟基烷基、苄氧羰基、取代或未取代的哌啶基、C1-C4烷氧基、取代或未取代的氨基羰基、取代或未取代的哌嗪基羰基、取代或未取代的四氢吡咯羰基、取代或未取代的哌嗪磺酰基、取代或未取代的C1-C4烷基羧基；其中，所述的取代基为具有一个或多个(如1-3个)选自下组的取代基：C1-C3烷基、C1-C4烷氧羰基、C1-C4烷氧基，n为0、1、2或3。
  10. 一种药物组合物，其包含治疗有效量的选自如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐中的一种或多种以及药学上可接受的赋形剂。
  11. 如权利要求1所述的化合物，其立体异构体、外消旋体、或其药学上可接受的盐，或权利要求10所述的药物组合物在制备用于预防和治疗与ERK激酶相关的疾病和ERK激酶靶向抑制剂的药物中的用途。
  12. 一种制备如权利要求1所述化合物的方法，其特征在于，包括步骤：
    a)在惰性溶剂中，在金属催化或者酸/碱催化下，(1e)与(1f)化合物进行反应，制得式I化合物；
    Figure PCTCN2016113838-appb-100007
    其中，X1、X2、X3、X4、X5、X6、R1、R2、R3各基团的定义如权利要求1所述；
    LG2为选自下组的离去基团：卤素、磺酸酯、甲硫基、甲基砜。
  13. 一种制备如权利要求1所述化合物的方法，其特征在于，包括步骤：
    b)在惰性溶剂中，在金属催化下，(1c)与(1g)化合物进行偶联反应，制得式I化合物；
    Figure PCTCN2016113838-appb-100008
    其中，X1、X2、X3、X4、X5、X6、R1、R2、R3各基团的定义如权利要求1所述；
    LG1为选自下组的离去基团：卤素、磺酸酯、硼酸、硼酸酯、硼酸盐、有机锡、有机锌；
    LG3为选自下组的离去基团：卤素、磺酸酯、硼酸、硼酸酯、硼酸盐。
  14. 一种非治疗性地抑制ERK激酶活性的方法，其特征在于，包括步骤：将权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐与ERK激酶接触，从而抑制ERK激酶。
  15. 一种如权利要求1所述的化合物、其立体异构体、外消旋体、或其药学上可接受的盐在制备预防和/或治疗与ERK激酶活性相关的疾病的药物中的用途。
  16. 如权利要求15所述的用途，其特征在于，所述的与ERK激酶活性相关的疾病选自下组：皮肤癌、大肠癌、卵巢癌、胰腺癌、肺癌、肾癌、肝癌、黑色素瘤、结直肠癌、急性骨髓性白血病、骨髓增生异常综合症、乳腺癌、胶质瘤。
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