WO2016050171A1 - 多环类间变性淋巴瘤激酶抑制剂 - Google Patents

多环类间变性淋巴瘤激酶抑制剂 Download PDF

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WO2016050171A1
WO2016050171A1 PCT/CN2015/090712 CN2015090712W WO2016050171A1 WO 2016050171 A1 WO2016050171 A1 WO 2016050171A1 CN 2015090712 W CN2015090712 W CN 2015090712W WO 2016050171 A1 WO2016050171 A1 WO 2016050171A1
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group
cancer
alkyl
amino
alkoxy
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PCT/CN2015/090712
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English (en)
French (fr)
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吴永谦
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山东轩竹医药科技有限公司
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Priority to JP2017517052A priority Critical patent/JP6554538B2/ja
Priority to ES15847288T priority patent/ES2796349T3/es
Priority to US15/515,056 priority patent/US10011592B2/en
Priority to CN201580052631.0A priority patent/CN107108586B/zh
Priority to KR1020177011948A priority patent/KR101909404B1/ko
Priority to EP15847288.6A priority patent/EP3202765B1/en
Publication of WO2016050171A1 publication Critical patent/WO2016050171A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Embodiments of the present invention provide a polycyclic anaplastic lymphoma kinase inhibitor, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a process for preparing the same, a pharmaceutical preparation containing the same, and a pharmaceutical composition, And the use of the compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof for the preparation of a medicament for the treatment and/or prevention of a cancer mediated by anaplastic lymphoma kinase or a non-cancerous related disease.
  • Anaplastic lymphoma kinase is a member of the receptor tyrosine kinase family, which recruits downstream proteins through autophosphorylation to express specific genes and regulate cell metabolism and growth.
  • the anaplastic lymphoma kinase was first discovered in the anaplastic large cell lymphoma (ALCL) and was later found to be highly expressed in non-small cell lung cancer (NSCLC).
  • Abnormal expression of ALK in certain ALCL/NSCLCs is derived from different chromosomal translocations. These chromosomal translocations can produce corresponding fusion proteins. Analysis of these fusion genes revealed that they all contain the gene sequence encoding the intracellular kinase region at the 3' end of the ALK gene, and the gene fragment fused to ALK contains a promoter element and a sequence encoding a self-dimerization, resulting in a cell. The fusion protein with ALK kinase activity is highly expressed and over-activated, causing malignant transformation of cells. Therefore, the activity of the intracellular kinase domain of ALK and the corresponding signaling pathway are important molecular mechanisms leading to the formation of ALCL.
  • ROS1 is currently a hot target gene in lung adenocarcinoma following ALK.
  • ROS1 is a member of the receptor tyrosine kinase family, and the incidence of ROS1 in NSCLC is about 1.7%.
  • the NSCLC became possible.
  • the second-generation ALK inhibitors currently on the market include Ceritinib from Novartis, and Alectinib from Roche's Chugai Company in Japan.
  • the ALK inhibitors in clinical phase include AZD-3463, AP26113 and so on.
  • embodiments of the present invention provide polycyclic anaplastic lymphoma kinase inhibitors that have a good effect on the treatment and/or prevention of ALK-mediated cancer or non-cancerous related diseases.
  • the technical solution is as follows:
  • R 1 is selected from -COR 5 , -CO 2 R 5 , -CONRR 5 , -SOR 5 , -SO 2 R 5 or -SO 2 NRR 5 ;
  • R 2 is selected from the group consisting of a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a halogenated C 1-6 alkyl group, and an amino group C 1- 6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkane Thiothio group, C 1-6 alkylcarbonyl group, C 1-6 alkylcarbonyloxy group, C 1-6 alkylsulfonylamino group, C 1-6 alkylaminosulfonyl group, (C 1-6 alkyl group) 2 aminosulfonyl or C 1-6 alkylsulfonyl;
  • R 3 is selected from a 5-14 membered heteroaryl group optionally substituted by 1 to 3 substituents W, or a 3-8 membered heterocyclic group optionally substituted by 1 to 3 substituents W,
  • W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 Amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl An oxy group, a C 1-6 alkylsulfonyl group, a C 2-8 alkenyl group or a C 2-8 alkynyl group;
  • R 4 is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a C 1-6 alkoxy group, a 3-8 membered carbocyclic ring-O-, a C 1-6 alkyl group, and a hydroxyl group C 1 .
  • R, R 5 are each independently selected from a hydrogen atom, a C 1-6 alkyl group or a 3-8 membered carbon ring;
  • A is selected from a 3-8 membered cycloalkyl group optionally substituted by a substituent Q, a 4-5 membered heterocyclic group containing 2 O, S and/or N atoms optionally substituted by a substituent Q, or optionally a 6-8 membered heterocyclic group having 1-2 O, S and/or N atoms substituted by a substituent Q selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, and a halogen atom.
  • R 1 is selected from -CO 2 R 5 , -CONRR 5 , -SO 2 R 5 or -SO 2 NRR 5 ;
  • R 2 is selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group or a halogenated C 1-6 alkyl group;
  • R 3 is selected from 5-8 membered heteroaryl groups containing 1-2 O, S and/or N, optionally substituted by 1-2 substituents W, or optionally substituted by 1-2 substituents W a 4-6 membered heterocyclic group containing 1-2 O, S and/or N,
  • W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 Amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyl An oxy group, a C 1-6 alkylsulfonyl group, a C 2-4 alkenyl group or a C 2-4 alkynyl group;
  • R 4 is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a halogenated C 1- 6 alkyl, hydroxy C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl or C 1-6 alkylcarbonyloxy;
  • R, R 5 are each independently selected from a hydrogen atom, a C 1-6 alkyl group or a 5-6 membered saturated or partially saturated carbocyclic ring;
  • A is selected from a 5-6 membered cycloalkyl group optionally substituted by a substituent Q, a 4-5 membered heterocyclic group containing 2 O, S and/or N atoms optionally substituted by a substituent Q, or optionally a 6-7 membered heterocyclic group having 1-2 O, S and/or N atoms substituted by a substituent Q selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, and a halogen atom. Or C 1-6 alkyl.
  • R 1 is selected from -SO 2 R 5 or -SO 2 NRR 5 ;
  • R 2 is selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group or a C 1-6 alkyl group;
  • R 3 is selected from a 5-6 membered heteroaryl group having 1-2 N atoms, optionally substituted by 1 to 2 substituents W, or 1-2, optionally substituted by 1 to 2 substituents W a 4-6 membered heterocyclic group of a N atom,
  • W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2
  • R 4 is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, and a C 1-6 An alkylamino group, a C 1-6 alkylcarbonyl group or a C 1-6 alkylcarbonyloxy group;
  • R, R 5 are each independently selected from a hydrogen atom or a C 1-6 alkyl group
  • A is selected from a 5-membered heterocyclic group containing 2 O, S and/or N atoms optionally substituted by 1-2 substituents Q, or 1-2 optionally substituted by 1-2 substituents Q a 6-membered heterocyclic group of O, S and/or N atoms, said substituent Q being selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom or a C 1-6 alkyl group.
  • R 1 is selected from -SO 2 R 5 or -SO 2 NRR 5 ;
  • R 2 is selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group or a C 1-4 alkyl group;
  • R 3 is selected from a 4-6 membered heterocyclic group having 1 to 2 N atoms, which may be optionally substituted by 1 to 2 substituents W;
  • W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2
  • R 4 is selected from a fluorine atom, a bromine atom or a chlorine atom
  • R, R 5 are each independently selected from C 1-4 alkyl
  • A is selected from a 5-membered heterocyclic group containing 2 O, S and/or N atoms optionally substituted by 1 substituent Q or a 6-membered heterocyclic group having 1 to 2 O, S and/or N atoms
  • the substituent Q is selected from a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom or a C 1-4 alkyl group.
  • R 1 is selected from -SO 2 R 5 or -SO 2 NRR 5 ;
  • R 2 is selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group or a C 1-4 alkyl group;
  • R 3 is selected from pyridyl, dihydropyridyl, tetrahydropyridyl, azetidinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, pyrazolyl, dihydropyrazolyl, tetrahydropyridyl An azolyl, imidazolyl, dihydroimidazolyl, tetrahydroimidazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, piperidinyl, piperazinyl or morpholinyl;
  • R 4 is selected from a fluorine atom, a bromine atom or a chlorine atom
  • R, R 5 are each independently selected from C 1-4 alkyl
  • A is selected from a 5-membered heterocyclic group having 2 O atoms or a 6-membered heterocyclic group having 1 to 2 O atoms, which is optionally substituted by 1 substituent Q, and the substituent Q is selected from a hydroxyl group and an amino group.
  • R 1 is selected from -SO 2 R 5 or -SO 2 NRR 5 ;
  • R 2 is selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a t-butyl group;
  • R 3 is selected from pyridyl, dihydropyridyl, tetrahydropyridyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl;
  • R 4 is selected from a fluorine atom, a bromine atom or a chlorine atom
  • R, R 5 are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;
  • A is selected from a 6-membered heterocyclic group containing 2 O atoms, which is optionally substituted by 1 substituent Q, which is selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, and a methyl group. , ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
  • R 3 is selected from the group consisting of tetrahydropyridyl, azetidinyl, tetrahydropyrrolyl, tetrahydropyrazolyl, tetrahydroimidazolyl, tetrahydropyrimidinyl, piperidinyl, piperazinyl or morpholinyl;
  • A is selected from a 5-membered heterocyclic group containing 2 O atoms, which is optionally substituted by 1 substituent Q, which is selected from a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom or C 1 -4 alkyl.
  • R 3 is selected from the group consisting of tetrahydropyridyl, azetidinyl, tetrahydropyrrolyl, pyrazolyl, tetrahydroimidazolyl, tetrahydropyrimidinyl, piperidinyl, piperazinyl or morpholinyl;
  • A is selected from a 6-membered heterocyclic group containing 2 O atoms, which is optionally substituted by 1 substituent Q, which is selected from a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom or C 1 -4 alkyl.
  • R 3 is selected from pyridyl, dihydropyridyl, tetrahydropyridyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, piperazinyl or morpholinyl;
  • A is selected from a 6-membered heterocyclic group having 1 O atom optionally substituted by 1 substituent Q selected from a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom or C 1 -4 alkyl.
  • R 3 is selected from a 1-2 N-containing 4-6 membered partially saturated heterocyclic group optionally substituted by 1-2 substituents W, and R 3 is bonded to the phenyl group through a carbon atom;
  • W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2
  • A is selected from a 6-membered heterocyclic group containing 1 O, S and/or N atom optionally substituted by 1-2 substituents Q, which is selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, a cyano group, A nitro group, a halogen atom or a C 1-6 alkyl group.
  • R 1 is selected from -SO 2 R 5 or -SO 2 NRR 5 ;
  • R 2 is selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group or a C 1-6 alkyl group;
  • R 3 is selected from a 4-6 membered saturated heterocyclic group having 1 to 2 N atoms, which is optionally substituted by 1 to 2 substituents W, and R 3 is bonded to the phenyl group through a carbon atom;
  • W is selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino;
  • R 4 is selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group;
  • R, R 5 are each independently selected from a hydrogen atom or a C 1-6 alkyl group
  • A is selected from a 5-membered heterocyclic group containing 2 O atoms optionally substituted by 1-2 substituents Q, or 6-membered with 1-2 O atoms optionally substituted by 1-2 substituents Q
  • the heterocyclic group, wherein the substituent Q is selected from a hydroxyl group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom or a C 1-6 alkyl group.
  • R 1 is selected from -SO 2 R 5 or -SO 2 NRR 5 ;
  • R 2 is selected from a hydrogen atom, a halogen atom, a nitro group, a cyano group, an amino group, a hydroxyl group, a carboxyl group or a C 1-4 alkyl group;
  • R 3 is selected from pyridyl, dihydropyridyl, tetrahydropyridyl, azetidinyl, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or morpholinyl;
  • R 4 is selected from a fluorine atom, a bromine atom or a chlorine atom
  • R, R 5 are independently selected from C 1-4 alkyl
  • A is selected from a 5-membered heterocyclic group having 2 N atoms or a 6-membered heterocyclic group having 1 to 2 N atoms, which is optionally substituted by 1 to 2 substituents Q, and the substituent Q is selected from a hydroxyl group. , amino, carboxyl, cyano, nitro, halogen atom or C 1-4 alkyl.
  • halogen atom described herein includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • C 1-6 alkyl group as used herein means a straight or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, "C 1-4 alkyl group", “C 1-3 alkyl group”, and the like. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, positive Pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2- Methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl Base, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2,3
  • C 2-8 alkenyl refers to a straight or branched or cyclic alkenyl group having from 2 to 8 carbon atoms containing at least one double bond, including, for example, "C 2-6 alkenyl”.
  • C 2-4 alkenyl examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2 -butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2 -methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl- 2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl 3-butenyl, 1,2-di
  • C 2-8 alkynyl refers to a straight or branched alkynyl group having 2 to 8 carbon atoms, including, for example, “C 2-6 alkynyl", “C 2 -4 alkynyl", “C 2-3 alkynyl” and the like, examples include, but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2- Pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl 2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentyne 1,1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyny
  • "" means C 1-6 alkyl-O-, C 1-6 alkyl-NH-, (C 1-6 alkyl) 2 -N-, C 1-6 alkyl-S-, C 1- 6- alkyl-C(O)-, C 1-6 alkyl-SO 2 NH-, C 1-6 alkyl-NHSO 2 -, (C 1-6 alkyl) 2 -NSO 2 -, C 1- A group formed by a 6- alkyl-SO 2 -, C 1-6 alkyl-C(O)-O
  • "" means C 1-4 alkyl-O-, C 1-4 alkyl-NH-, (C 1-4 alkyl) 2 -N-, C 1-4 alkyl-S-, C 1- 4- alkyl-C(O)-, C 1-4 alkyl-SO 2 NH-, C 1-4 alkyl-NHSO 2 -, (C 1-4 alkyl) 2 -NSO 2 -, C 1- A group formed by a 4- alkyl-SO 2 -, C 1-4 alkyl-C(O)-O
  • the oxy C 1-6 alkoxy group, hydroxy C 1-6 alkylamino group means one to more, for example, 1-4, 1-3, 1-2 halogen atoms, hydroxyl group, amino group, carboxyl group, C
  • the 1-6 alkoxy group is substituted with a hydrogen atom in a C 1-6 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-6 alkoxy group or a C 1-6 alkylamino group, respectively.
  • An oxy C 1-4 alkoxy group, a hydroxy C 1-4 alkylamino group means one to more, for example, 1-4, 1-3, 1-2 halogen atoms, a hydroxyl group, an amino group, a carboxyl group, C The 1-4 alkoxy group is substituted with a hydrogen atom in a C 1-4 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-4 alkoxy group or a C 1-4 alkylamino group, respectively.
  • 3-8 membered cycloalkyl refers to a monocyclic cyclic alkyl group derived from a hydrogen atom of 3 to 8 carbon atoms, including, for example, a "3-6 membered cycloalkyl group”, “4-7 membered cycloalkyl group”, “4-6 membered cycloalkyl group”, “5-6 membered cycloalkyl group” and the like.
  • Examples thereof include, but are not limited to, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, methylcyclopropane, dimethylcyclopropane, A A butane group, a dimethylcyclobutane group, a methylcyclopentyl group, a dimethylcyclopentanyl group, a methylcyclohexane group, a dimethylcyclohexane group or the like.
  • heteroaryl refers to a heteroaryl group having from 5 to 14 members having at least one hetero atom, including "5-8 membered heteroaryl", “6-14 members".
  • the heteroatom aryl group has nitrogen, oxygen, sulfur, and the like, and includes a case where a carbon atom, a nitrogen atom, and a sulfur atom are substituted by oxo.
  • it may be "5-8 membered heteroaryl group having 1-3 O, S and/or N", “5-8 membered heteroaryl group having 1-2 O, S and/or N”, " A 5-8 membered heteroaryl group containing 2-3 O, S and/or N".
  • the "5-8 membered heteroaryl group” described herein includes, for example, “5-7 membered heteroaryl group", “5-6 membered heteroaryl group” and the like. For example, it may be “5-6 membered heteroaryl group having 1-2 N” and “5-6 membered heteroaryl group having 2-3 N”.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2 , 3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 1,4-dioxadienyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl
  • the "6-14 membered fused heteroaryl group" as used herein includes, for example, “6-10 membered fused heteroaryl group”, “7-10 membered fused heteroaryl group”, “9-10 membered fused heteroaryl group”, etc. .
  • Examples include, but are not limited to, benzofuranyl, benzisofuranyl, benzothienyl, fluorenyl, isoindole, benzoxazolyl, benzimidazolyl, oxazolyl, benzotriazolyl , quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthryl, benzoxazinyl, pyridazinyl, quinazoline Base, quinoxalinyl, phenolzinyl, acridinyl, fluorenyl, naphthyridinyl, phenazine, phenothiazine, and the like.
  • 3-8 membered heterocyclyl refers to a single or saturated salt containing from 3 to 8 ring atoms and containing at least one hetero atom (eg 1, 2, 3, 4 or 5 heteroatoms). A group obtained by removing a hydrogen atom from a ring heterocyclic compound.
  • it may be: "3-5-membered heterocyclic group containing 2 O, S and/or N atoms", “6-8 membered heterocyclic group containing 1-2 O, S and/or N atoms", “4-6 membered heterocyclic group containing 1-2 O, S and/or N", “4-5 membered heterocyclic group containing 2 O, S and/or N atoms", "1-2 a 6-7 membered heterocyclic group of O, S and/or N atoms", "a 5-membered heterocyclic group containing 2 O, S and/or N atoms", "containing 1-2 O, S and/ Or a 6-membered heterocyclic group of N atom", "a 5-membered heterocyclic group containing 2 N atoms", “6-membered heterocyclic group containing 1-2 N atoms", “5 yuan containing 2 O atoms” "heterocyclic group”, "6-membered heterocyclic group having 1-2 O atoms", "6-membered
  • the 3-8 membered partially saturated monoheterocyclic group means a cyclic group containing a double bond or a hetero atom.
  • the 3-8-membered saturated monoheterocyclic group means a hetero atom-containing cyclic group which is all a saturated bond.
  • Examples include, but are not limited to, aziridine, 2H-azepine, diaziryl, 3H-diazapropenyl, azetidinyl, 1,4-dioxen Cyclohexane group, 1,3-dioxanyl group, 1,3-dioxolyl group, 1,4-dioxadienyl group, tetrahydrofuranyl group, dihydropyridyl group, Dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothiophenyl , 4,5-dihydrothiazolyl, dihydropyrimidinyl, tetrahydropyrimidinyl, piperidinyl, piperazinyl, morpholinyl,
  • heteroatom means N, O, C (O) , S, SO and / or SO 2 and the like, preferably N, O, S, more preferably N, O.
  • 3-8 membered carbocyclic ring refers to a saturated, partially saturated or unsaturated monocyclic compound containing from 3 to 8 carbon atoms. Examples include, for example, “3-7 membered carbon ring”, “3-6 membered carbocyclic ring”, “4-7 membered carbocyclic ring”, “4-6 membered carbon ring”, “5-6 membered carbon ring”, and the like.
  • Examples include, but are not limited to, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, cyclopentenyl, 1,3-cyclopentadienyl, Cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, phenyl, and the like.
  • a "5-6 membered saturated or partially saturated carbocyclic ring" is preferred.
  • partially saturated means that the ring portion includes at least one double or triple bond.
  • the embodiments of the present invention also provide two preparation methods of the above compounds, but are not limited to the following methods, and the reaction equation is as follows:
  • Intermediate 1 is dissolved in a suitable solvent (eg N,N-dimethylformamide) and an appropriate amount of N-bromo is added.
  • a suitable solvent eg N,N-dimethylformamide
  • Succinimide heated (for example, 30-70 ° C) stirring (for example, 10-20 hours), cooling to room temperature, quenching with water, extraction with an organic solvent (such as ethyl acetate), concentration, by appropriate method (such as silica gel column Purification by chromatography) gave Intermediate 2.
  • the intermediate 3 is dissolved in toluene and acetic acid, and an appropriate amount (for example, 0.5-1.5 equivalents) of N-iodosuccinimide is added at room temperature, stirred (for example, 1-2 hours), and the reaction is quenched with water, such as acetic acid.
  • the ethyl ester is extracted, concentrated, and purified by a suitable method (for example, silica gel column chromatography) to afford Intermediate 4.
  • the intermediate 4 and the starting material 1 are dissolved in a solvent (for example, dioxane), and a metal palladium catalyst (for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) is added, and an appropriate amount is added (for example, 1-2 equivalents of an inorganic base (such as potassium carbonate), heated (for example, 50-100 ° C) under nitrogen protection (for example, 1-3 hours), suction filtration, the filtrate is extracted with an organic solvent (such as ethyl acetate), combined The organic phase is purified by a suitable method (e.g., silica gel column chromatography) to afford Intermediate 5.
  • a solvent for example, dioxane
  • a metal palladium catalyst for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • an appropriate amount for example, 1-2 equivalents of an inorganic base (such as potassium carbonate), heated (
  • the intermediate 5 is dissolved in a suitable solvent (e.g., methanol), palladium on carbon is added, hydrogen is introduced at room temperature, stirred (e.g., 10-20 hours), filtered, and the filtrate is concentrated to afford intermediate 6.
  • a suitable solvent e.g., methanol
  • palladium on carbon is added, hydrogen is introduced at room temperature, stirred (e.g., 10-20 hours), filtered, and the filtrate is concentrated to afford intermediate 6.
  • the intermediate 7 and the intermediate 6 are dissolved in a solvent (for example, dioxane), and a metal palladium catalyst (for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) is added, and an appropriate amount is added.
  • a metal palladium catalyst for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • Inorganic base such as cesium carbonate
  • heated for example, 70-90 ° C
  • nitrogen protection for example, 12-18 hours
  • suction filtration filtrate concentration
  • the compound of the formula (I) of the present invention is obtained by purification by a suitable method (e.g., silica gel column chromatography).
  • the intermediate 1 is dissolved in a suitable solvent (for example, ethanol), and Pd/C is added thereto, and the reaction is carried out at room temperature under a hydrogen atmosphere (for example, 1-5 hours). After completion of the reaction, the solid is filtered off and the filtrate is concentrated to give Intermediate 2.
  • a suitable solvent for example, ethanol
  • the intermediate 3 and the starting material 1 are dissolved in a solvent (for example, dioxane), and a metal palladium catalyst (for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride) is added, and an appropriate amount is added (for example, 1-2 equivalents of an inorganic base (such as cesium carbonate), heating (for example, 50-100 ° C) reaction (for example, 3-8 hours), adding an organic solvent (such as ethyl acetate), drying, concentration, by appropriate methods (for example Purification by silica gel column chromatography gave Intermediate 4.
  • a solvent for example, dioxane
  • a metal palladium catalyst for example, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • an appropriate amount for example, 1-2 equivalents of an inorganic base (such as cesium carbonate), heating (for example, 50-100 ° C) reaction (for example, 3-8
  • the preparation method of the intermediate method 7 was prepared by referring to the preparation method.
  • Intermediate 4 is dissolved in a solvent (for example, pivalanol), heated (for example, 100 ° C - 130 ° C) reaction (for example, 10-16 hours), cooled, added with an organic solvent (such as ethyl acetate), alkaline
  • a solvent for example, pivalanol
  • an organic solvent such as ethyl acetate
  • the solution e.g., sodium bicarbonate
  • R 1 , R 2 , R 3 , R 4 and the A ring are as defined above, and X represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the "stereoisomer" of the compound of the formula (I) herein means that when the compound of the formula (I) has an asymmetric carbon atom, an enantiomer is produced, and when the compound has a carbon-carbon double bond or a cyclic structure, The cis-trans isomer is produced.
  • a tautomer is produced, and all enantiomers, diastereomers, racemic isomers, and cis of the compound of formula (I) are produced.
  • Trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof are included within the scope of the invention.
  • the desired enantiomerically pure compound can be obtained by chiral resolution: chromatography by a chiral stationary phase can be obtained. (such as high pressure preparative liquid chromatography, supercritical fluid chromatography).
  • Chiral fillers include, but are not limited to, Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
  • the pharmaceutically acceptable salt of any one of the compounds of the formula (I) herein refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including an organic acid salt, a mineral acid salt, an organic alkali salt, Inorganic alkali salt.
  • An embodiment of the present invention further provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising the above formula (I), and one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms. It is administered to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration.
  • oral administration it can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution, an oral suspension, a syrup or the like.
  • a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
  • parenteral administration it can be prepared as an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection.
  • the injection it can be produced by a conventional method in the prior art of pharmacy, and when the injection is formulated, the additive may be added or the drug may be used. The nature of the substance is added to a suitable additive.
  • rectal administration it can be made into a suppository or the like.
  • pulmonary administration it can be prepared as an inhalant or a spray.
  • Embodiments of the present invention further provide a compound comprising any of Formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more other anti-tumor agents and/or immunosuppressive agents, as described above.
  • Pharmaceutical composition comprising any of Formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more other anti-tumor agents and/or immunosuppressive agents, as described above.
  • the antitumor agent and/or immunosuppressant is an antimetabolite selected from the group consisting of capecitabine, gemcitabine, and pemetrexed disodium; or the antitumor agent and/or immunosuppressant is growth factor inhibitory And selected from the group consisting of pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib; or the antitumor agent and/or immunosuppressant is an antibody, Selected from Herceptin, bevacizumab; or the anti-tumor agent and/or immunosuppressant is a mitotic inhibitor selected from the group consisting of paclitaxel, vinorelbine, docetaxel, doxorubicin; or Antitumor agents and/or immunosuppressants are antitumor hormones selected from the group consisting of letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; or the
  • the antitumor agent and/or immunosuppressant is immunosuppressive, From everolimus, sirolimus, special cancer; or the antitumor agent and/or immunosuppressive agent is a purine analog selected from the group consisting of 6-mercaptopurine, 6-thioguanine, azathioprine; Or the anti-tumor agent and/or immunosuppressant is an antibiotic class selected from the group consisting of bacteriocin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, pucamycin; or The antitumor agent and/or immunosuppressant is a platinum complex selected from the group consisting of cisplatin and carboplatin; or the antitumor agent and/or immunosuppressant is an adrenocortical inhibitor selected from the group consisting of aminoglutethimide; Or the antitumor agent and/
  • Embodiments of the present invention also provide a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for treating and/or preventing ALK-mediated cancer or a non-cancerous related disease.
  • the cancer-related diseases are selected from the group consisting of brain tumors, lung cancer, non-small cell lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, Cervical cancer, endometrial cancer, colorectal cancer, liver cancer, hepatoblastoma, papillary renal cell tumor, head and neck squamous cell tumor, nephroblastoma, renal cancer, esophageal adenocarcinoma, esophageal squamous cell Cancer, non-Hodgkin's lymphoma, central nervous system tumor, female genital tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer Testis Pill cancer, small cell lung cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanom
  • Embodiments of the present invention also provide a compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutical composition thereof for use in the treatment and/or prevention of ALK-mediated Cancer or non-cancerous related diseases
  • the cancer-related diseases are selected from the group consisting of brain tumors, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical Cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-Hodgkin's lymphoma, central nervous system tumor, prostate cancer, thyroid cancer, small cell lung cancer, female reproduction Cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor
  • Embodiments of the present invention also provide a method of treating and/or preventing an ALK-mediated cancer or a non-cancerous related disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) herein, A pharmaceutically acceptable salt, a stereoisomer thereof or the pharmaceutical composition, wherein the cancer-related disease is selected from the group consisting of a brain tumor, a lung cancer, a squamous cell carcinoma, a bladder cancer, a gastric cancer, an ovarian cancer, and a peritoneal cancer.
  • pancreatic cancer breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-Hodgkin's lymphoma, central nervous system tumor, Prostate cancer, thyroid cancer, small cell lung cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, colon cancer, testicular cancer, non-small cell lung cancer, gastrointestinal interstitial Tumor, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma; non-cancerous related diseases, selected from benign hyperplasia of the skin or prostate.
  • the compound provided by the embodiment of the invention has a simple preparation process, high drug purity, stable quality, and is easy to carry out large-scale industrial production.
  • the compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof thereof has a drug-resistant cell such as BaF3 (ALK-F1174L), BaF3 (ALK-C1156Y), BaF3 (ALK-L1196M) or the like. Good inhibitory activity.
  • DTT Dithiothreitol (DL-Dithiothreitol)
  • SEB Enzyme Catalyst Buffer Solution (Supplement Enzymatic Buffer)
  • ALK Anaplastic Lymphoma Kinase
  • SA-XL665 Streptavidin-labeled donor (Streptavidin-XL665)
  • EDTA ethylenediaminetetraacetic acid
  • the full English name is derived from the kit instructions.
  • Test Samples Compounds 1, 2, 3, and 4 provided in the examples of the present invention, the chemical names and preparation methods thereof can be found in the preparation examples of the respective compounds.
  • Control drug Ceritinib, self-made (prepared by the preparation method of WO2008/073687A2).
  • Preparation of the 1 mM stock solution of the reference drug Weigh 1.48 mg of the reference drug, add appropriate amount of DMSO to dissolve, mix, and set aside.
  • Formulation of 1 mM stock solution of the compound weigh the appropriate amount of the compound (see the table below for the sample amount). Add appropriate amount of DMSO to dissolve, mix and set aside.
  • a 1 mM stock solution was separately taken and diluted with DMSO to prepare a solution having a concentration of 200 ⁇ M as a mother liquid.
  • the above mother liquor was diluted three times in DMSO to prepare a series of solutions, and then each concentration was diluted 80 times with ALK kinase buffer to prepare 2.5 ⁇ test solutions, respectively, at concentrations of 2500 nM and 833.33 nM. 277.78 nM, 92.59 nM, 30.86 nM, 10.29 nM, 3.43 nM, 1.14 nM, 0.38 nM, 0.13 nM, 0.04 nM.
  • the required 5 ⁇ ALK kinase solution, 5 ⁇ substrate solution, and 5 ⁇ ATP solution were separately prepared in ALK kinase buffer and used.
  • the desired concentration of SA-XL665 was prepared by using a detection buffer, and then mixed with an equal volume of tyrosine kinase antibody, and 10 ⁇ L of the prepared antibody solution was added to the corresponding wells to terminate the reaction. Incubate for 1 h at 25 °C.
  • the plate reader was read at 665 nm/615 nm.
  • the compounds provided by the examples of the present invention have good inhibitory activity against ALK kinase and can be used for treating kinase-related diseases, particularly ALK kinase-mediated diseases or conditions, and have significant clinical significance.
  • Test Specimens Compounds 5, 6, and 8 provided in the examples of the present invention, the chemical names and preparation methods thereof can be found in the preparation examples of the respective compounds.
  • Control drug Ceritinib, self-made (prepared by the preparation method of WO2008/073687 A2).
  • Coating Reagent #3 (12-sipper chip used in Caliper instrument), HEPES with a mother liquor concentration of 1000 mM, and EDTA with a mother liquor concentration of 0.5 M were taken from the coating solution with a mother liquor concentration of 4%.
  • Brij-35 with a mother liquor concentration of 30% was mixed with ultrapure water to make the final concentration of Coating Reagent#3 0.2%, the final concentration of HEPES was 100 mM, the final concentration of EDTA was 50 mM, and the final concentration of Brij-35 was 0.015%.
  • DMSO stock solution for the test sample weigh the appropriate amount of the compound (see the table below for the sample amount), add the appropriate amount of DMSO to dissolve, mix, and set aside.
  • the DMSO stock solution of the test sample was taken and diluted with DMSO to prepare a solution having a concentration of 50 ⁇ M.
  • a mother liquor As a mother liquor.
  • the above mother liquid was diluted four times in DMSO, and each concentration was diluted 10-fold with 1 time of kinase buffer to prepare a test solution of 5 times.
  • the required 2.5-fold ALK kinase solution and 2.5-fold polypeptide solution were separately prepared in 1 time kinase buffer, and used.
  • the reaction was terminated by adding 25 ⁇ L of stop solution to each of the corresponding wells.
  • the Caliper instrument reads the data and calculates the inhibition rate from the data.
  • Inhibition rate (%) (maximum - sample value) / (maximum - minimum value) ⁇ 100, curve fitting was performed using XLFIT software to obtain an IC50 value.
  • the compounds provided by the examples of the present invention have good inhibitory activity against ALK kinase and can be used for treating kinase-related diseases, particularly ALK kinase-mediated diseases or conditions, and have significant clinical significance.
  • Test sample Compound 1, Compound 2, Compound 3, Compound 4 and Compound 8 provided in the examples of the present invention, the chemical names and preparation methods thereof can be found in the preparation examples of the respective compounds.
  • Coating Reagent #3 (12-sipper chip used in Caliper instrument), HEPES with a mother liquor concentration of 1000 mM, and EDTA with a mother liquor concentration of 0.5 M were taken from the coating solution with a mother liquor concentration of 4%.
  • Brij-35 with a mother liquor concentration of 30% was mixed with ultrapure water to make the final concentration of Coating Reagent#3 0.2%, the final concentration of HEPES was 100 mM, the final concentration of EDTA was 50 mM, and the final concentration of Brij-35 was 0.015%.
  • DMSO stock solution for the test sample weigh the appropriate amount of the compound (see the table below for the sample amount), add the appropriate amount of DMSO to dissolve, mix, and set aside.
  • the DMSO stock solution of the test sample was taken and diluted with DMSO to prepare a solution having a concentration of 50 ⁇ M as a mother liquid.
  • the above mother liquid was diluted four times in DMSO, and each concentration was diluted 10-fold with 1 time of kinase buffer to prepare a test solution of 5 times.
  • the required 2.5-fold ROS1 kinase solution and 2.5-fold polypeptide solution were separately prepared in 1x kinase buffer, and used.
  • the reaction was terminated by adding 25 ⁇ L of stop solution to each of the corresponding wells.
  • the Caliper instrument reads the data and calculates the inhibition rate from the data.
  • Inhibition rate (%) (maximum - sample value) / (maximum - minimum value) ⁇ 100, curve fitting was performed using XLFIT software to obtain an IC50 value.
  • test results show that the compounds of the present invention have inhibitory activities against ROS1 kinase of less than 1 nM, and the inhibitory activity of Ceritinib against ROS1 kinase is greater than 10 nM, indicating that the compound of the present invention has better ROS1 kinase inhibitory activity than Ceritinib.
  • the advantages are even more pronounced in the treatment of kinase-related diseases.
  • Test Specimens Compounds 1-6 and 8 provided in the examples of the present invention, the chemical names and preparation methods thereof are shown in the preparation examples of the respective compounds.
  • the reference drug, Ceritinib was prepared (prepared by the preparation method of WO2008/073687A2), and its structural formula is as described in the background art.
  • DMSO dimethyl sulfoxide
  • MTS thiazole blue tetrazolium bromide
  • RPMI 1640 1640 medium (RPMI: Roswell Park Memorial Institute);
  • the cells were incubated with RPMI-1640 medium containing 10% fetal bovine serum, 100 U/ml penicillin, 100 mg/ml streptomycin in an incubator at 5% CO 2 and 37 ° C until 80% confluence, and was used.
  • the cells were digested with trypsin, centrifuged at 1000 rpm for 4 min, the supernatant was removed, resuspended in RPMI-1640 medium containing 2.5% fetal bovine serum, the cell density was adjusted, and 90 ⁇ L of the cell suspension was inoculated into a 96-well plate. The final cell density was obtained at 3000 cells/well; then cultured in a 5% CO 2 , 37 ° C incubator for 24 h.
  • test solution For the preparation of the test solution: weigh the appropriate amount of the test sample (see the table below for the sample amount), add the appropriate amount of DMSO to dissolve and dilute with DMSO to prepare a series of mother liquor (1000 ⁇ test solution), and then Diluted the mother liquor 100 times with the medium to obtain 10 ⁇ test solution, respectively, 10 ⁇ L of the solution was added to the corresponding well of the 96-well plate to obtain the final concentration of each test solution: 10 ⁇ M, 2.5 ⁇ M, 625 nM, 156 nM, 39 nM, 9.8 nM, 2.5 nM.
  • Vehicle control 0.1% DMSO.
  • Cell control cells were seeded only without compound.
  • Blank control medium, instrument zero.
  • the 96-well plate was cultured in a 37 ° C, 5% CO 2 incubator for 72 h.
  • the 96-well plate was placed in a 5% CO 2 and cultured in a 37 ° C incubator for 40 min.
  • cell viability (%) (OD sample value - OD blank value ) / (OD maximum - OD blank value ) ⁇ 100, curve fitting was performed using Graph prisim software, and IC 50 value was obtained.
  • OD maxima cell control without addition of compound plus vehicle
  • OD blank value blank control value
  • the cells were cultured to 80% confluence in RPMI-1640 medium containing 10% fetal calf serum in an incubator at 5% CO 2 and 37 ° C, and used.
  • the cells were digested with trypsin, centrifuged at 1000 rpm for 4 min, the supernatant was removed, and the cells were resuspended in RPMI-1640 medium containing 2.5% fetal bovine serum to adjust the cell density to 2 ⁇ 10 4 /mL, and the cell suspension was 100 ⁇ L. Inoculation into 96-well plates yielded a final cell density of 2000 cells/well.
  • test solution Preparation of test solution: Weigh the appropriate amount of the test sample (see the table below for the sample amount), add appropriate amount of DMSO, dissolve and mix, and dilute the solution with DMSO to obtain a series of solutions. spare.
  • Vehicle control 0.5% DMSO.
  • Cell control cells were seeded only without compound.
  • Blank control medium, instrument zero.
  • the 96-well plate was cultured for 96 hours in an incubator at 5% CO 2 and 37 ° C.
  • the 396-well plate was incubated with a microplate shaker in the dark for 2 min to lyse the cells.
  • the microplate reader reads the result in luminescence mode.
  • OD max cell control without solvent plus vehicle
  • OD blank medium blank
  • the compounds provided in the examples of the present invention have good inhibitory activity against BaF3 (ALK-F1174L), BaF3 (ALK-C1156Y), BaF3 (ALK-L1196M) cells, and are superior to Ceritinib, indicating the compounds provided by the embodiments of the present invention. It has a strong inhibitory effect on ALK-resistant cells and has important clinical significance in the treatment of diseases caused by ALK mutations.
  • Test sample Compound 4, self-made, the chemical name and preparation method are shown in the preparation examples of the respective compounds.
  • test sample Take the appropriate amount of the test sample (see the table below for the sample amount), add the prepared solvent and place it in the tissue grinder, and disperse it at 1000 rpm to obtain the solution.
  • HP- ⁇ -CD hydroxypropyl beta-cyclodextrin
  • test solution is administered according to the following method:
  • the blood collection time point is set as follows:
  • Iv 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h after drug administration.
  • Po 0.167h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h after drug administration.
  • protein precipitation method take 30 ⁇ L of plasma, add 200 ⁇ L of internal standard (containing acetonitrile solution with a concentration of 50 ng/mL of Alectinib), vortex at 1000 rpm for 10 min, then centrifuge at 4000 rpm for 20 min, take 100 ⁇ L of the supernatant, and add 100 ⁇ L. Water, vortex mixing, LC-MS/MS analysis.
  • internal standard containing acetonitrile solution with a concentration of 50 ng/mL of Alectinib
  • the bioavailability of the compound 4 is between 30% and 50%, indicating that the compound provided by the embodiment of the present invention has good pharmacokinetic properties in rats, and has good drug-forming properties and clinical development prospects.
  • NBS N-bromosuccinimide
  • PE petroleum ether
  • 6-Methyl-4-nitrobenzo[d][1,3]dioxole (5.1 g, 28.2 mmol) was dissolved in DMF (100 mL) and NBS (10 g, 56.2 mmol). The reaction was stirred for 16 hours while heating to 55 °C. After completion of the reaction, it was cooled to room temperature, and then water (200 mL) was added, and ethyl acetate (200 mL ⁇ 3) was extracted and the organic phase was combined. The organic phase was washed with aq. EtOAc EtOAc (EtOAc m. %).
  • N,N-Dimethyl-2-nitrobenzenesulfonamide (2.5 g, 10.9 mmol) was dissolved in methanol (100 mL), palladium carbon (250 mg) was added, and the mixture was stirred at room temperature for 12 hours. The palladium on carbon was removed by rotary evaporation to give the product (2 g, yield: 92%).
  • 6-Bromo-8-iodo-7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (8 g, 21.62 mmol) was dissolved in dioxane ( In 100 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 ( 2H)-carboxylate (6 g, 19.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium chloride dichloromethane complex (800 mg), potassium carbonate (8.03 g, 58.2 mmol) The reaction was carried out at 90 ° C for 16 hours under nitrogen atmosphere.
  • 6-Bromo-7-methyl-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin (7.3 g, 26.6 mmol) was dissolved in ethanol (150 mL) and added Acetic acid (30 mL) and iron powder (7.4 g, 132 mmol) were stirred and stirred at 80 ° C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered, and then filtered, and ethyl acetate (200 mL) The organic phase was washed with aq. EtOAc EtOAc (EtOAc m. %).
  • 6-Bromo-7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (4.5 g, 18.4 mmol) was dissolved in toluene (40 mL). (6.2 g, 27.6 mmol) and acetic acid (1.5 mL) were stirred at room temperature for 2 hr. After completion of the reaction, 50 mL of ice water was added, and extracted with ethyl acetate (100 mL ⁇ 3), and the organic phase was combined. The organic phase was washed with aq. EtOAc EtOAc (EtOAc m. %).
  • tert-Butyl 3-oxopyrrolidine-1-carboxylate (5.0 g, 27 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium diisopropylamide (20 mL) was slowly added dropwise to the system at -78 °C. 40 mmol, 2 M), after stirring for 10 minutes, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (11.6 g, 32.5 mmol) in tetrahydrofuran (50 mL) The solution was stirred for 30 minutes and then allowed to react to room temperature for 2 hours. The reaction was completed and concentrated to give a crude material which was taken to the next step without purification.
  • tert-Butyl 3-hydroxyazetidine-1-carboxylate (2.0 g, 11.5 mmol) was dissolved in 50 mL of tetrahydrofuran and triethylamine (2.34 g, 23.1 mmol). Under ice water bath, methanesulfonyl chloride (1.58 g, 13.8 mmol) was slowly added, and the mixture was warmed to room temperature, and the reaction was continued for 4 hours. After the reaction was completed, the solvent was evaporated, evaporated, evaporated, evaporated Filtration and removal of the solvent by rotary evaporation afforded product (2.6 g, ⁇ RTIgt;
  • 2-methoxy-4-methyl-6-nitrophenol (20.0 g, 0.109 mol) was added to 150 mL of hydrobromic acid (80%), 15 g of tetrabutylammonium fluoride was added, and heated to 110 ° C. Reaction for 18 hours. After the reaction was completed, 800 mL of water was added, and the mixture was extracted with 5 ⁇ 400 mL of ethyl acetate. The solvent was removed by EtOAc (EtOAc)EtOAc.
  • 6-Bromo-7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (8 g, 32.77 mmol) was dissolved in 100 mL of toluene, and 5 mL of acetic acid and N were added.
  • - Iodobutylimide (11.1 g, 49.34 mmol)
  • the reaction was completed, extracted with 100 mL of water and ethyl acetate (3 ⁇ 200 mL).
  • the organic phase was combined, washed with 200 mL of sodium hydrogensulfite solution, and the organic phase was evaporated to remove solvent.
  • 2,4,5-Trichloropyrimidine (4.42 g, 24.1 mmol) was dissolved in 25 mL of N,N-dimethylformamide, and sodium hydride (60%) (1.61 g, 40.2 mmol) After 10 minutes, 2-(isopropylsulfonyl)aniline (4.0 g, 20.1 mmol) was slowly added and allowed to react at room temperature for 16 hours. After the reaction was completed, 100 mL of water was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Yield 28.7%).
  • 6-methyl-8-nitrochroman (4 g, 20.7 mmol) was added.
  • Ethanol 50 mL
  • Pd/C 0.5 g, 10%
  • hydrogen gas was introduced, and the reaction was carried out for 3 hours at room temperature.
  • the reaction was completed by LC-MS, filtered, filtered, and washed with ethyl acetate (50 mL ⁇ 3). The filtrate was collected, and the solvent was removed by rotary evaporation.

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Abstract

通式(Ⅰ)所示的多环类间变性淋巴瘤激酶抑制剂、其药学上可接受的盐或其立体异构体，其中R1、R2、R3、R4和A环如说明书中所定义。还涉及这些化合物的制备方法，含有这些化合物的药物制剂和药物组合物，以及该化合物、其药学上可接受的盐或其立体异构体在制备治疗和/或预防由间变性淋巴瘤激酶介导的癌症或非癌性相关疾病的药物中的应用。

Description

多环类间变性淋巴瘤激酶抑制剂 技术领域
本发明的实施例提供一种多环类间变性淋巴瘤激酶抑制剂、其药学上可接受的盐或其立体异构体，这些化合物的制备方法，含有这些化合物的药物制剂和药物组合物，以及该化合物、其药学上可接受的盐或其立体异构体在制备治疗和/或预防由间变性淋巴瘤激酶介导的癌症或非癌性相关疾病的药物中的应用。
背景技术
间变性淋巴瘤激酶(Anaplastic lymphoma kinase，ALK)是受体酪氨酸激酶家族成员，可通过自身磷酸化募集下游蛋白，进而表达特定的基因，调节细胞代谢和生长。间变性淋巴瘤激酶最早发现于间变性大细胞淋巴瘤(Anaplastic large cell lymphoma，ALCL)中，后来发现在非小细胞肺癌(NSCLC)中亦有高表达。
ALK在某些ALCL/NSCLC中的异常表达来源于不同的染色体易位。这些染色体易位均可产生相应的融合蛋白。对这些融合基因分析表明，它们都含有ALK基因3’端编码胞内激酶区的基因序列，而与ALK融合的基因片段均含启动子元件及编码介导自身二聚化的序列，从而导致细胞内具有ALK激酶活性的融合蛋白高表达及过度激活，引起细胞的恶性转化。所以，ALK胞内激酶区的活性及相应的信号传导途径是导致ALCL形成的重要分子机制。ROS1是目前继ALK之后在肺腺癌中研究比较火热的靶向基因。ROS1是受体酪氨酸激酶家族的一员，ROS1在NSCLC中的发病率为1.7％左右。ROS1和间变性淋巴瘤激酶ALK之间在氨基酸激酶结构域范围内有49％的同源性，并且在ATP结合位点77％的存在同一性，这使得运用ALK激酶抑制剂治疗ROS1重排阳性的NSCLC成为可能。
由此可见，研发针对ALK/ROS1的小分子抑制剂，可以有效的降低突变的ALK/ROS1基因对下游蛋白的影响，进而影响到肿瘤细胞侵袭、增殖等效应，最终影响肿瘤细胞的生长，起到抗肿瘤的作用。目前已经有辉瑞公司的 克唑替尼(Crizotinib)成功上市，其针对EML4-ALK突变的非小细胞肺癌具有良好的疗效，得到业界的广泛认可，并且伴随Crizotinib上市的还有专门的诊断试剂盒，在药物应用之前，先通过试剂盒测定患者是否存在ALK突变，对于特定的患者，ALK抑制剂展示出了良好的抑制活性。并且Crizotinib针对ROS1的研究已经进入临床阶段，获得了突破性药物治疗地位。但已有大量临床证明Crizotinib，对ALK fusion的患者通常在1-2年后出现耐药。Crizotinib产生耐药的机制非常复杂，大约1/3是由于ALK出现突变，这些突变位点主要有L1196M，C1156Y，F1174L等。因此，设计并筛选对Crizotinib产生耐药的患者也有良好的疗效的二代ALK抑制剂，具有显著的临床意义。
目前上市的二代ALK抑制剂包括Novartis的Ceritinib，Roche旗下日本chugai公司的Alectinib，正在临床阶段的ALK抑制剂有AZD-3463，AP26113等。
Figure PCTCN2015090712-appb-000001
因此，通过化合物结构修饰寻找新的对ALK fusion及耐药突变有非常好的抑制活性的小分子化合物结构，努力改善化合物的理化性质，提高成药性， 如提高化合物的生物利用度，对于临床上因ALK突变引起的疾病的治疗，具有重要的意义。
发明内容
为开发针对ALK的小分子抑制剂，本发明的实施例提供了对治疗和/或预防ALK介导的癌症或非癌性相关疾病具有良好效果的多环类间变性淋巴瘤激酶抑制剂。技术方案为如下：
方案1.通式(Ⅰ)所述的化合物、其药学上可接受的盐或其立体异构体：
Figure PCTCN2015090712-appb-000002
其中，
R1选自-COR5，-CO2R5，-CONRR5，-SOR5，-SO2R5或-SO2NRR5；
R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、氨基C1-6烷基、C1-6烷氧基、羟基C1-6烷氧基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基硫基、C1-6烷基羰基、C1-6烷基羰基氧基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、(C1-6烷基)2氨基磺酰基或C1-6烷基磺酰基；
R3选自任选被1-3个取代基W取代的5-14元杂芳基，或任选被1-3个取代基W取代的3-8元杂环基，
W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C1-6烷基羰基、C1-6烷基羰基氧基、C1-6烷基磺酰基、C2-8烯基或C2-8炔基；
R4选自氢原子、卤素原子、氰基、硝基、氨基、羟基、羧基、C1-6烷氧基、3-8元碳环-O-、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、羟基C1-6烷氧基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基氨基、C1-6烷基羰基、C1-6烷基羰基氧基或(C1-6烷基)2氨基；
R、R5分别独立地选自氢原子、C1-6烷基或3-8元碳环；
A选自任选被取代基Q取代的3-8元环烷基，任选被取代基Q取代的含2个O、S和/或N原子的4-5元杂环基，或任选被取代基Q取代的含1-2个O、S和/或N原子的6-8元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C2-8烯基、C2-8炔基或3-8元杂环基。
方案2.如方案1所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R1选自-CO2R5、-CONRR5、-SO2R5或-SO2NRR5；
R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基、C1-6烷基、羟基C1-6烷基或卤代C1-6烷基；
R3选自任选被1-2个取代基W取代的含1-2个O、S和/或N的5-8元杂芳基，或任选被1-2个取代基W取代的含1-2个O、S和/或N的4-6元杂环基，
W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C1-6烷基羰基、C1-6烷基羰基氧基、C1-6烷基磺酰基、C2-4烯基或C2-4炔基；
R4选自氢原子、卤素原子、氰基、硝基、氨基、羟基、羧基、C1-6烷氧基、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、羟基C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6烷基羰基或C1-6烷基羰基氧基；
R、R5分别独立地选自氢原子、C1-6烷基或5-6元饱和或部分饱和的碳环；
A选自任选被取代基Q取代的5-6元环烷基，任选被取代基Q取代的含2个O、S和/或N原子的4-5元杂环基，或任选被取代基Q取代的含1-2个O、S和/或N原子的6-7元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-6烷基。
方案3.如方案2所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R1选自-SO2R5或-SO2NRR5；
R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基或C1-6烷基；
R3选自任选被1-2个取代基W取代的含1-2个N原子的5-6元杂芳基，或任选被1-2个取代基W取代的含1-2个N原子的4-6元杂环基，
W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷基羰基、C1-6烷基羰基氧基或C1-6烷基磺酰基；
R4选自氢原子、卤素原子、氰基、硝基、氨基、羟基、羧基、C1-6烷氧基、C1-6烷基、卤代C1-6烷基、C1-6烷基氨基、C1-6烷基羰基或C1-6烷基羰基氧基；
R、R5分别独立地选自氢原子或C1-6烷基；
A选自任选被1-2个取代基Q取代的含2个O、S和/或N原子的5元杂环基，或任选被1-2个取代基Q取代的含1-2个O、S和/或N原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-6烷基。
方案4.如方案3所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R1选自-SO2R5或-SO2NRR5；
R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基或C1-4烷基；
R3选自任选被1-2个取代基W取代的含1-2个N原子的4-6元杂环基；
W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-4烷基、C1-4烷氧基、C1-4烷基氨基、(C1-4烷基)2氨基、卤代C1-4烷基、卤代C1-4烷氧基、C1-4烷基羰基、C1-4烷基羰基氧基或C1-4烷基磺酰基；
R4选自氟原子、溴原子或氯原子；
R、R5分别独立地选自C1-4烷基；
A选自任选被1个取代基Q取代的含2个O、S和/或N原子的5元杂环基或含1-2个O、S和/或N原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-4烷基。
方案5.如方案3所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R1选自-SO2R5或-SO2NRR5；
R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基或C1-4烷基；
R3选自吡啶基、二氢吡啶基、四氢吡啶基、氮杂环丁烷基、吡咯基、二氢吡咯基、四氢吡咯基、吡唑基、二氢吡唑基、四氢吡唑基、咪唑基、二氢咪唑基、四氢咪唑基、嘧啶基、二氢嘧啶基、四氢嘧啶基、哌啶基、哌嗪基或吗啉基；
R4选自氟原子、溴原子或氯原子；
R、R5分别独立地选自C1-4烷基；
A选自任选被1个取代基Q取代的含2个O原子的5元杂环基或含1-2个O原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-4烷基。
方案6.如方案5所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R1选自-SO2R5或-SO2NRR5；
R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基、甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基；
R3选自吡啶基、二氢吡啶基、四氢吡啶基、吡咯基、二氢吡咯基、四氢吡咯基、氮杂环丁烷基、哌啶基、哌嗪基或吗啉基；
R4选自氟原子、溴原子或氯原子；
R、R5分别独立地选自甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基；
A选自任选被1个取代基Q取代的含2个O原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子、甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基。
方案7.如方案5所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R3选自四氢吡啶基、氮杂环丁烷基、四氢吡咯基、四氢吡唑基、四氢咪唑基、四氢嘧啶基、哌啶基、哌嗪基或吗啉基；
A选自任选被1个取代基Q取代的含2个O原子的5元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-4烷基。
方案8.如方案5所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R3选自四氢吡啶基、氮杂环丁烷基、四氢吡咯基、吡唑基、四氢咪唑基、四氢嘧啶基、哌啶基、哌嗪基或吗啉基；
A选自任选被1个取代基Q取代的含2个O原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-4烷基。
方案9.如方案5所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R3选自吡啶基、二氢吡啶基、四氢吡啶基、吡咯基、二氢吡咯基、四氢吡咯基、氮杂环丁烷基、哌啶基、哌嗪基或吗啉基；
A选自任选被1个取代基Q取代的含1个O原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-4烷基。
方案10.如方案3所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R3选自任选被1-2个取代基W取代的含1-2个N的4-6元部分饱和杂环基，且R3通过碳原子与苯基相连接；
W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷基羰基、C1-6烷基羰基氧基或C1-6烷基磺酰基；
A选自任选被1-2个取代基Q取代的含1个O、S和/或N原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-6烷基。
方案11.如方案3所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R1选自-SO2R5或-SO2NRR5；
R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基或C1-6烷基；
R3选自任选被1-2个取代基W取代的含1-2个N原子的4-6元饱和杂环基，且R3通过碳原子与苯基相连接；
W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基；
R4选自氢原子、卤素原子、氰基、硝基、氨基、羟基、羧基、C1-6烷氧 基、C1-6烷基；
R、R5分别独立地选自氢原子或C1-6烷基；
A选自任选被1-2个取代基Q取代的含2个O原子的5元杂环基，或任选被1-2个取代基Q取代的含1-2个O原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-6烷基。
方案12.如方案3所述的化合物、其药学上可接受的盐或其立体异构体：
其中，
R1选自-SO2R5或-SO2NRR5；
R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基或C1-4烷基；
R3选自吡啶基、二氢吡啶基、四氢吡啶基、氮杂环丁烷基、吡咯基、二氢吡咯基、四氢吡咯基、哌啶基、哌嗪基或吗啉基；
R4选自氟原子、溴原子或氯原子；
R、R5独立地选自C1-4烷基；
A选自任选被1-2个取代基Q取代的含2个N原子的5元杂环基或含1-2个N原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-4烷基。
本发明实施例中的部分化合物
Figure PCTCN2015090712-appb-000003
Figure PCTCN2015090712-appb-000004
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面对本发明实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于所描述的本发明的实施例，本领域普通技术人员在无需创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
本文所述的“卤素原子”包括氟原子、氯原子、溴原子和碘原子等。
本文所述的“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C1-4烷基”、“C1-3烷基”等，实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、2-甲基丙基、1-甲基丙基、1,1-二甲基乙基、正戊基、3-甲基丁基、2-甲基丁基、1-甲基丁基、1-乙基丙基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。
本文所述的“C2-8烯基”是指含有至少一个双键的碳原子数为2-8的直链或支链或环状的烯基，包括例如“C2-6烯基”、“C2-4烯基”、“C2-3烯基”、“C3-6环烯基”等，实例包括但不限于：乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、2-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1-乙基-2-丙烯基、2-己烯基、3-己烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、1-甲基-2-戊烯基、3-甲基-2-戊烯基、2-甲基-3-戊烯基、1-甲基-4-戊烯基、3-甲基-4-戊烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-3-丁烯基、1,3-二 甲基-2-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-2-丁烯基、2,3-二甲基-1-丁烯基、2-乙基-1-丁烯基、2-乙基-3-丁烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、4-辛烯基、1,3-丁二烯基、2,4-戊二烯基、1,4-己二烯基、2,4-己二烯基、1,5-庚二烯基、2,5-庚二烯基、2,6-辛二烯基、环戊烯基、1,3-环戊二烯基、环己烯基、1,4-环己二烯基、环庚烯基、1,4-环庚二烯基、环辛烯基等。
本文所述的“C2-8炔基”是指含有三键的碳原子数为2-8的直链或支链的炔基，其中包括例如“C2-6炔基”、“C2-4炔基”、“C2-3炔基”等，实例包括但不限于：乙炔基、1-丙炔基、2-丁炔基、1-甲基-2-丙炔基、2-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-甲基-3-丁炔基、1,1-二甲基-2-丙炔基、1-乙基-2-丙炔基、2-己炔基、3-己炔基、1-甲基-2-戊炔基、1-甲基-3-戊炔基、2-甲基-3-戊炔基、1,1-二甲基-3-丁炔基、2-乙基-3-丁炔基、2-庚炔基、3-庚炔基、4-甲基-2-己炔基、5-甲基-2-己炔基、2-甲基-3-己炔基、5-甲基-3-己炔基、2-甲基-4-己炔基4-甲基-5-己炔基、2-辛炔基、3-辛炔基、4-辛炔基、4-甲基-2-庚炔基、5-甲基-3-庚炔基、6-甲基-3-庚炔基、2-甲基-4-庚炔基、2-甲基-5-庚炔基、3-甲基-6-庚炔基等。
本文所述的“C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、C1-6烷基硫基、C1-6烷基羰基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、(C1-6烷基)2氨基磺酰基、C1-6烷基磺酰基、C1-6烷基羰基氧基”是指以C1-6烷基-O-、C1-6烷基-NH-、(C1-6烷基)2-N-、C1-6烷基-S-、C1-6烷基-C(O)-、C1-6烷基-SO2NH-、C1-6烷基-NHSO2-、(C1-6烷基)2-NSO2-、C1-6烷基-SO2-、C1-6烷基-C(O)-O-方式形成的基团，其中“C1-6烷基”的定义如前文所述。
本文所述的“C1-4烷氧基、C1-4烷基氨基、(C1-4烷基)2氨基、C1-4烷基硫基、C1-4烷基羰基、C1-4烷基磺酰氨基、C1-4烷基氨基磺酰基、(C1-4烷基)2氨基磺酰基、C1-4烷基磺酰基、C1-4烷基羰基氧基”是指以C1-4烷基-O-、C1-4烷基-NH-、(C1-4烷基)2-N-、C1-4烷基-S-、C1-4烷基-C(O)-、C1-4烷基-SO2NH-、C1-4烷基-NHSO2-、(C1-4烷基)2-NSO2-、C1-4烷基-SO2-、C1-4烷基-C(O)-O-方式形成的基团，其中“C1-4烷基”的定义如前文所述。
本文所述的“卤代C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、C1-6烷氧基C1-6烷基、羟基C2-8烯基、羧基C2-8烯基、羟基C2-8炔基、羧基C2-8炔基、卤 代C1-6烷氧基、羟基C1-6烷氧基、C1-6烷氧基C1-6烷氧基、羟基C1-6烷基氨基”是指一至多个，例如1-4个、1-3个、1-2个卤素原子、羟基、氨基、羧基、C1-6烷氧基分别取代C1-6烷基、C2-8烯基、C2-8炔基、C1-6烷氧基、C1-6烷基氨基中的氢原子所形成的基团。
本文所述的“卤代C1-4烷基、羟基C1-4烷基、氨基C1-4烷基、C1-4烷氧基C1-4烷基、羟基C2-6烯基、羧基C2-6烯基、羟基C2-6炔基、羧基C2-6炔基、卤代C1-4烷氧基、羟基C1-4烷氧基、C1-4烷氧基C1-4烷氧基、羟基C1-4烷基氨基”是指一至多个，例如1-4个、1-3个、1-2个卤素原子、羟基、氨基、羧基、C1-4烷氧基分别取代C1-4烷基、C2-6烯基、C2-6炔基、C1-4烷氧基、C1-4烷基氨基中的氢原子所形成的基团。
本文所述的“3-8元环烷基”，是指3-8个碳原子的烷烃部分去除一个氢原子衍生的单环环状烷基，包括例如“3-6元环烷基”、“4-7元环烷基”、“4-6元环烷基”、“5-6元环烷基”等。其实例包括但不限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基、甲基环丙烷基、二甲基环丙烷基、甲基环丁烷基、二甲基环丁烷基、甲基环戊烷基、二甲基环戊烷基、甲基环己烷基、二甲基环己烷基等。
本文所述的“5-14元杂芳基”是指含有至少一个杂原子的环原子数为5-14元的杂芳基，包括“5-8元杂芳基”、“6-14元稠杂芳基”，所述的杂原子有氮、氧和硫等，同时包括碳原子、氮原子和硫原子被氧代的情况。例如可以为“含1-3个O、S和/或N的5-8元杂芳基”、“含1-2个O、S和/或N的5-8元杂芳基”、“含2-3个O、S和/或N的5-8元杂芳基”。
本文所述的“5-8元杂芳基”，包括例如“5-7元杂芳基”、“5-6元杂芳基”等。例如可以为“含1-2个N的5-6元杂芳基”、“含2-3个N的5-6元杂芳基”。实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮、4-吡啶酮、嘧啶基、1,4-二氧杂环己二烯基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等，优 选为“5-6元杂芳基”。
本文所述的“6-14元稠杂芳基”，包括例如“6-10元稠杂芳基”、“7-10元稠杂芳基”、“9-10元稠杂芳基”等。实例包括但不限于：苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮、4-喹啉酮、1-异喹啉酮、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、吩嗪、吩噻嗪等。
本文所述的“3-8元杂环基”是指含有3-8个环原子、且含有至少一个杂原子(例如1、2、3、4或5个杂原子)饱和或部分饱和的单环杂环化合物除去一个氢原子得到的基团。包括例如“3-7元杂环基”、“3-6元杂环基”、“3-5元杂环基”、“4-7元杂环基”、“4-6元杂环基”、“4-5元杂环基”、“5-6元杂环基”、“5-7元杂环基”、“5-8元杂环基”、“6-7元杂环基”、“6-8元杂环基”等。例如可以为：“含2个O、S和/或N原子的3-5元杂环基”、“含1-2个O、S和/或N原子的6-8元杂环基”、“含1-2个O、S和/或N的4-6元杂环基”、“含2个O、S和/或N原子的4-5元杂环基”、“含1-2个O、S和/或N原子的6-7元杂环基”、“含2个O、S和/或N原子的5元杂环基”、“含1-2个O、S和/或N原子的6元杂环基”、“含2个N原子的5元杂环基”、“含1-2个N原子的6元杂环基”、“含2个O原子的5元杂环基”、“含1-2个O原子的6元杂环基”、“含2个O原子的6元杂环基”、“含2个O原子的5-6元杂环基”、“含1个O、S和/或N原子的6元杂环基”、“含1-2个N原子的4-6元杂环基”。3-8元部分饱和单杂环基，是指含有双键、杂原子的环状基团。3-8元饱和单杂环基，是指全部为饱和键的含有杂原子的环状基团。实例包括但不仅限于：氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡啶基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、二氢嘧啶基、四氢嘧啶基、哌啶基、哌嗪基、吗啉基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、2H-1,2-噁嗪基、6H-1,3-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4- 二氢-2H-吡喃基、2,5-二氢噻吩基、3,4-二氢-2H-吡喃基、5,6-二氢-4H-1,3-噁嗪基、1,2,3,6-四氢吡啶基、1,2,3,4-四氢吡啶基、2,3,4,5-四氢吡啶基等，优选为“5-6元杂环基”。
本文所述的“杂原子”是指N、O、C(O)、S、SO和/或SO2等，优选N、O、S，更优选N、O。
本文所述的“3-8元碳环”是指含有3-8个碳原子的饱和、部分饱和或不饱和的单环化合物。包括例如“3-7元碳环”、“3-6元碳环”、“4-7元碳环”、“4-6元碳环”、“5-6元碳环”等。实例包括但不仅限于：环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基、环戊烯基、1,3-环戊二烯基、环己烯基、1,4-环己二烯基、环庚烯基、1,4-环庚二烯基、环辛烯基、苯基等。优选“5-6元饱和或部分饱和的碳环”。
本文所述“部分饱和”是指环部分包括至少一个双键或三键。
本发明的实施例还提供了上述化合物的两个制备方法，但不仅限于以下方法，反应方程式如下：
制备方法一：
Figure PCTCN2015090712-appb-000005
步骤1 中间体1的制备
购买或制备中间体1。
步骤2 中间体2的制备
中间体1溶于适当溶剂(例如N,N-二甲基甲酰胺)，加入适量N-溴代 琥珀酰亚胺，加热(例如30-70℃)搅拌(例如10-20小时)，降温至室温，加水淬灭反应，有机溶剂(例如乙酸乙酯)萃取，浓缩，经适当方法(例如硅胶柱层析)纯化得到中间体2。
步骤3 中间体3的制备
将中间体2溶于适当溶剂(例如乙醇)，加入乙酸，分批加入还原铁粉，加热(例如50-100℃)搅拌(例如10-20小时)，滤除固体，加水淬灭反应，有机溶剂(例如乙酸乙酯)萃取，浓缩，经适当方法(例如硅胶柱层析)纯化得到中间体3。
步骤4 中间体4的制备
将中间体3溶于甲苯和乙酸中，室温下加入适量(例如0.5-1.5当量)N-碘代琥珀酰亚胺，搅拌(例如1-2小时)，加水淬灭反应，有机溶剂(例如乙酸乙酯)萃取，浓缩，经适当方法(例如硅胶柱层析)纯化得到中间体4。
步骤5 中间体5的制备
将中间体4和原料1溶于溶剂(例如二氧六环)，加入金属钯催化剂(例如[1,1'-双(二苯基膦)二茂铁]二氯化钯)，加入适量(例如1-2当量)无机碱(例如碳酸钾)，氮气保护下加热(例如50-100℃)反应(例如1-3小时)，抽滤，滤液用有机溶剂(例如乙酸乙酯)萃取，合并的有机相经适当方法(例如硅胶柱层析)纯化得到中间体5。
步骤6 中间体6的制备
将中间体5溶于适当溶剂(例如甲醇)，加入钯碳，室温下通入氢气，搅拌(例如10-20小时)，过滤，滤液浓缩得到中间体6。
步骤7 中间体7的制备
将N,N-二甲基-2-硝基苯磺酰胺或2-(异丙基磺酰基)苯胺溶于适当溶剂，加入2,4,5-三氯嘧啶，室温下搅拌反应(例如16小时)，加水淬灭反应，有机溶剂(例如乙酸乙酯)萃取，浓缩，经适当方法(硅胶柱层析)纯化得到中间体7。
步骤8 本发明通式(I)化合物的制备
将中间体7和中间体6溶于溶剂(例如二氧六环)，加入金属钯催化剂(例如[1,1'-双(二苯基膦)二茂铁]二氯化钯)，加入适量无机碱(例如碳酸铯)，氮气保护下加热(例如70-90℃)反应(例如12-18小时)，抽滤，滤液浓 缩，经适当方法(例如硅胶柱层析)纯化得到本发明通式(I)化合物。
制备方法二：
Figure PCTCN2015090712-appb-000006
步骤1 中间体1的制备
购买或制备中间体1。
步骤2 中间体2的制备
中间体1溶于适当溶剂(例如乙醇)，加入Pd/C，氢气保护下室温反应(例如1-5小时)，反应完成后，滤除固体，滤液浓缩，得到中间体2。
步骤3 中间体3的制备
将中间体2溶于适当溶剂(例如乙酸)，降温(例如5-20℃)，加入NIS，反应(例如30-50分钟)，除去乙酸，加入溶剂(例如乙酸乙酯)稀释，硫代硫酸钠溶液洗涤，水洗，干燥，过滤，浓缩，经适当方法(例如硅胶柱层析)纯化得到中间体3。
步骤4 中间体4的制备
将中间体3和原料1溶于溶剂(例如二氧六环)，加入金属钯催化剂(例如[1,1'-双(二苯基膦)二茂铁]二氯化钯)，加入适量(例如1-2当量)无机碱(例如碳酸铯)，加热(例如50-100℃)反应(例如3-8小时)，加入有机溶剂(例如乙酸乙酯)，干燥，浓缩，经适当方法(例如硅胶柱层析)纯化得到中间体4。
步骤5 中间体5的制备
参考制备方法一中间体7的制备方法制备。
步骤6 本发明通式(I)化合物的制备
将中间体4、中间体5溶于溶剂(例如特戊醇)，加热(例如100℃-130℃)反应(例如10-16小时)，冷却，加入有机溶剂(例如乙酸乙酯)，碱性溶液(例如碳酸氢钠)洗涤，干燥，浓缩，经适当方法(例如硅胶柱层析)纯化得到本发明通式(I)化合物。
反应方程式中，R1、R2、R3、R4和A环如前文所定义，X代表氟原子、氯原子、溴原子和碘原子。
本文式(I)化合物的“立体异构体”是指当式(I)化合物存在不对称碳原子时，会产生对映异构体，当化合物存在碳碳双键或环状结构时，会产生顺反异构体，当化合物存在酮或肟时，会产生互变异构体，所有式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。
本文的通式(I)所示的任一化合物合成得到的若是消旋体，所需要的对映体纯的化合物可以通过手性拆分的方法得到：可以通过具有手性固定相的色谱法(如高压制备液相色谱、超临界流体色谱)。手性填料包括但不限于：Chiralcel OJ-H,Chiralpak AD-H，Chiralpak IA，Chiralpak AS-H。
本文的通式(I)所示的任一化合物药学上可接受的盐是指由药学上可接受的、非毒性碱或酸制备的盐，包括有机酸盐、无机酸盐、有机碱盐、无机碱盐。
本发明的实施例进一步提供了包括上述的式(I)所示的任一化合物、其药学上可接受的盐或其立体异构体与一种或多种药用载体和/或稀释剂的药物组合物，可以制成药学上可接受的任一剂型。以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药 物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
本发明的实施例进一步提供了包括上面所述的式(I)任一化合物、其药学上可接受的盐或其立体异构体与其它一种或多种抗肿瘤剂和/或免疫抑制剂的药物组合物。所述的抗肿瘤剂和/或免疫抑制剂为抗代谢物，选自卡培他滨、吉西他滨、培美曲塞二钠；或者所述的抗肿瘤剂和/或免疫抑制剂为生长因子抑制剂，选自帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼；或者所述的抗肿瘤剂和/或免疫抑制剂为抗体，选自赫赛汀、贝伐单抗；或者所述的抗肿瘤剂和/或免疫抑制剂为有丝分裂抑制剂，选自紫杉醇、长春瑞滨、多西他赛、多柔比星；或者所述的抗肿瘤剂和/或免疫抑制剂为抗肿瘤激素类，选自来曲唑、他莫西芬、氟维司群、氟他胺、曲普瑞林；或者所述的抗肿瘤剂和/或免疫抑制剂为烷化剂类，选自环磷酰胺、氮芥、马法兰、瘤可宁、卡莫司汀、替莫唑胺；或者所述的抗肿瘤剂和/或免疫抑制剂为金属铂类，选自卡铂、顺铂、奥沙利铂；或者所述的抗肿瘤剂和/或免疫抑制剂为免疫抑制类，选自依维莫司、西罗莫司、特癌适；或者所述的抗肿瘤剂和/或免疫抑制剂为嘌呤类似物，选自6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤；或者所述的抗肿瘤剂和/或免疫抑制剂为抗生素类，选自菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素；或者所述的抗肿瘤剂和/或免疫抑制剂为铂配合物，选自顺铂、卡波铂；或者所述的抗肿瘤剂和/或免疫抑制剂为肾上腺皮质抑制剂类，选自氨鲁米特；或者所述的抗肿瘤剂和/或免疫抑制剂为酶抑制剂，选自阿糖胞苷、甲氨蝶呤、羟基脲、羟喜树碱、喜树碱、拓扑特肯、拓扑替康、依立替康。
本发明的实施例还提供了本文式(I)所示的化合物、其药学上可接受的盐或其立体异构体在制备治疗和/或预防ALK介导的癌症或非癌性相关疾病的药物中的应用，所述癌症相关的疾病选自脑瘤、肺癌、非小细胞性肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、结直肠癌、肝癌、肝母细胞瘤、乳头状肾细胞瘤、头颈部鳞状细胞瘤、肾母细胞瘤、肾癌、食管腺癌、食管鳞状细胞癌、非霍奇金淋巴瘤、中枢神经系统肿瘤、雌性生殖道癌、原位癌、淋巴瘤、成神经细胞瘤、神经纤维瘤病、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾 丸癌、小细胞肺癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、星形细胞瘤、神经母细胞瘤、肉瘤或神经胶质瘤；非癌性相关疾病，选自皮肤或前列腺的良性增生。
本发明的实施例还提供了本文式(I)所述的化合物、其药学上可接受的盐、其立体异构体或者所述的药物组合物，其用于治疗和/或预防ALK介导的癌症或非癌性相关疾病，所述的癌症相关疾病选自脑瘤，肺癌，鳞状上皮细胞癌，膀胱癌，胃癌，卵巢癌，腹膜癌，胰腺癌，乳腺癌，头颈癌，子宫颈癌，子宫内膜癌，结直肠癌，肝癌，肾癌，食管腺癌，食管鳞状细胞癌，非霍奇金淋巴瘤，中枢神经系统肿瘤，前列腺癌，甲状腺癌，小细胞肺癌，雌性生殖道癌，原位癌，淋巴瘤，神经纤维瘤病，骨癌，皮肤癌，结肠癌，睾丸癌，非小细胞性肺癌，胃肠道间质瘤，肥大细胞肿瘤，多发性骨髓瘤，黑色素瘤，胶质瘤，星形细胞瘤，神经母细胞瘤，肉瘤；非癌性相关疾病，选自皮肤或前列腺的良性增生。
本发明的实施例还提供了一种治疗和/或预防ALK介导的癌症或非癌性相关疾病的方法，包括给予有需要的患者治疗有效量的本文式(I)所述的化合物、其药学上可接受的盐、其立体异构体或者所述的药物组合物，其中所述的癌症相关疾病选自脑瘤，肺癌，鳞状上皮细胞癌，膀胱癌，胃癌，卵巢癌，腹膜癌，胰腺癌，乳腺癌，头颈癌，子宫颈癌，子宫内膜癌，结直肠癌，肝癌，肾癌，食管腺癌，食管鳞状细胞癌，非霍奇金淋巴瘤，中枢神经系统肿瘤，前列腺癌，甲状腺癌，小细胞肺癌，雌性生殖道癌，原位癌，淋巴瘤，神经纤维瘤病，骨癌，皮肤癌，结肠癌，睾丸癌，非小细胞性肺癌，胃肠道间质瘤，肥大细胞肿瘤，多发性骨髓瘤，黑色素瘤，胶质瘤，星形细胞瘤，神经母细胞瘤，肉瘤；非癌性相关疾病，选自皮肤或前列腺的良性增生。
本发明实施例提供的化合物具有以下优点：
(1)本文式(I)化合物、其药学上可接受的盐或其立体异构体具有优异的ALK/ROS1抑制活性；
(2)本文式(I)化合物、其药学上可接受的盐或其立体异构体显示出良好的生物稳定性，作用更持久，生物利用度高；
(3)本发明实施例提供的化合物制备工艺简单，药品纯度高，质量稳定，易于进行大规模工业生产。
(4)本文式(I)化合物、其药学上可接受的盐或其立体异构体对BaF3(ALK-F1174L)、BaF3(ALK-C1156Y)、BaF3(ALK-L1196M)等耐药型细胞具有良好的抑制活性。
以下通过实验进一步阐述本发明实施例提供的化合物的有益效果，但不应将此理解为本发明实施例提供的化合物仅具有下列有益效果。
下述实验中的缩写所代表的含义如下：
DMSO：二甲基亚砜(Dimethyl sulfoxide)
DTT：二硫苏糖醇(DL-Dithiothreitol)
SEB：酶催化剂缓冲溶液(Supplement Enzymatic buffer)
ATP：腺嘌呤核苷三磷酸(Adenosine Triphosphate)
ALK：间变性淋巴瘤激酶(Anaplastic Lymphoma Kinase)
SA-XL665：链霉亲和素标记的供体(Streptavidin-XL665)
HEPES：4-羟乙基哌嗪乙磺酸
Brij-35：十二烷基聚乙二醇醚
EDTA：乙二胺四乙酸
2.5×、5×、10×其中的“×”：倍
英文全称来源于试剂盒说明书
实验例1 本发明实施例提供的化合物的体外ALK激酶抑制活性实验
供试品：本发明实施例提供的化合物1、2、3、4，其化学名称和制备方法请见各化合物的制备实施例。
对照药：Ceritinib，自制(参考专利WO2008/073687A2制备方法制备)。
实验方法：
ALK激酶缓冲液配制：
分别取适量母液浓度为1000mM的MgCl2、2500nM的SEB、100mM的DTT、5×酶缓冲液，加入到超纯水中，使得最终浓度分别为：5mM、25nM、1mM、1×酶缓冲液，混匀，待用。
2.5×供试品溶液配制：
对照药的1mM储备液配制：称取对照药1.48mg，加入适量DMSO溶解，混匀，备用。
化合物的1mM储备液配制：分别称取化合物适量(称样量请见下表)， 加入适量DMSO溶解，混匀，备用。
Figure PCTCN2015090712-appb-000007
分别取1mM储备液，用DMSO稀释制成浓度为200μM的溶液，作为母液。用DMSO将上述母液三倍逐级稀释制成一系列浓度的溶液，然后每个浓度分别用ALK激酶缓冲液稀释80倍，制成各2.5×供试品溶液，浓度分别为：2500nM、833.33nM、277.78nM、92.59nM、30.86nM、10.29nM、3.43nM、1.14nM、0.38nM、0.13nM、0.04nM。
各种其他试剂配制：
用ALK激酶缓冲液分别配制所需要的5×ALK激酶溶液、5×底物溶液、5×ATP溶液，备用。
ALK酶学反应：
1)384孔板中相对应的孔中分别加入4μL配制好的2.5×供试品溶液、2μL配制好的5×ALK激酶溶液，25℃孵育10分钟。
2)相对应的孔中再分别加入2μL配制好的5×底物溶液和2μL配制好的5×ATP溶液，启动酶反应，25℃孵育30分钟。
酶学检测：
用检测缓冲液(detection buffer)配制所需浓度的SA-XL665，然后和等体积的酪氨酸激酶抗体混匀，相对应的孔中分别加入10μL配制好的此抗体溶液，终止反应。25℃孵育1h。
酶标仪665nm/615nm读板。
IC50：计算抑制率(％)＝(最大值－样本值)/(最大值－最小值)×100，采用Graph prisim软件进行曲线拟合，得出IC50值。
最大值：不加化合物的阳性对照，最小值：不加酶的阴性对照。
实验结果和结论：
表1本发明实施例提供的化合物的体外酶学抑制活性
Figure PCTCN2015090712-appb-000008
Figure PCTCN2015090712-appb-000009
由表1可见，本发明实施例提供的化合物对ALK激酶具有良好的抑制活性，可用于治疗与激酶相关的疾病，特别是ALK激酶介导的病症或病况，具有显著的临床意义。
实验例2 本发明实施例提供的化合物的体外ALK激酶抑制活性实验
供试品：本发明实施例提供的化合物5、6、8，其化学名称和制备方法请见各化合物的制备实施例。
对照药：Ceritinib，自制(参考专利WO2008/073687 A2制备方法制备)。
实验方法：采用Caliper Mobility Shift方法进行ALK激酶的抑制活性测定
1.1倍激酶缓冲液配制：
分别取pH7.5的HEPES、浓度为30％的Brij-35、母液浓度为1M的MgCl2溶液、母液浓度为1M的DTT，加入超纯水混匀，使HEPES的终浓度为50mM，Brij-35的终浓度为0.0015％，MgCl2的终浓度为10mM，DTT的终浓度为2mM。
2.终止液的配制
分别取母液浓度为4％的包被液Coating Reagent#3(Caliper仪器所使用的12-sipper chip中自带包被液)、母液浓度为1000mM pH7.5的HEPES、母液浓度为0.5M的EDTA、母液浓度为30％的Brij-35，加入超纯水混匀，使Coating Reagent#3终浓度为0.2％，HEPES终浓度为100mM，EDTA终浓度为50mM，Brij-35终浓度为0.015％。
3.5倍供试品溶液配制：
供试品的DMSO储备液配制：分别称取化合物适量(称样量请见下表)，加入适量DMSO溶解，混匀，备用。
Figure PCTCN2015090712-appb-000010
取供试品的DMSO储备液，用DMSO稀释制成浓度为50μM的溶液， 作为母液。用DMSO将上述母液四倍逐级稀释，然后每个浓度分别用1倍激酶缓冲液稀释10倍，制成5倍供试品溶液。
4.各种其他试剂的配制
用1倍激酶缓冲液分别配制所需要的2.5倍ALK激酶溶液、2.5倍多肽溶液，备用。
5.酶学反应：
1)384孔板中相对应的孔中分别加入5μL配制好的5倍供试品溶液、10μL配制好的2.5倍激酶溶液，室温孵育10分钟。
2)相对应的孔中再分别加入10μL配制好的2.5倍多肽溶液，使测试物终浓度为1000nM、250nM、63nM、16nM、4nM、1nM、0.2nM、0.1nM、0.02nM、0.004nM。启动酶反应，28℃孵育1小时。
6.酶学检测：
每个相对应的孔中分别加入25μL终止液，终止反应。Caliper仪器读取数据，并通过数据计算抑制率，
抑制率(％)＝(最大值-样本值)/(最大值-最小值)×100，采用XLFIT软件进行曲线拟合，得出IC50值。
最大值：不加测试物的阳性对照，最小值：不加酶的阴性对照。
实验结果和结论：
表2本发明实施例提供的化合物的体外酶学抑制活性
Figure PCTCN2015090712-appb-000011
由表2可见，本发明实施例提供的化合物对ALK激酶具有良好的抑制活性，可用于治疗与激酶相关的疾病，特别是ALK激酶介导的病症或病况，具有显著的临床意义。
实验例3 本发明实施例提供的化合物的体外ROS1激酶抑制活性实验
供试品：本发明实施例提供的化合物1、化合物2、化合物3、化合物4和化合物8，其化学名称和制备方法请见各化合物的制备实施例。
实验方法：采用Caliper Mobility Shift方法进行ROS1激酶的抑制活性测定
1.1倍激酶缓冲液配制：
分别取pH7.5的HEPES、浓度为30％的Brij-35、母液浓度为1M的MgCl2溶液、母液浓度为1M的DTT，加入超纯水混匀，使HEPES的终浓度为50mM，Brij-35的终浓度为0.0015％，MgCl2的终浓度为10mM，DTT的终浓度为2mM。
2.终止液的配制
分别取母液浓度为4％的包被液Coating Reagent#3(Caliper仪器所使用的12-sipper chip中自带包被液)、母液浓度为1000mM pH7.5的HEPES、母液浓度为0.5M的EDTA、母液浓度为30％的Brij-35，加入超纯水混匀，使Coating Reagent#3终浓度为0.2％，HEPES终浓度为100mM，EDTA终浓度为50mM，Brij-35终浓度为0.015％。
3.5倍供试品溶液配制：
供试品的DMSO储备液配制：分别称取化合物适量(称样量请见下表)，加入适量DMSO溶解，混匀，备用。
Figure PCTCN2015090712-appb-000012
取供试品的DMSO储备液，用DMSO稀释制成浓度为50μM的溶液，作为母液。用DMSO将上述母液四倍逐级稀释，然后每个浓度分别用1倍激酶缓冲液稀释10倍，制成5倍供试品溶液。
4.各种其他试剂的配制
用1倍激酶缓冲液分别配制所需要的2.5倍ROS1激酶溶液、2.5倍多肽溶液，备用。
5.酶学反应：
1)384孔板中相对应的孔中分别加入5μL配制好的5倍供试品溶液、10μL配制好的2.5倍激酶溶液，室温孵育10分钟。
2)相对应的孔中再分别加入10μL配制好的2.5倍多肽溶液，使测试物终浓度为1000nM、250nM、63nM、16nM、4nM、1nM、0.2nM、0.1nM、0.02nM、0.004nM。启动酶反应，28℃孵育。
6.酶学检测：
每个相对应的孔中分别加入25μL终止液，终止反应。Caliper仪器读取数据，并通过数据计算抑制率，
抑制率(％)＝(最大值-样本值)/(最大值-最小值)×100，采用XLFIT软件进行曲线拟合，得出IC50值。
最大值：不加测试物的阳性对照，最小值：不加酶的阴性对照。
实验结果和结论：
试验结果表明，本发明实施例提供的化合物对ROS1激酶的抑制活性均小于1nM，而Ceritinib对ROS1激酶的抑制活性大于10nM，说明了本发明化合物与Ceritinib相比，具有更好的ROS1激酶抑制活性，在治疗与激酶相关的疾病方面，优势更加明显。
实验例4 本发明实施例提供的化合物的体外细胞活性实验
供试品：本发明实施例提供的化合物1-6和8,其化学名称和制备方法见各化合物的制备实施例。
对照药Ceritinib，自制(参考专利WO2008/073687A2制备方法制备)，其结构式如背景技术所述。
下述中实验的缩写所代表的含义如下：
rpm：转每分钟；
DMSO：二甲基亚砜；
MTS：溴化噻唑蓝四氮唑；
RPMI1640：1640培养基(RPMI:Roswell Park Memorial Institute)；
500×、1000×、10×其中的“×”：倍。
实验方法：
(一)NCI-H3122、Karpas-299细胞：
(1)细胞制备：
用含10％胎牛血清、100U/ml青霉素、100mg/ml链霉素的RPMI-1640培养基，在5％CO2、37℃条件的培养箱中，培养细胞至80％融合，备用。
(2)接种细胞：
用胰酶消化细胞，1000rpm离心4min，去除上清液，用含2.5％胎牛血清的RPMI-1640培养基重新混悬，调整细胞密度，取该细胞混悬液90μL接 种到96孔板中，获得最终细胞密度为3000个/孔；然后在5％CO2、37℃培养箱中培养24h。
(3)加入供试品：
(3.1)供试品溶液配制
供试品溶液配制：分别称取供试品适量(称样量请见下表)，加入适量DMSO溶解并分别用DMSO梯度稀释制成一系列浓度的母液(1000×供试品溶液)，再分别用培养基稀释该母液100倍得到10×供试品溶液，分别取该溶液10μL，加入到96孔板相应的孔中，得到各供试品溶液最终浓度为：10μM、2.5μM、625nM、156nM、39nM、9.8nM、2.5nM。
Figure PCTCN2015090712-appb-000013
(3.2)对照孔设置：
溶媒对照：0.1％DMSO。
细胞对照：只接种细胞，不加化合物。
空白对照：培养基，仪器调零。
(3.3)将96孔板放37℃、5％CO2培养箱中培养72h。
(4)检测:
MTS检测方法：
①将CellTiter 
Figure PCTCN2015090712-appb-000014
单溶液96孔细胞增殖检测试剂盒中的试剂室温放置90min。
②向96孔板的每个试验孔中加入CellTiter 
Figure PCTCN2015090712-appb-000015
 AQueous单溶液试剂20μL。
③将96孔板放5％CO2、37℃培养箱中培养40min。
④设置酶标仪检测波长490nm，读取结果。
(5)结果处理：
IC50计算：细胞存活率(％)＝(OD样本值－OD空白值)/(OD最大值－OD空白值)×100，采用Graph prisim软件进行曲线拟合，得出IC50值。
OD最大值：不加化合物只加溶媒的的细胞对照，OD空白值：空白对照值。
(二)NCI-H2228细胞：
(1)细胞制备：
用含10％胎牛血清的RPMI-1640培养基，在5％CO2、37℃条件的培养箱中，培养细胞至80％融合，备用。
(2)接种细胞：
用胰酶消化细胞，1000rpm离心4min，去除上清液，用含2.5％胎牛血清的RPMI-1640培养基重新混悬，调整细胞密度2×104个/mL，取该细胞混悬液100μL接种到96孔板中，获得最终细胞密度为：2000个细胞/孔。
(3)加入供试品：
(3.1)供试品溶液配制：分别称取供试品适量(称样量请见下表)，加入适量DMSO，溶解，混匀，将溶液用DMSO梯度稀释，得到各一系列浓度的溶液，备用。
Figure PCTCN2015090712-appb-000016
取99μL培养基分别加入到96孔板每一孔中，然后取上述配制好的不同浓度的溶液1μL加入到对应的孔中，使得化合物和对照药的最终浓度为：10000nM、2500nM、625nM、156.25nM、39.06nM、9.77nM、2.44nM、0.61nM。
(3.2)对照孔设置：
溶媒对照：0.5％DMSO。
细胞对照：只接种细胞，不加化合物。
空白对照：培养基，仪器调零。
(3.3)将此96孔板放5％CO2、37℃条件的培养箱中培养96h。
(4)检测：
CTG检测方法：
①将96孔板每孔中培养基移除80μL，室温平衡30min。
②向96孔板的每个试验孔中加入
Figure PCTCN2015090712-appb-000017
试剂60μL。
③96孔板用微孔板振荡器避光振荡混匀2min，使细胞裂解。
④将96孔板避光室温孵育10min，使产生的光信号值稳定。
⑤酶标仪在luminescence模式下读取结果。
(5)结果处理：
IC50计算：细胞抑制率(％)＝(OD最大值－OD化合物)/(OD最大值－OD空白)×100， 采用Graph prisim软件进行曲线拟合，得出IC50值。
OD最大值：不加化合物只加溶媒的的细胞对照，OD空白：培养基空白对照
实验结果：
表3本发明实施例提供的化合物的细胞抑制活性
Figure PCTCN2015090712-appb-000018
备注：表中“/”表示没有测定此值。
由表3可见，本发明实施例提供的化合物对细胞NCI-H3122、Karpas-299和NCI-H2228均具有良好的抑制活性，可用于治疗ALK激酶介导的病症或病况，具有显著的临床意义。
实验例5 本发明实施例提供的化合物的体外细胞活性实验
本发明实施例提供的化合物对BaF3(ALK-F1174L)、BaF3(ALK-C1156Y)、BaF3(ALK-L1196M)细胞均具有良好的抑制活性，且优于Ceritinib，说明了本发明实施例提供的化合物对ALK耐药型细胞的抑制作用较强，在用于治疗因ALK突变引起的疾病方面，具有重要的临床意义。
实验例6 本发明实施例提供的化合物的大鼠药代动力学实验
供试品：化合物4，自制，其化学名称和制备方法见各化合物的制备实施例。
内标物：Alectinib，自制(参考专利CN102459172A制备方法制备)。
一、供试品溶液的制备：
1、口服给药(po)
0.1％吐温80+2％HPC的配制：称取HPC(羟丙基纤维素)20g，缓慢加入搅拌着的纯化水(1000mL)，再加入吐温80(1mL)，搅拌至澄清，得到0.1％吐温80+2％HPC的空白溶媒。
取供试品适量(称样量请见下表)，加入配制好的上述溶媒并置于组织研磨器中，以1000转速/分钟的转速分散均匀即得灌胃给药溶液。
Figure PCTCN2015090712-appb-000019
2、静脉注射(iv)
40％HP-β-CD的配制：称取HP-β-CD(羟丙基倍他环糊精)4.0g，加入5mL纯化水超声使溶解，用纯化水定容至10mL，得到40％HP-β-CD溶液。取供试品适量(称样量请见下表)，加入DMSO超声溶解(DMSO量＝5％总体积)，加入40％HP-β-CD溶液(40％HP-β-CD量＝20％总体积)，涡旋混匀，置于50℃恒温水浴锅中保温20min，再加入灭菌注射用水(灭菌注射用水量＝75％总体积)，涡旋，混匀，过0.22μm滤膜即得澄清透明的静脉注射给药溶液。
Figure PCTCN2015090712-appb-000020
将供试品药液按照下表方法进行给药：
Figure PCTCN2015090712-appb-000021
二、实验方法
1、采血时间点设置如下：
iv：药后0.083h、0.25h、0.5h、1h、2h、4h、6h、8h、24h。
po：药后0.167h、0.5h、1h、2h、4h、6h、8h、24h。
每个时间点通过尾静脉采取100μL左右全血，加入到K2EDTA抗凝管里，低温离心机中8000转/分钟离心6min分离血浆，血浆于-80℃冰箱冻存。
2、血浆样品分析：
采用蛋白沉淀法：取30μL血浆，加入200μL内标(含Alectinib浓度50ng/mL的乙腈溶液)，1000转/分钟涡旋10min，然后4000转/分钟离心20min，取上清液100μL，再加入100μL水，涡旋混匀，LC-MS/MS分析。
三、实验结果
化合物4的生物利用度在30％-50％之间，说明了本发明实施例提供的化合物在大鼠体内药代动力学性质良好，具有良好的成药性和临床开发前景。
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
下述缩写所代表的定义如下：
DMF:N,N-二甲基甲酰胺
NBS:N-溴代丁二酰亚胺
NIS:N-碘代丁二酰亚胺
X-phos:2-双环己基膦-2',4',6'-三异丙基联苯
Boc:叔丁氧基羰基
TFA:三氟乙酸
THF:四氢呋喃
Tf:三氟甲磺酰基
DCM:二氯甲烷
DMSO:二甲基亚砜
EA:乙酸乙酯
PE:石油醚
DEAD：偶氮二甲酸二乙酯
实施例1 5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(6-甲基-7-(哌啶-4-基)苯 并[d][1,3]二氧杂环戊烯-4-基)嘧啶-2,4-二胺(化合物1)的制备
Figure PCTCN2015090712-appb-000022
(1)6-甲基-4-硝基苯并[d][1,3]二氧杂环戊烯的制备
Figure PCTCN2015090712-appb-000023
将5-甲基-3-硝基苯-1,2-二醇(10g,59.1mmol)溶于DMF(200mL)中，加入二碘甲烷(31.6g,118mmol)和碳酸钾(24.4g,177mmol)，加热至55℃下搅拌反应16小时。反应完毕，冷却至室温，加入300mL水，用乙酸乙酯(200mL×3)萃取，合并有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱层析(石油醚：乙酸乙酯＝30:1)纯化，得产物(5.1g,产率48％)。
(2)5-溴-6-甲基-4-硝基苯并[d][1,3]二氧杂环戊烯的制备
Figure PCTCN2015090712-appb-000024
将6-甲基-4-硝基苯并[d][1,3]二氧杂环戊烯(5.1g,28.2mmol)溶于DMF(100mL)中，加入NBS(10g,56.2mmol)，加热至55℃下搅拌反应16小时。反应完毕，冷却至室温，加入200mL水，用乙酸乙酯(200mL×3)萃取，合并有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱层析(石油醚：乙酸乙酯＝30:1)纯化，得产物(5.0g,产率68％)。
(3)5-溴-6-甲基苯并[d][1,3]二氧杂环戊烯-4-胺的制备
Figure PCTCN2015090712-appb-000025
将5-溴-6-甲基-4-硝基苯并[d][1,3]二氧杂环戊烯(5.0g,19.2mmol)溶于乙醇(100mL)中，加入醋酸(20mL)和铁粉(5.4g,96.7mmol)，加热至80℃下搅拌反应16小时。反应完毕，冷却至室温，过滤，滤液中加入200mL水，用乙酸乙酯(200mL×3)萃取，合并有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱层析(石油醚：乙酸乙酯＝20:1)纯化，得产物(2.9g,产率66％)。
(4)5-溴-7-碘-6-甲基苯并[d][1,3]二氧杂环戊烯-4-胺的制备
Figure PCTCN2015090712-appb-000026
将5-溴-6-甲基苯并[d][1,3]二氧杂环戊烯-4-胺(2.9g,12.6mmol)溶于甲苯(40mL)中，加入NIS(4.26g,18.9mmol)和醋酸(1.0mL)，室温搅拌反应2小时。反应完毕，加入50mL冰水，用乙酸乙酯(100mL×3)萃取，合并有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱层析(石油醚：乙酸乙酯＝20:1)纯化，得产物(2.4g,产率53％)。
(5)叔丁基4-(7-氨基-6-溴-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)-3,6-二氢吡啶-1(2H)-羧酸酯的制备
Figure PCTCN2015090712-appb-000027
将叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,6-二氢吡啶-1(2H)-羧酸酯(2.5g,8.1mmol)和5-溴-7-碘-6-甲基苯并[d][1,3]二氧杂环戊烯-4-胺(2.4g,6.7mmol)溶于1,4-二氧六环(50mL)和水(20mL)的混合溶剂中，向该体系中加入碳酸钾(2.77g,20.0mmol)和1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(493mg,0.6mmol)，氮气保护下，在80℃下搅拌反应2小时。反应完毕，冷却至室温，加入100mL水，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗产物，经硅胶柱层析(石油醚：乙酸乙酯＝10:1)纯化，得产物(1.3g,产率47％)。
(6)叔丁基4-(7-氨基-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)哌啶-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000028
将叔丁基4-(7-氨基-6-溴-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)-3,6-二氢吡啶-1(2H)-羧酸酯(1.3g,3.16mmol)溶于甲醇(50mL)中，氮气保护下向该体 系中加入Pd/C(1.3g)，然后体系在氢气环境下室温搅拌反应16小时。反应完毕，过滤，浓缩得产物(800mg,产率76％)。
(7)叔丁基4-(7-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)哌啶-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000029
将叔丁基4-(7-氨基-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)哌啶-1-羧酸酯(200mg,0.6mmol)和2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(制备方法见实施例5步骤(11),168mg,0.49mmol)溶于1,4-二氧六环(20mL)中，加入X-phos(48mg,0.1mmol)，碳酸铯(473mg,1.5mmol)和三(二亚苄基丙酮)二钯(46mg,0.05mmol)，氮气保护下升温至80℃反应16小时，抽滤，滤液浓缩，经硅胶柱层析(石油醚：乙酸乙酯＝1:1)得产物(160mg,产率51％)。
(8)5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(6-甲基-7-(哌啶-4-基)苯并[d][1,3]二氧杂环戊烯-4-基)嘧啶-2,4-二胺的制备
Figure PCTCN2015090712-appb-000030
将叔丁基4-(7-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)哌啶-1-羧酸酯(160mg,0.25mmol)溶于二氯甲烷(20mL)中，加入10mL的三氟乙酸，室温搅拌1小时。反应完毕，用碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产物，经硅胶柱层析(二氯甲烷：甲醇＝10:1)得终产物(70mg,产率52％)。
分子式：C26H30ClN5O4S  分子量：544.07  LC-MS(m/z):544.2[M+H]+
1H-NMR(400MHz,MeOD)δ:8.56(d,J＝8.0Hz,1H),8.10(s,1H),7.87(dd,J＝1.2Hz,8.0Hz,1H),7.53-7.58(m,1H),7.27-7.31(m,1H),6.93(s,1H),5.86(s,2H),3.47-3.50(m,2H),3.09-3.15(m,3H),2.33-2.43(m,2H),2.25(s,3H),1.90-1.94(m,2H),1.22-1.28(m,6H).
实施例2 2-((5-氯-2-((6-甲基-7-(哌啶-4-基)苯并[d][1,3]二氧杂环戊烯-4- 基)氨基)嘧啶-4-基)氨基)-N,N-二甲基苯磺酰胺(化合物2)的制备
Figure PCTCN2015090712-appb-000031
(1)N,N-二甲基-2-硝基苯磺酰胺的制备
Figure PCTCN2015090712-appb-000032
将2-硝基苯磺酰氯(3g,13.5mmol)溶于50mL DMF中，然后加入二甲胺(730mg,16.2mmol)和K2CO3(3.7g,26.8mmol)，80℃下反应6小时。反应完毕，冷却至室温，加入100mL水，用乙酸乙酯(200mL x 2)萃取，合并有机相，并用无水硫酸钠干燥。过滤，浓缩得产物(2.8g，产率90％)。
(2)2-氨基-N,N-二甲基苯磺酰胺的制备
Figure PCTCN2015090712-appb-000033
将N,N-二甲基-2-硝基苯磺酰胺(2.8g,12.2mmol)溶于50mL EtOH/H2O＝4:1中，然后加入铁粉(3.4g,60.7mmol)和NH4Cl(64mg,1.2mmol)，80℃下搅拌2小时，反应完毕。冷却至室温，滤去不溶物，滤液用乙酸乙酯萃取，有机相依次用碳酸氢钠溶液、氯化钠水溶液洗涤，无水硫酸钠干燥，经柱层析(石油醚：乙酸乙酯＝5:1)得产物(2.0g,产率82％)。
(3)2-((2,5-二氯嘧啶-4-基)氨基)-N,N-二甲基苯磺酰胺的制备
Figure PCTCN2015090712-appb-000034
将2-氨基-N,N-二甲基苯磺酰胺(2g,10mmol)溶于DMF(10mL)和DMSO(1mL)的混合溶剂中，冰浴下缓慢滴加NaH(600mg,15mmol,60％)的DMF/DMSO(20/2mL)的混合溶剂，然后缓慢滴加入2,4,5-三氯嘧啶(3.66g,20 mmol)的DMF/DMSO(10/1mL)的混合溶剂，室温搅拌反应16小时。反应完毕，加入100mL水，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗产物，经硅胶柱层析(石油醚：乙酸乙酯＝20:1)纯化，得到产物(1.6g,产率46％)。
(4)叔丁基4-(7-((5-氯-4-((2-(N,N-二甲基氨磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)哌啶-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000035
将叔丁基4-(7-氨基-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)哌啶-1-羧酸酯(制备方法见实施例1步骤(1)-(6),200mg,0.6mmol)和2-((2,5-二氯嘧啶-4-基)氨基)-N,N-二甲基苯磺酰胺(173mg,0.5mmol)溶于1,4-二氧六环(20mL)中，加入X-phos(48mg,0.1mmol)，碳酸铯(585mg,1.8mmol)和三(二亚苄基丙酮)二钯(46mg,0.05mmol)，氮气保护下升温至80℃反应16小时，抽滤，滤液浓缩，经硅胶柱层析(石油醚：乙酸乙酯＝1:1)得产物(90mg,产率23％)。
(5)2-((5-氯-2-((6-甲基-7-(哌啶-4-基)苯并[d][1,3]二氧杂环戊烯-4-基)氨基)嘧啶-4-基)氨基)-N,N-二甲基苯磺酰胺的制备
Figure PCTCN2015090712-appb-000036
将叔丁基4-(7-((5-氯-4-((2-(N,N-二甲基氨磺酰基)苯基)氨基)嘧啶-2-基)氨基)-5-甲基苯并[d][1,3]二氧杂环戊烯-4-基)哌啶-1-甲酸叔丁酯(90mg,0.14mmol)溶于二氯甲烷(10mL)中，加入5mL的三氟乙酸，室温搅拌1小时。反应完毕，用碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产物，经硅胶柱层析(二氯甲烷：甲醇＝10:1)得终产物(45mg,产率59％)。
分子式：C25H29ClN6O4S  分子量：545.06  LC-MS(m/z):545.2[M+H]+
1H-NMR(400MHz,CDCl3)δ:9.44(s,1H),8.54(d,J＝8.4Hz,1H),8.13(s,1H),7.87(dd,J＝1.2Hz,8.0Hz,1H),7.52-7.55(m,1H),7.36(s,1H),7.21-7.25 (m,1H),6.79(s,1H),5.94(s,2H),3.58-3.61(m,2H),2.88-3.01(m,3H),2.74(s,6H),2.52-2.58(m,2H),2.21(s,3H),1.81-1.88(m,2H).
实施例3 2-((5-氯-2-((7-甲基-8-(哌啶-4-基)-2,3-二氢苯并[b][1,4]二恶英 -5-基)氨基)嘧啶-4-基)氨基)-N,N-二甲基苯磺酰胺(化合物3)的制备
Figure PCTCN2015090712-appb-000037
(1)N,N-二甲基-2-硝基苯磺酰胺的制备
Figure PCTCN2015090712-appb-000038
将2-硝基苯磺酰氯(4.43g,20mmol)溶于二氯甲烷(50mL)中，加入三乙胺(8.08g,80mmol)，二甲胺盐酸盐(1.63g,20mmol)，室温反应12小时。加水(100mL)，乙酸乙酯萃取(150mL×2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)纯化得产物(2.53g,产率55％)。
(2)2-氨基-N,N-二甲基苯磺酰胺的制备
Figure PCTCN2015090712-appb-000039
将N,N-二甲基-2-硝基苯磺酰胺(2.5g,10.9mmol)溶解于甲醇(100mL)中，加入钯碳(250mg)，通氢气室温下搅拌12小时，反应完毕，滤去钯碳，旋转蒸发除去溶剂得产物(2g,产率92％)。
(3)2-((2,5-二氯嘧啶-4-基)氨基)-N,N-二甲基苯磺酰胺的制备
Figure PCTCN2015090712-appb-000040
将2-氨基-N,N-二甲基苯磺酰胺(2g,9.99mmol)溶于N,N-二甲基甲酰胺 (50mL)中，加入氢化钠(质量分数60％,800mg,20mmol)和2,4,5-三氯嘧啶(2.2g,12mmol)，室温反应12小时。加水(100mL)，乙酸乙酯萃取(150mL×2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)纯化得产物(500mg,产率14.4％)。
(4)叔丁基4-(8-((5-氯-4-((2-(N,N-二甲氨基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)哌啶-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000041
将叔丁基4-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)哌啶-1-羧酸酯(制备方法见实施例4步骤(1)-(8),348mg,1mmol)，2-((2,5-二氯嘧啶-4-基)氨基)-N,N-二甲基苯磺酰胺(347mg,1mmol)，三(二亚苄基丙酮)二钯(35mg)，2-二环己基磷-2',4',6'-三异丙基联苯(70mg)和碳酸铯(977mg,3mmol)加入到二氧六环(10mL)中，氮气保护下微波加热至120℃反应2小时。冷却至室温，滤去不溶物，真空浓缩，粗品经硅胶柱层析(乙酸乙酯：石油醚＝1:2)纯化得产物(75mg,产率11.4％)。
(5)2-((5-氯-2-((7-甲基-8-(哌啶-4-基)-2,3-二氢苯并[b][1,4]二恶英-5-基)氨基)嘧啶-4-基)氨基)-N,N-二甲基苯磺酰胺的制备
Figure PCTCN2015090712-appb-000042
将叔丁基4-(8-((5-氯-4-((2-(N,N-二甲氨基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)哌啶-1-羧酸酯(75mg,0.114mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(1mL)，室温下搅拌12小时，TLC检测原料消失，加水(20mL)，分液，水相用二氯甲烷萃取两次(20mL×2)，合并有机相，无水硫酸钠干燥，旋转蒸发除去溶剂，粗品经硅胶柱层析(甲醇:二氯甲烷＝1:50)纯化得终产物(30mg,产率47.2％)。
分子式：C26H31ClN6O4S  分子量：559.08  LC-MS(m/z)：280.2[M/2+H]+
1H-NMR(400MHz,MeOD)δ:8.44(d,1H,J＝1.2),8.11(s,1H),7.86(d,1H,J＝1.2),7.56-7.60(m,1H),7.28-7.35(m,2H),4.26(s,4H),3.45-3.48(m,2H),3.06-3.15(m,3H),2.56-2.74(m,8H),2.17(s,3H),1.76-1.80(m,2H).
实施例4 5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(7-甲基-8-(哌啶-4- 基)-2,3-二氢苯并[b][1,4]二恶英-5-基)嘧啶-2,4-二胺(化合物4)的制备
Figure PCTCN2015090712-appb-000043
(1)2-甲氧基-4-甲基-6-硝基苯酚的制备
Figure PCTCN2015090712-appb-000044
将2-甲氧基-4-甲基苯酚(55g,398.1mmol)溶解于三氯甲烷(1000mL)中，冷却至-10℃，将发烟硝酸(25.1g,398.4mmol)溶于冰醋酸(100mL)，滴加入反应瓶中，滴加完毕，TLC检测原料消失，加水淬灭，分液，有机相用水洗，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空浓缩，甲醇重结晶得产物(35g,产率48％)。
(2)5-甲基-3-硝基苯-1,2-二醇的制备
Figure PCTCN2015090712-appb-000045
将2-甲氧基-4-甲基-6-硝基苯酚(35g,191.1mmol)溶解于氢溴酸(500mL)中，加入四丁基氟化铵三水合物(3.5g,11.1mmol)，110℃反应12小时，TLC检测原料反应完全，滤去不溶物，加水(1L)，乙酸乙酯萃取(500mL×2)，合并有机相，无水硫酸钠干燥，旋转蒸发除去溶剂得产物(23.3g,产率72％)。
(3)7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英的制备
Figure PCTCN2015090712-appb-000046
将5-甲基-3-硝基苯-1,2-二醇(23.3g,137.8mmol)溶解于N,N-二甲基甲酰胺(200mL)中，加入碳酸钾(57.07g,413.6mmol)，1,2-二溴乙烷(51.8g,275.7mmol)，55℃下搅拌12小时，反应完毕，滤去不溶物，加水(500mL)，乙酸乙酯萃取(500mL×2)，合并有机相，无水硫酸钠干燥，旋转蒸发除去溶剂，粗品经硅胶柱层析(石油醚：乙酸乙酯＝10:1)纯化得到产物(20.7g,产率77％)。
(4)6-溴-7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英的制备
Figure PCTCN2015090712-appb-000047
将7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英(20g,102.5mmol)溶于N,N-二甲基甲酰胺(250mL)中，加入N-溴代丁二酰亚胺(36.5g,205.1mmol)，55℃反应12小时，滤去不溶物，加水(500mL)，乙酸乙酯萃取(250mL×2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝10:1)纯化得产物(17.5g,产率62％)。
(5)6-溴-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺的制备
Figure PCTCN2015090712-appb-000048
将6-溴-7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英(17.5g,63.85mmol)溶于乙醇(500mL)中，加入铁粉(54g,964.3mmol)，冰醋酸(100mL)，80℃反应2小时。滤去不溶物，加水(500mL)，乙酸乙酯萃取(250mL×2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)纯化得产物(10g,产率64％)。
(6)6-溴-8-碘-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺的制备
Figure PCTCN2015090712-appb-000049
将6-溴-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺(10g,40.97mmol)加入到甲苯(100mL)中，加入N-碘代丁二酰亚胺(14g,62.22mmol)，冰醋酸(2.5mL)，室温反应2小时。滤去不溶物，加水(200mL)，乙酸乙酯萃取(150mL×2)， 有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)纯化得产物(8g,产率53％)。
(7)叔丁基4-(8-氨基-7-溴-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯的制备
Figure PCTCN2015090712-appb-000050
将6-溴-8-碘-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺(8g,21.62mmol)溶于二氧六环(100mL)中，加入叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,6-二氢吡啶-1(2H)-羧酸酯(6g,19.4mmol)，1,1’-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(800mg)，碳酸钾(8.03g,58.2mmol)，氮气保护下90℃反应16小时，TLC检测原料反应完全，滤去不溶物，加水(200mL)，乙酸乙酯萃取(200mL×2)，合并有机相，无水硫酸钠干燥，粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)纯化得产物(4.5g,产率55％)。
(8)叔丁基4-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)哌啶-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000051
将叔丁基4-(8-氨基-7-溴-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯(4.5g,10.58mmol)溶解于甲醇(200mL)中，加入钯碳(4.5g)，室温下搅拌12小时，反应完毕，滤去钯碳，旋转蒸发除去溶剂得产物(1.5g,产率41％)。
(9)2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺的制备
Figure PCTCN2015090712-appb-000052
将2-(异丙基磺酰基)苯胺(1.99g,10mmol)和2,4,5-三氯嘧啶(2.2g,11.99mmol)溶于N,N-二甲基甲酰胺(30mL)中，加入氢化钠(质量分数60％,0.8g,20mmol)，室温反应12小时。加水(100mL)，乙酸乙酯萃取(150mL×2)，有机相合并，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，真空浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝25:1)得产物(1.59g,产率46％)。
(10)叔丁基4-(8-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)哌啶-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000053
将叔丁基4-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)哌啶-1-羧酸酯(348mg,1mmol)，2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(346mg,1mmol)，三(二亚苄基丙酮)二钯(35mg)，2-二环己基磷-2',4',6'-三异丙基联苯(70mg)和碳酸铯(977mg,3mmol)，加入到二氧六环(10mL)中，氮气保护下加热至90℃反应12小时。冷却至室温，滤去不溶物，真空浓缩，粗品经硅胶柱层析(乙酸乙酯：石油醚＝1:2)纯化得产物(90mg,产率13.7％)。
(11)5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(7-甲基-8-(哌啶-4-基)-2,3-二氢苯并[b][1,4]二恶英-5-基)嘧啶-2,4-二胺的制备
Figure PCTCN2015090712-appb-000054
将叔丁基4-(8-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)哌啶-1-羧酸酯(90mg,0.137mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(1mL)，室温下搅拌12小时，TLC检测原料消失。加水(10mL)，分液，水相用二氯甲烷萃取(10mL×2)，合并有机相，无水硫酸钠干燥，旋转蒸发除去溶剂，粗品经硅胶柱层析(甲醇：二氯甲烷＝1:50)纯化得终产物(50mg,产率65.5％)。
分子式：C27H32ClN5O4S  分子量：558.09  LC-MS(m/z)：279.7[M/2+H]+
1H-NMR(400MHz,MeOD)δ:8.49(d,1H,J＝1.2),8.14(s,1H),7.91(dd,1H,J1＝1.2,J2＝8.0),7.63-7.67(m,1H),7.33-7.37(m,2H),4.27(s,4H),3.45-3.48(m,2H),3.06-3.17(m,3H),2.57-2.67(m,2H),2.18(s,3H),1.78-1.81(m,2H),1.25-1.29(m,6H).
实施例5 5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(7-甲基-8-(吡咯烷-3- 基)-2,3-二氢苯并[b][1,4]二恶英-5-基)嘧啶-2,4-二胺(化合物5)的制备
Figure PCTCN2015090712-appb-000055
(1)2-甲氧基-4-甲基-6-硝基苯酚的制备
Figure PCTCN2015090712-appb-000056
将2-甲氧基-4-甲基苯酚(60g,434mmol)溶于氯仿(500mL)中，0℃下向该体系中加入醋酸(150mL)，然后滴加发烟硝酸(27.4g,435mmol)。反应完毕，蒸干溶剂，甲醇重结晶得产物(29g,收率36％)。
(2)5-甲基-3-硝基苯-1,2-二醇的制备
Figure PCTCN2015090712-appb-000057
将2-甲氧基-4-甲基-6-硝基苯酚(29g,158mmol)溶于HBr(40％,500mL)中，加入四丁基氟化铵(41g,157mmol)，110℃下搅拌反应4小时。反应完毕，冷却至室温，加入500mL水，乙酸乙酯(200mL×3)萃取，合并有机相，有机相用饱和氯化钠水溶液(300mL)洗涤，无水硫酸钠干燥，过滤，浓缩滤液得产物(19.5g,产率73％)。
(3)7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英的制备
Figure PCTCN2015090712-appb-000058
将5-甲基-3-硝基苯-1,2-二醇(9.5g,56.2mmol)溶于DMF(200mL)中，加入1,2-二溴乙烷(21g,112mmol)和碳酸钾(23g,167mmol)，加热至55℃下搅拌反应16小时。反应完毕，冷却至室温，加入300mL水，用乙酸乙酯(200mL×3)萃取，合并有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱层析(石油醚：乙酸乙酯＝30:1)纯化，得到产物(8.5g,产率78％)。
(4)6-溴-7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英的制备
Figure PCTCN2015090712-appb-000059
将7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英(8.5g,43.6mmol)溶于DMF(150mL)中，加入NBS(15.5g,87.1mmol)，加热至55℃下搅拌反应16小时。反应完毕，冷却至室温，加入300mL水，用乙酸乙酯(200mL×3)萃取，合并有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱层析(石油醚：乙酸乙酯＝30:1)纯化，得产物(7.3g,产率61％)。
(5)6-溴-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺的制备
Figure PCTCN2015090712-appb-000060
将6-溴-7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英(7.3g,26.6mmol)溶于乙醇(150mL)中，加入醋酸(30mL)和铁粉(7.4g，132mmol)，加热至80℃下搅拌反应16小时。反应完毕，冷却至室温，过滤，滤液中加入200mL水，用乙酸乙酯(200mL×3)萃取，合并有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱层析(石油醚：乙酸乙酯＝20:1)纯化，得产物(4.5g,产率69％)。
(6)6-溴-8-碘-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺的制备
Figure PCTCN2015090712-appb-000061
将6-溴-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺(4.5g,18.4mmol)溶于甲苯(40mL)中，加入NIS(6.2g,27.6mmol)和醋酸(1.5mL)，室温搅拌反应2小时。反应完毕，加入50mL冰水，用乙酸乙酯(100mL×3)萃取，合并有机相。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩，粗产物经硅胶柱层析(石油醚：乙酸乙酯＝20:1)纯化，得产物(4.0g,产率59％)。
(7)叔丁基3-(((三氟甲基)磺酰基)氧基)-2,5-二氢-1H-吡咯-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000062
将叔丁基3-氧代吡咯烷-1-羧酸酯(5.0g,27mmol)溶解于四氢呋喃(50mL)中，-78℃下向该体系中缓慢滴加二异丙基氨基锂(20mL,40mmol,2M)，搅拌10分钟后加入1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(11.6g,32.5mmol)的四氢呋喃(50mL)溶液，搅拌30分钟后移至室温下反应2小时。反应完毕，浓缩得到粗产物，未经纯化直接进行下一步。
(8)叔丁基3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-2,5-二氢-1H-吡咯-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000063
将叔丁基3-(((三氟甲基)磺酰基)氧基)-2,5-二氢-1H-吡咯-1-羧酸酯的粗产物，联硼酸频那醇酯(3.8g,15.0mmol)，醋酸钾(3.7g,37.7mmol)，1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(308mg,0.4mmol)和1,1'-双(二苯基膦)二茂铁(210mg,0.4mmol)溶解于1,4-二氧六环(50mL)中，氮气保护下，80℃搅拌反应16小时。反应完毕，冷却至室温，加入100mL水，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗产物，未经纯化直接进行下一步。
(9)叔丁基3-(8-氨基-7-溴-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)-2,5-二氢-1H-吡咯-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000064
将叔丁基3-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-2,5-二氢-1H-吡咯-1-羧酸酯的粗产物和6-溴-8-碘-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺(4.0g，10.8mmol)溶于1,4-二氧六环(50mL)和水(20mL)的混合溶剂中，向该体系中加入碳酸钾(4.46g,32.3mmol)和1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物(444mg,0.54mmol)，氮气保护下，在80℃下搅拌反应2小时。反应完毕，冷却至室温，加入100mL水，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗产物，经硅胶柱层析(石油醚：乙酸乙酯＝10:1)纯化，得产物(200mg)。
(10)叔丁基3-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)吡咯烷-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000065
将叔丁基3-(8-氨基-7-溴-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)-2,5-二氢-1H-吡咯-1-羧酸酯(200mg,0.49mmol)溶于甲醇(20mL)中，氮气保护下向该体系中加入Pd/C(200mg)，然后体系在氢气环境下室温搅拌反应16小时。反应完毕，过滤，制备得产物(100mg,产率61％)。
(11)2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺的制备
Figure PCTCN2015090712-appb-000066
将2-(异丙基磺酰基)苯胺(2g,10mmol)溶于DMF(10mL)和DMSO(1mL)的混合溶剂中，冰浴下缓慢滴加NaH(600mg,15mmol,60％)的DMF/DMSO(20/2mL)的混合溶剂，然后缓慢滴加入2,4,5-三氯嘧啶(3.66g,20mmol)的DMF/DMSO(10/1mL)的混合溶剂，室温搅拌反应16小时。反应完 毕，加入100mL水，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗产物，经硅胶柱层析(石油醚：乙酸乙酯＝20:1)纯化，得产物(1.8g,收率52％)。
(12)叔丁基3-(8-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)吡咯烷-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000067
将叔丁基3-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)吡咯烷-1-羧酸酯(100mg,0.3mmol)和2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(124mg,0.36mmol)溶于1,4-二氧六环(20mL)中，加入X-phos(29mg,0.06mmol)，碳酸铯(293mg,0.9mmol)和三(二亚苄基丙酮)二钯(28mg,0.03mmol)，氮气保护下升温至80℃反应16小时，抽滤，滤液浓缩，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝1:1)得产物(50mg,产率26％)。
(13)5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(7-甲基-8-(吡咯烷-3-基)-2,3-二氢苯并[b][1,4]二恶英-5-基)嘧啶-2,4-二胺的制备
Figure PCTCN2015090712-appb-000068
将叔丁基3-(8-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)吡咯烷-1-羧酸酯(50mg,0.08mmol)溶于二氯甲烷(10mL)中，加入5mL的三氟乙酸，室温搅拌1小时。反应完毕，用碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤，浓缩得到粗产物，经硅胶柱层析(二氯甲烷：甲醇＝10:1)得终产物(16mg,产率38％)。
分子式：C26H30ClN5O4S  分子量：544.07  LC-MS(m/z):544.2[M+H]+
1H-NMR(400MHz,CDCl3)δ:9.55(s,1H),8.56(d,J＝8.0Hz,1H),8.16(s,1H),7.93(dd,J＝1.6Hz,8.0Hz,1H),7.61-7.67(m,2H),7.33(s,1H),7.25-7.29(m,1H),4.42-4.53(m,2H),4.31(t,J＝4.0Hz,2H),3.65-3.78(m,3H),3.48-3.53 (m,1H),3.33-3.36(m,1H),3.23-3.27(m,1H),2.32-2.35(m,1H),2.22-2.28(m,1H),2.19(s,3H),1.22-1.32(m,6H).
实施例6 N2-(8-(氮杂环丁烷-3-基)-7-甲基-2,3-二氢苯并[b][1,4]二恶英 -5-基)-5-氯-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺(化合物6)的制备
Figure PCTCN2015090712-appb-000069
(1)叔丁基3-((甲磺酰)氧基)氮杂环丁烷-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000070
将叔丁基3-羟基氮杂环丁烷-1-羧酸酯(2.0g,11.5mmol)溶解在50mL四氢呋喃中，加入三乙胺(2.34g,23.1mmol)。冰水浴条件下，将甲烷磺酰氯(1.58g,13.8mmol)慢慢加入，升至室温，继续反应4小时。反应完成，旋转蒸发除去溶剂，剩余物加入50mL水，用3×50mL乙酸乙酯萃取，有机相合并，无水硫酸钠干燥。过滤，旋转蒸发除去溶剂得到产物(2.67g,产率92％)。
(2)叔丁基3-碘代氮杂环丁烷-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000071
将叔丁基3-((甲磺酰)氧基)氮杂环丁烷-1-羧酸酯(2.67g,10.62mmol)溶解在20mL N,N-二甲基甲酰胺中，加入碘化钾(5.3g,31.93mmol)。加热至110℃，反应16小时。反应完成，溶剂旋转蒸发除去溶剂，加入50mL水，用3×30mL乙酸乙酯萃取，有机相合并，无水硫酸钠干燥。过滤，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝4:1)得到产物(2.5g,产率83％)。
(3)2-甲氧基-4-甲基-6-硝基苯酚的制备
Figure PCTCN2015090712-appb-000072
将2-甲氧基-4-甲基苯酚(30.0g,0.217mol)溶解在0.8L氯仿中，降温至0℃将发烟硝酸(13.7g,0.217mol)溶解在70mL乙酸中，慢慢滴加至溶液中，内部温度控制在0℃以下，升至室温继续反应0.5小时。反应完全，旋转蒸发除去溶剂，剩余物加入150mL甲醇，过滤，真空干燥得产物(20g,产率50％)。
(4)5-甲基-3-硝基苯-1,2-二醇的制备
Figure PCTCN2015090712-appb-000073
将2-甲氧基-4-甲基-6-硝基苯酚(20.0g,0.109mol)加入到150mL氢溴酸中(80％)，加入15g四丁基氟化铵，加热至110℃，反应18小时。反应完成，加入800mL水，用5×400mL乙酸乙酯萃取，有机相合并，250mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥。过滤，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝5:1)得到产物(15g,产率81％)。
(5)7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英的制备
Figure PCTCN2015090712-appb-000074
将5-甲基-3-硝基苯-1,2-二醇(15g,88.7mmol)溶于80mL N,N-二甲基甲酰胺中，加入1,2-二溴乙烷(33.4g,177.8mmol)和碳酸钾(36.7g,265.6mmol)。加热至60℃，反应过夜。反应完成，加入200mL水，乙酸乙酯萃取(3×100mL)，合并有机相，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝5:1)得到产物(13g,产率75％)。
(6)6-溴-7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英的制备
Figure PCTCN2015090712-appb-000075
将7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英(13g,66.61mmol)溶解在 200mL N,N-二甲基甲酰胺中，分批加入N-溴代丁二酰亚胺(23.7g,133.2mmol)。加热至60℃，反应过夜。反应完成，加入200mL水，乙酸乙酯(3×200mL)萃取，合并有机相，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝5:1)得到产物(12g,产率66％)。
(7)6-溴-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺的制备
Figure PCTCN2015090712-appb-000076
将6-溴-7-甲基-5-硝基-2,3-二氢苯并[b][1,4]二恶英(12g,43.78mmol)溶解在160mL乙醇中，加入20mL乙酸，加热至70℃，将铁粉(24.5g,437.5mmol)分批加入。升温至80℃，反应3小时，反应完成后，冷却至室温，过滤，滤液中加入300mL水，乙酸乙酯萃取(3×300mL)，合并有机相，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝2:1)得到产物(8g,产率75％)。
(8)6-溴-8-碘-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺的制备
Figure PCTCN2015090712-appb-000077
将6-溴-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺(8g,32.77mmol)溶于100mL甲苯中，加入5mL乙酸和N-碘代丁二酰亚胺(11.1g,49.34mmol)，室温下反应3小时。反应完成，加入100mL水，乙酸乙酯(3×200mL)萃取，合并有机相，用200mL亚硫酸氢钠溶液洗涤，有机相旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝2:1)得产物(5g,产率41％)。
(9)叔丁基3-(8-氨基-7-溴-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)氮杂环丁烷-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000078
将锌粉(351.0mg,5.40mmol)加入至5mL N,N-二甲基甲酰胺中，加入1,2- 二溴乙烷(76.1mg,0.405mmol)，加热至60℃，反应10分钟，冷却至室温，加入三甲基氯硅烷(43.7mg,0.402mmol)，加热至60℃，反应10分钟，冷却至室温，加入叔丁基3-碘代氮杂环丁烷-1-羧酸酯(1.15g,4.06mmol)，室温下继续搅拌40分钟。将6-溴-8-碘-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-胺(1.0g,2.70mmol)，三(二亚苄基丙酮)二钯(124mg,0.135mmol)和三(二-呋喃基)膦(63mg,0.271mmol)溶解在5mL N,N-二甲基甲酰胺中并加至反应液中，升温至70℃，反应16小时。反应完成，过滤，滤饼用20mL乙酸乙酯洗涤，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝2:1)得到产物(300mg,产率27.8％)。
(10)叔丁基3-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)氮杂环丁烷-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000079
将叔丁基3-(8-氨基-7-溴-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)氮杂环丁烷-1-羧酸酯(300mg,0.751mmol)溶解在20mL甲醇中，加入250mg钯炭，通入氢气，室温下反应过夜。反应完成，过滤，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝2:1)得到产物(120mg,产率50％)。
(11)2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺的制备
Figure PCTCN2015090712-appb-000080
将2,4,5-三氯嘧啶(4.42g,24.1mmol)溶于25mL N,N-二甲基甲酰胺中，冰水浴下加入氢化钠(60％)(1.61g,40.2mmol)，搅拌10分钟，将2-(异丙基磺酰基)苯胺(4.0g,20.1mmol)慢慢加入，室温下反应16小时。反应完成，加入100mL水，用3×60mL乙酸乙酯萃取，合并有机相，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝2:1)得到产物(2.0g,产率28.7％)。
(12)叔丁基3-(8-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)氮杂环丁烷-1-羧酸酯的制备
Figure PCTCN2015090712-appb-000081
将2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(156mg,0.451mmol)，叔丁基3-(8-氨基-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)氮杂环丁烷-1-羧酸酯(120mg,0.375mmol)溶解在10mL1,4-二氧六环中，加入三(二亚苄基丙酮)二钯(34mg,0.037mmol)，2-二环己基膦-2,4,6-三异丙基联苯(36mg,0.0755mmol)和碳酸铯(365mg,1.12mmol)，加热至80℃，反应过夜。反应完成，过滤，滤液旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝2:1)得到产物(50mg,产率21％)。
(13)N2-(8-(氮杂环丁烷-3-基)-7-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)-5-氯-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的制备
Figure PCTCN2015090712-appb-000082
将叔丁基3-(8-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-6-甲基-2,3-二氢苯并[b][1,4]二恶英-5-基)氮杂环丁烷-1-羧酸酯(50mg,0.079mmol)溶于10mL二氯甲烷中，加入2mL三氟乙酸，室温下搅拌3小时。反应完成，旋转蒸发除去溶剂，加入50mL乙酸乙酯，饱和碳酸氢钠溶液洗涤，有机相旋转蒸发除去溶剂，剩余物经硅胶柱层析(二氯甲烷：甲醇＝15:1)得到终产物(25mg,产率59.7％)。
分子式：C25H28ClN5O4S  分子量：530.04  LC-MS(M/e)：530.0[M+H+]
1H-NMR(400MHz,MeOD)δ:8.48(d,J＝8.4Hz,1H),8.14(d,J＝6.0Hz,1H),7.90-7.92(m,1H),7.64-7.68(m,1H),7.44(s,1H),7.34-7.37(m,1H),4.52-4.58(m,2H),4.41-4.48(m,2H),4.33-4.39(m,5H),3.44-3.46(m,1H),2.12(s,3H),1.24(d,J＝6.8Hz,6H).
实施例7 5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(6-甲基-5-(1,2,3,6-四氢吡 啶-4-基)苯并二氢吡喃-8-基)嘧啶-2,4-二胺(化合物8)的制备
Figure PCTCN2015090712-appb-000083
(1)1-(烯丙氧基)-4-甲基-2-硝基苯的制备
Figure PCTCN2015090712-appb-000084
在1L三口瓶，氮气保护下，将4-甲基-2-硝基苯酚(50g,0.327mol)加入到500mL的丙酮中，加入碳酸钾(45.1g,0.327mol)，分批加入烯丙基溴(39.2g,0.324mol)。室温搅拌24h。TLC显示仍有原料剩余，补加0.5当量的碳酸钾(22.6g,0.164mol)，反应8小时，TLC显示反应未动，补加0.5当量的烯丙基溴(19.6g,0.162mol)，室温反应24h，GC-MS检测反应完全。将体系旋转蒸发除去溶剂，加入300mL水，用乙酸乙酯分三次(每次100mL)萃取，合并有机相，用饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，旋转蒸发除去溶剂，得产物(50g,产率79％)。
(2)2-烯丙基-4-甲基-6-硝基苯酚的制备
Figure PCTCN2015090712-appb-000085
氮气保护下，在100mL三口瓶中加1-(烯丙氧基)-4-甲基-2-硝基苯(23g,0.119mol)，190-200℃反应30分钟，GC-MS检测反应完全，加乙酸乙酯100mL稀释，经硅胶柱层析(乙酸乙酯：石油醚＝1:50)，得产物(11.2g,产率48.7％)。
(3)2-(3-羟丙基)-4-甲基-6-硝基苯酚制备
Figure PCTCN2015090712-appb-000086
在2000mL三口瓶中，加入2-烯丙基-4-甲基-6-硝基苯酚(22.1g,0.115mol)、四氢呋喃(500mL)，氮气保护下，冰浴冷至0℃，滴加硼烷四氢呋喃溶液(1mol/L,240mL)，加入完毕，除去冰浴，自然升温至室温反应4h，冰浴降至0℃，将氢氧化钠(4.6g,0.115mol)溶至12mL的水中，滴加到体系中，加入完毕，再滴加30％的H2O2(260mL)，加入完毕，自然升至室温反应24h，GC-MS检测反应完全，分别加入300mL的水和100mL的乙酸乙酯，分出有机相，水相用乙酸乙酯(100mL×3)萃取，饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，旋转蒸发除去溶剂，经柱层析(乙酸乙酯：石油醚＝1:20)，得产物(16.7g,产率69％)。
(4)6-甲基-8-硝基苯并二氢吡喃的制备
Figure PCTCN2015090712-appb-000087
N2保护下，在500mL三口瓶中，分别加入THF(500mL),2-(3-羟丙基)-4-甲基-6-硝基苯酚(16.7g,0.079mol)，降至0℃，分批加入三苯基膦(29.3g,0.111mol)，加入完毕，滴加DEAD(19.3g,0.111mol)，滴加完毕，自然升至室温反应24h。GC-MC显示反应完全，加水100mL，分出有机相，水相用乙酸乙酯(50mL×3)萃取，合并有机相，饱和氯化钠水溶液(100mL×1)洗涤，无水硫酸钠干燥，旋转蒸发除去溶剂，经柱层析(EA:PE＝1:50)，得产物(8.3g,产率54％)。
(5)6-甲基苯并二氢吡喃-8-胺的制备
Figure PCTCN2015090712-appb-000088
在100mL单口瓶中，加入6-甲基-8-硝基苯并二氢吡喃(4g,20.7mmol)、 乙醇(50mL)、Pd/C(0.5g,10％)。置换空气4次后通入氢气，室温反应3小时，LC-MS检测反应完全，抽滤，滤饼用乙酸乙酯洗涤(50mL×3)，收集滤液，旋转蒸发除去溶剂后直接进行下一步。
(6)5-碘-6-甲基苯并二氢吡喃-8-胺的制备
Figure PCTCN2015090712-appb-000089
在250mL三口瓶中加入6-甲基苯并二氢吡喃-8-胺(500mg,3.04mmol)和HOAc(100mL)，降温至15℃，分批加入NIS(0.88g,3.96mmol)，此温度反应40分钟，旋转蒸发除去HOAc，加入300mLEA稀释，Na2S2O3溶液洗涤(100mL×3)，水洗(100mL×3)，无水Na2SO4干燥，过滤，浓缩后经柱层析(PE:EA＝100:1-50:1)，得产物(1.3g)。
(7)叔丁基4-(8-氨基-6-甲基苯并二氢吡喃-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯的制备
Figure PCTCN2015090712-appb-000090
将5-碘-6-甲基苯并二氢吡喃-8-胺(289mg,1.0mmol)，叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-3,6-二氢吡啶-1(2H)-羧酸酯(310mg,1.0mmol)，pd(dppf)Cl2(29mg)，碳酸铯(390mg,1.2mmol)，溶于10mL的1,4-二氧六环中，70℃反应5小时，加入50mL乙酸乙酯，用饱和氯化钠水溶液洗涤。有机相用无水硫酸钠干燥，旋转蒸发除去溶剂，经柱层析(石油醚：乙酸乙酯＝5:1)得到产物(171mg,产率49.6％)。
(8)2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺的制备
Figure PCTCN2015090712-appb-000091
将2-(异丙基磺酰基)苯胺(597mg,3.0mmol)溶于10mL THF中，冰水浴下加入氢化钠(86.4mg,3.6mmol)，搅拌10分钟，将2,4,5-三氯嘧啶(549mg, 3.0mmol)慢慢加入，升至室温搅拌2小时，加入饱和氯化钠水溶液20mL，用二氯甲烷萃取，有机相用无水硫酸钠干燥，旋转蒸发除去溶剂，剩余物经硅胶柱层析(石油醚：乙酸乙酯＝10:1)得到产物(306mg,产率29.5％)。
(9)5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(6-甲基-5-(1,2,3,6-四氢吡啶-4-基)苯并二氢吡喃-8-基)嘧啶-2,4-二胺的制备
Figure PCTCN2015090712-appb-000092
将叔丁基4-(8-氨基-6-甲基苯并二氢吡喃-5-基)-3,6-二氢吡啶-1(2H)-羧酸酯(78mg,0.23mmol)，2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(78mg,0.23mmol)，对甲苯磺酸(39mg,0.23mmol)溶于5mL的特戊醇中，120℃反应12h。冷至室温，加入20mL的乙酸乙酯，用10mL饱和碳酸氢钠溶液洗涤，有机相用无水硫酸钠干燥，旋转蒸发除去溶剂，经柱层析(石油醚：乙酸乙酯＝1:1)得到终产物(70mg,产率56％)。
分子式：C28H32ClN5O3S  分子量：554.11  LC-MS(M/e)：554.0[M+H]+
1H-NMR(400MHz,MeOD)δ:8.47(d,1H,J＝8.0Hz),8.09(s,1H),7.88(dd,1H,J1＝8.0Hz,J2＝1.6Hz),7.70(s,1H),7.67(m,1H),7.33(t,1H,J＝7.2Hz),6.07-6.09(m,1H),5.53-5.56(m,1H),4.17(t,2H,J＝4.8Hz),3.79(d,2H,J＝2.4Hz),3.41(t,1H,J＝6.0Hz),3.27-3.29(m,2H),2.73-2.77(m,1H),2.57-2.60(m,1H),2.41(s,2H),2.04(s,3H),1.92-1.98(m,2H),1.25(d,6H,J＝10.4Hz).
以上所述仅是本发明的示范性实施方式，而非用于限制本发明的保护范围，本发明的保护范围由所附的权利要求确定。
本申请要求于2014年9月29日递交的中国专利申请第201410515596.9号的优先权，在此全文引用上述中国专利申请公开的内容以作为本申请的一部分。

Claims (13)

  1. 通式(Ⅰ)所示的化合物、其药学上可接受的盐或其立体异构体：
    Figure PCTCN2015090712-appb-100001
    其中，
    R1选自-COR5，-CO2R5，-CONRR5，-SOR5，-SO2R5或-SO2NRR5；
    R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、氨基C1-6烷基、C1-6烷氧基、羟基C1-6烷氧基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基硫基、C1-6烷基羰基、C1-6烷基羰基氧基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、(C1-6烷基)2氨基磺酰基或C1-6烷基磺酰基；
    R3选自任选被1-3个取代基W取代的5-14元杂芳基，或任选被1-3个取代基W取代的3-8元杂环基，
    W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C1-6烷基羰基、C1-6烷基羰基氧基、C1-6烷基磺酰基、C2-8烯基或C2-8炔基；
    R4选自氢原子、卤素原子、氰基、硝基、氨基、羟基、羧基、C1-6烷氧基、3-8元碳环-O-、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、羟基C1-6烷氧基、卤代C1-6烷氧基、C2-8烯基、C2-8炔基、C1-6烷基氨基、C1-6烷基羰基、C1-6烷基羰基氧基或(C1-6烷基)2氨基；
    R、R5分别独立地选自氢原子、C1-6烷基或3-8元碳环；
    A选自任选被取代基Q取代的3-8元环烷基，任选被取代基Q取代的含2个O、S和/或N原子的4-5元杂环基，或任选被取代基Q取代的含1-2个O、S和/或N原子的6-8元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C2-8烯基、C2-8 炔基或3-8元杂环基。
  2. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体：
    其中，
    R1选自-CO2R5、-CONRR5、-SO2R5或-SO2NRR5；
    R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基、C1-6烷基、羟基C1-6烷基或卤代C1-6烷基；
    R3选自任选被1-2个取代基W取代的含1-2个O、S和/或N的5-8元杂芳基，或任选被1-2个取代基W取代的含1-2个O、S和/或N的4-6元杂环基，
    W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷氧基C1-6烷基、C1-6烷基羰基、C1-6烷基羰基氧基、C1-6烷基磺酰基、C2-4烯基或C2-4炔基；
    R4选自氢原子、卤素原子、氰基、硝基、氨基、羟基、羧基、C1-6烷氧基、C1-6烷基、羟基C1-6烷基、卤代C1-6烷基、羟基C1-6烷氧基、卤代C1-6烷氧基、C1-6烷基氨基、C1-6烷基羰基或C1-6烷基羰基氧基；
    R、R5分别独立地选自氢原子、C1-6烷基或5-6元饱和或部分饱和的碳环；
    A选自任选被取代基Q取代的5-6元环烷基，任选被取代基Q取代的含2个O、S和/或N原子的4-5元杂环基，或任选被取代基Q取代的含1-2个O、S和/或N原子的6-7元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-6烷基。
  3. 如权利要求2所述的化合物、其药学上可接受的盐或其立体异构体：
    其中，
    R1选自-SO2R5或-SO2NRR5；
    R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基或C1-6烷基；
    R3选自任选被1-2个取代基W取代的含1-2个N原子的5-6元杂芳基，或任选被1-2个取代基W取代的含1-2个N原子的4-6元杂环基，
    W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、(C1-6烷基)2氨基、卤代C1-6烷基、卤代C1-6烷氧基、C1-6烷基羰基、C1-6烷基羰基氧基或C1-6烷基磺酰基；
    R4选自氢原子、卤素原子、氰基、硝基、氨基、羟基、羧基、C1-6烷氧基、C1-6烷基、卤代C1-6烷基、C1-6烷基氨基、C1-6烷基羰基或C1-6烷基羰基氧基；
    R、R5分别独立地选自氢原子或C1-6烷基；
    A选自任选被1-2个取代基Q取代的含2个O、S和/或N原子的5元杂环基，或任选被1-2个取代基Q取代的含1-2个O、S和/或N原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-6烷基。
  4. 如权利要求3所述的化合物、其药学上可接受的盐或其立体异构体：
    其中，
    R1选自-SO2R5或-SO2NRR5；
    R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基或C1-4烷基；
    R3选自任选被1-2个取代基W取代的含1-2个N原子的4-6元杂环基；W选自羟基、氨基、羧基、氰基、硝基、卤素原子、C1-4烷基、C1-4烷氧基、C1-4烷基氨基、(C1-4烷基)2氨基、卤代C1-4烷基、卤代C1-4烷氧基、C1-4烷基羰基、C1-4烷基羰基氧基或C1-4烷基磺酰基；
    R4选自氟原子、溴原子或氯原子；
    R、R5分别独立地选自C1-4烷基；
    A选自任选被1个取代基Q取代的含2个O、S和/或N原子的5元杂环基或含1-2个O、S和/或N原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-4烷基。
  5. 如权利要求3所述的化合物、其药学上可接受的盐或其立体异构体：
    其中，
    R1选自-SO2R5或-SO2NRR5；
    R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基或C1-4烷基；
    R3选自吡啶基、二氢吡啶基、四氢吡啶基、氮杂环丁烷基、吡咯基、二氢吡咯基、四氢吡咯基、吡唑基、二氢吡唑基、四氢吡唑基、咪唑基、二氢咪唑基、四氢咪唑基、嘧啶基、二氢嘧啶基、四氢嘧啶基、哌啶基、哌嗪基或吗啉基；
    R4选自氟原子、溴原子或氯原子；
    R、R5分别独立地选自C1-4烷基；
    A选自任选被1个取代基Q取代的含2个O原子的5元杂环基或含1-2个O原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子或C1-4烷基。
  6. 如权利要求5所述的化合物、其药学上可接受的盐或其立体异构体：
    其中，
    R1选自-SO2R5或-SO2NRR5；
    R2选自氢原子、卤素原子、硝基、氰基、氨基、羟基、羧基、甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基；
    R3选自吡啶基、二氢吡啶基、四氢吡啶基、吡咯基、二氢吡咯基、四氢吡咯基、氮杂环丁烷基、哌啶基、哌嗪基或吗啉基；
    R4选自氟原子、溴原子或氯原子；
    R、R5分别独立地选自甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基；
    A选自任选被1个取代基Q取代的含2个O原子的6元杂环基，所述的取代基Q选自羟基、氨基、羧基、氰基、硝基、卤素原子、甲基、乙基、丙基、异丙基、丁基、异丁基或叔丁基。
  7. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中所述化合物选自：
    Figure PCTCN2015090712-appb-100002
    Figure PCTCN2015090712-appb-100003
  8. 权利要求1-7任一权利要求所述的化合物、其药学上可接受的盐或其立体异构体与一种或多种药用载体和/或稀释剂制成的药物制剂，为药学上可接受的任一剂型。
  9. 含有权利要求1-7任一权利要求所述的化合物、其药学上可接受的盐或其立体异构体的药物组合物，还含有一种或多种抗肿瘤剂和/或免疫抑制剂。
  10. 如权利要求9所述的药物组合物，所述的抗肿瘤剂和/或免疫抑制剂为抗代谢物，选自卡培他滨、吉西他滨、培美曲塞二钠；或者所述的抗肿瘤剂和/或免疫抑制剂为生长因子抑制剂，选自帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼；或者所述的抗肿瘤剂和/或免疫抑制剂为抗体，选自赫赛汀、贝伐单抗；或者所述的抗肿瘤剂和/或免疫抑制剂为有丝分裂抑制剂，选自紫杉醇、长春瑞滨、多西他赛、多柔比星；或者所述的抗肿瘤剂和/或免疫抑制剂为抗肿瘤激素类，选自来曲唑、他莫西芬、氟维司群、氟他胺、曲普瑞林；或者所述的抗肿瘤剂和/或免疫抑制剂为烷化剂类，选自环磷酰胺、氮芥、马法兰、瘤可宁、卡莫司汀、替莫唑胺；或者所述的抗肿 瘤剂和/或免疫抑制剂为金属铂类，选自卡铂、顺铂、奥沙利铂；或者所述的抗肿瘤剂和/或免疫抑制剂为免疫抑制类，选自依维莫司、西罗莫司、特癌适；或者所述的抗肿瘤剂和/或免疫抑制剂为嘌呤类似物，选自6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤；或者所述的抗肿瘤剂和/或免疫抑制剂为抗生素类，选自菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素；或者所述的抗肿瘤剂和/或免疫抑制剂为铂配合物，选自顺铂、卡波铂；或者所述的抗肿瘤剂和/或免疫抑制剂为肾上腺皮质抑制剂类，选自氨鲁米特；或者所述的抗肿瘤剂和/或免疫抑制剂为酶抑制剂，选自阿糖胞苷、甲氨蝶呤、羟基脲、羟喜树碱、喜树碱、拓扑特肯、拓扑替康、依立替康。
  11. 如权利要求1-7任一权利要求所述的化合物、其药学上可接受的盐或其立体异构体在制备用于治疗和/或预防ALK介导的癌症或非癌性相关疾病的药物中的应用，所述癌症相关的疾病选自脑瘤，肺癌，鳞状上皮细胞癌，膀胱癌，胃癌，卵巢癌，腹膜癌，胰腺癌，乳腺癌，头颈癌，子宫颈癌，子宫内膜癌，结直肠癌，肝癌，肾癌，食管腺癌，食管鳞状细胞癌，非霍奇金淋巴瘤，中枢神经系统肿瘤，前列腺癌，甲状腺癌，小细胞肺癌，雌性生殖道癌，原位癌，淋巴瘤，神经纤维瘤病，骨癌，皮肤癌，结肠癌，睾丸癌，非小细胞性肺癌，胃肠道间质瘤，肥大细胞肿瘤，多发性骨髓瘤，黑色素瘤，胶质瘤，星形细胞瘤，神经母细胞瘤，肉瘤；所述非癌性相关疾病，选自皮肤或前列腺的良性增生。
  12. 权利要求1-7中任一项所述的化合物、其药学上可接受的盐或其立体异构体或者权利要求8-10中任一项所述的药物组合物，其用于治疗和/或预防ALK介导的癌症或非癌性相关疾病，所述的癌症相关疾病选自脑瘤，肺癌，鳞状上皮细胞癌，膀胱癌，胃癌，卵巢癌，腹膜癌，胰腺癌，乳腺癌，头颈癌，子宫颈癌，子宫内膜癌，结直肠癌，肝癌，肾癌，食管腺癌，食管鳞状细胞癌，非霍奇金淋巴瘤，中枢神经系统肿瘤，前列腺癌，甲状腺癌，小细胞肺癌，雌性生殖道癌，原位癌，淋巴瘤，神经纤维瘤病，骨癌，皮肤癌，结肠癌，睾丸癌，非小细胞性肺癌，胃肠道间质瘤，肥大细胞肿瘤，多发性骨髓瘤，黑色素瘤，胶质瘤，星形细胞瘤，神经母细胞瘤，肉瘤；所述的非癌性相关疾病，选自皮肤或前列腺的良性增生。
  13. 一种治疗和/或预防ALK介导的癌症或非癌性相关疾病的方法，包 括给予有需要的患者治疗有效量的权利要求1-7中任一项所述的化合物、其药学上可接受的盐、其立体异构体或者权利要求8-10中任一项所述的药物组合物，其中所述的癌症相关疾病选自脑瘤，肺癌，鳞状上皮细胞癌，膀胱癌，胃癌，卵巢癌，腹膜癌，胰腺癌，乳腺癌，头颈癌，子宫颈癌，子宫内膜癌，结直肠癌，肝癌，肾癌，食管腺癌，食管鳞状细胞癌，非霍奇金淋巴瘤，中枢神经系统肿瘤，前列腺癌，甲状腺癌，小细胞肺癌，雌性生殖道癌，原位癌，淋巴瘤，神经纤维瘤病，骨癌，皮肤癌，结肠癌，睾丸癌，非小细胞性肺癌，胃肠道间质瘤，肥大细胞肿瘤，多发性骨髓瘤，黑色素瘤，胶质瘤，星形细胞瘤，神经母细胞瘤，肉瘤；所述的非癌性相关疾病，选自皮肤或前列腺的良性增生。
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