WO2017162215A1 - 取代的吡咯并嘧啶类cdk抑制剂、包含其的药物组合物以及它们的用途 - Google Patents

取代的吡咯并嘧啶类cdk抑制剂、包含其的药物组合物以及它们的用途 Download PDF

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WO2017162215A1
WO2017162215A1 PCT/CN2017/078260 CN2017078260W WO2017162215A1 WO 2017162215 A1 WO2017162215 A1 WO 2017162215A1 CN 2017078260 W CN2017078260 W CN 2017078260W WO 2017162215 A1 WO2017162215 A1 WO 2017162215A1
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group
compound
cancer
pharmaceutically acceptable
hydrogen
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PCT/CN2017/078260
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English (en)
French (fr)
Inventor
王树龙
陈坤成
刘希杰
胡远东
刘波
彭勇
罗鸿
韩永信
王善春
刘美
徐宏江
Original Assignee
正大天晴药业集团股份有限公司
北京赛林泰医药技术有限公司
连云港润众制药有限公司
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Application filed by 正大天晴药业集团股份有限公司, 北京赛林泰医药技术有限公司, 连云港润众制药有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to EP17769492.4A priority Critical patent/EP3434676B1/en
Priority to CN201780018459.6A priority patent/CN108884101B/zh
Priority to US16/087,918 priority patent/US10570141B2/en
Publication of WO2017162215A1 publication Critical patent/WO2017162215A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of medicinal chemistry, and relates to substituted pyrrolopyrimidine CDK inhibitors, preparation methods thereof, pharmaceutical compositions, and to compounds and pharmaceutical compositions thereof for use in the preparation of a medicament for treating diseases associated with CDK inhibition. use.
  • Cyclin kinase belongs to the serine/threonine protein kinase and is primarily involved in the regulation of the cell cycle.
  • CDK1, CDK2, CDK4, and CDK6 are involved in the regulation of cell cycle progression and checkpoints, in addition to which CDK8 and CDK9 are involved in the regulation of cellular transcriptional activity.
  • Cyclin Cyclin is involved in the regulation of cell cycle by phosphorylating downstream substrates by binding to CDKs to activate the latter's kinase activity. Different CDKs bind to specific cyclins.
  • CDK4 and CDK6 after being activated by binding to the Cyclin D family protein, phosphorylate the downstream RB protein, thereby abolishing the inhibitory effect of RB on the transcription factor E2F, thereby activating its transcriptional activity and causing the cell cycle to transition from the G1 phase to the S phase.
  • CDK4/CDK6 by inhibiting the kinase activity of CDK4/CDK6, the purpose of inhibiting tumor growth can be achieved, and its effectiveness is verified in many in vivo and in vitro tumor models, and inhibition of its activity can block the cell cycle to the G1 phase, thereby inhibiting tumors.
  • the mouse knockout model showed that knocking out CDK4 or CDK6 had little effect on the growth and development of the animals, only abnormalities occurred in individual organs, and knockout of CDK1 caused embryonic lethality.
  • selective targeting of CDK4/CDK6 inhibitors may have a larger therapeutic window than a broad spectrum of CDKs family inhibitors.
  • the compound ribociclib (also known as LEE011), which is a CDK4/CDK6 inhibitor, which was developed by Novartis and which has entered Phase III clinical trials, is disclosed in WO2010020675.
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof
  • R 1 is selected from the group consisting of -S(O) 2 R 4 and -C(O)NR 5 R 6 ;
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl And a 5-10 membered heteroaryl group, wherein said group is optionally substituted with one or more R a ;
  • R 5 and R 6 are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5 a 10-membered aryl group and a 5-10 membered heteroaryl group, wherein the group is optionally substituted with one or more R a ;
  • R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl, wherein said group is optionally substituted with one or more R a ;
  • X 1 , X 2 , X 3 and X 4 are independently selected from CH and N, and 1-2 of X 1 , X 2 , X 3 and X 4 are N, the remainder being CH;
  • W is selected from the group consisting of O, S, CR 7 R 8 and NR 9 ;
  • R 3 is optionally the same or different, and R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 5-10 membered aryl and 5- a 10-membered heteroaryl group, wherein the group is optionally substituted with one or more R a ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, -NR 10 R 11 , C 1-6 alkyl, C 3-6 cycloalkyl, 5-10 membered aryl, and 5-10 membered heteroaryl, wherein The group is optionally substituted with one or more R a ;
  • R 10 and R 11 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-10 membered aryl, and 5-10 membered heteroaryl, wherein the group is optionally One or more R a substitutions;
  • R 9 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-10 membered aryl, and 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R a substitution;
  • the condition is: when R 1 is selected from -C(O)NR 5 R 6 , a group for And Y is C.
  • the invention provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof
  • R 1 is selected from the group consisting of -S(O) 2 R 4 and -C(O)NR 5 R 6 ;
  • R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl And a 5-10 membered heteroaryl group, wherein said group is optionally substituted with one or more R a ;
  • R 5 and R 6 are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5 a 10-membered aryl group and a 5-10 membered heteroaryl group, wherein the group is optionally substituted with one or more R a ;
  • R 2 is selected from the group consisting of hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl, wherein said group is optionally substituted with one or more R a ;
  • X 1 , X 2 , X 3 and X 4 are independently selected from CH and N, and 1-2 of X 1 , X 2 , X 3 and X 4 are N, the remainder being CH;
  • W is selected from the group consisting of O, S, CR 7 R 8 and NR 9 ;
  • R 3 is optionally the same or different, and R 3 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, 5-10 membered aryl and 5- a 10-membered heteroaryl group, wherein the group is optionally substituted with one or more R a ;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, -NR 10 R 11 , C 1-6 alkyl, C 3-6 cycloalkyl, 5-10 membered aryl, and 5-10 membered heteroaryl, wherein The group is optionally substituted with one or more R a ;
  • R 10 and R 11 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-10 membered aryl, and 5-10 membered heteroaryl, wherein the group is optionally One or more R a substitutions;
  • R 9 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 5-10 membered aryl, and 5-10 membered heteroaryl, wherein the group is optionally substituted with one or more R a substitution;
  • the condition is: when R 1 is selected from -C(O)NR 5 R 6 , a group for And Y is C.
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • R a is -R, R is not hydrogen.
  • R 4 is selected from C 1-6 alkyl and phenyl, wherein said group is optionally substituted with one or more R a ; in some embodiments of a compound of Formula I R 4 is selected from C 1-4 alkyl and phenyl, wherein said group is optionally substituted by one or more R a ; in some embodiments of the compound of formula I, R 4 is selected from methyl, B And a phenyl group, wherein said group is optionally substituted with one or more R a ; in some preferred embodiments of the compound of formula I, R 4 is selected from the group consisting of methyl, ethyl and phenyl.
  • R 5 and R 6 are, independently, selected from C 1-6 alkyl, wherein said group is optionally substituted with one or more R a ; some embodiments of a compound of Formula I In the scheme, R 5 and R 6 are independently selected from C 1-4 alkyl, wherein the group is optionally substituted by one or more R a ; in some embodiments of the compound of formula I, R 5 and R 6 independently selected from the group consisting of methyl and ethyl, wherein said group is optionally substituted by one or more R a ; in some preferred embodiments of the compound of formula I, R 5 and R 6 are independently selected from methyl .
  • R 2 is selected from C 3-6 cycloalkyl, wherein said group is optionally substituted with one or more R a ; in some embodiments of a compound of Formula I, R is selected from cyclopentyl, wherein said group is optionally substituted with one or more substituents R a; in some embodiments of compounds of formula I, R 2 is selected from cyclopentyl.
  • X 1 , X 2 , X 3 , and X 4 are independently selected from CH and N, and one of X 1 , X 2 , X 3 , and X 4 is N, and the remainder is CH; In some embodiments of the compound of Formula I, X 1 is N, and X 2 , X 3 and X 4 are CH.
  • a group for or And W is selected from the group consisting of CR 7 R 8 and NR 9 , preferably CHR 8 and NR 9 , wherein R 7 , R 8 and R 9 are as defined above; in some embodiments of the compound of formula I, the group for or And W is selected from the group consisting of CR 7 R 8 and NR 9 , preferably CHR 8 and NR 9 , wherein R 7 , R 8 and R 9 are as defined above; in some embodiments of the compound of formula I, the group for or Wherein R 8 and R 9 are as defined above; in some preferred embodiments of the compound of formula I, a group for or
  • R 7 is hydrogen
  • R 8 is selected from the group consisting of hydrogen, —NR 10 R 11 , C 1-6 alkyl, and C 3-6 cycloalkyl, wherein said group is optional Substituted by one or more R a ; in some embodiments of the compound of Formula I, R 7 is hydrogen, and R 8 is selected from -NR 10 R 11 .
  • R 10 and R 11 are, independently, selected from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl, wherein the group is optionally substituted with one or more R a substitution; in some embodiments of a compound of Formula I, R 10 and R 11 are, independently, selected from hydrogen and C 1-4 alkyl, wherein said group is optionally substituted with one or more R a ; In some preferred embodiments of the compound I, R 10 and R 11 are independently selected from methyl.
  • R 7 is hydrogen and R 8 is -N (CH 3) 2.
  • R 9 is selected from the group consisting of hydrogen and C 1-4 alkyl, wherein said group is optionally substituted with one or more R a ; in some preferred embodiments of the compound of Formula I R 9 is selected from hydrogen.
  • R 3 is optionally the same or different, and R 3 is selected from C 1-6 alkyl, wherein said group is optionally One or more R a substitutions; in some preferred embodiments of the compounds of formula I, R 3 is absent.
  • the invention provides a compound of formula II or a pharmaceutically acceptable salt or solvate thereof
  • R 1 a group And R 3 are defined as described above.
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the present invention provides a compound of formula III or a pharmaceutically acceptable salt or solvate thereof
  • W is selected from the group consisting of O, S, CR 7 R 8 and NR 9 ;
  • R 1 , R 7 , R 8 and R 9 are as defined above;
  • the condition is: when R 1 is selected from -C(O)NR 5 R 6 , a group for And Y is C.
  • W is selected from the group consisting of CR 7 R 8 and NR 9 .
  • W is selected from the group consisting of CHR 8 and NR 9 .
  • a group for or in some embodiments of a compound of Formula III a group for or In some preferred embodiments of the compound of formula III, a group for or
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the present invention provides a compound of Formula IV or a pharmaceutically acceptable salt or solvate thereof
  • W is selected from CR 7 R 8 and NR 9 ;
  • R 5 , R 6 , R 7 , R 8 and R 9 are as defined above.
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the invention provides the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the invention provides the following compounds:
  • the invention provides the following compounds, or a pharmaceutically acceptable salt or solvate thereof:
  • the invention provides the following compounds:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable Accepted carrier or excipient.
  • the pharmaceutical composition of the present invention can be prepared by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with a suitable pharmaceutically acceptable carrier, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet.
  • a suitable pharmaceutically acceptable carrier for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation such as a tablet.
  • Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, Transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous and intravenous administration.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical compositions may be formulated by admixing the active compound withpharmaceutically acceptable carriers such carriers.
  • pharmaceutically acceptable carriers such carriers.
  • These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbus Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber Or cross-linked polyvinylpyrrolidone.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • Suitable excipients such as fillers, buffers or surfactants.
  • the compound of formula I, II, III or IV, or a pharmaceutically acceptable salt or solvate thereof, of the invention may be administered by any suitable route and method, for example by oral or parenteral (e.g., intravenous) administration.
  • a therapeutically effective amount of a compound of Formula I, II, III or IV is from about 0.0001 to 20 mg/Kg body weight per day, such as from 0.001 to 10 mg/Kg body weight per day.
  • the dosage frequency of a compound of formula I, II, III or IV is determined by the individual patient's needs, for example, once or twice a day, or more times per day. Administration can be intermittent, for example, wherein the patient receives a daily dose of a compound of formula I over a period of several days, followed by a patient not receiving formula I, II, III or IV for several days or more. The daily dose of the compound.
  • the invention provides a method of treating and/or preventing a disease associated with CDK inhibition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, II, III or IV or a pharmaceutical thereof An acceptable salt or solvate, or a pharmaceutical composition comprising a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt or solvate thereof; preferably, said disease associated with CDK inhibition refers to A disease associated with inhibition of CDK4 and/or CDK6; in some embodiments of the invention, the disease associated with inhibition of CDK4 and/or CDK6 comprises cancer.
  • the present invention provides a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt or solvate thereof, or a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt or solvent thereof
  • a pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of a disease associated with CDK inhibition; preferably, the disease associated with CDK inhibition is associated with inhibition of CDK4 and/or CDK6 Disease; In some embodiments of the invention, the disease associated with inhibition of CDK4 and/or CDK6 comprises cancer.
  • the invention provides a method of treating and/or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt thereof, or A solvate, or a pharmaceutical composition comprising a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt or solvate thereof, or a compound of Formula I, II, III or IV, or a pharmaceutically acceptable salt or solvent thereof Use of a pharmaceutical composition of a compound for the preparation of a medicament for the treatment and/or prevention of cancer.
  • the cancer includes, but is not limited to, bladder cancer; breast cancer, such as metastatic breast cancer; colon cancer; kidney cancer; epidermal cancer; liver cancer; lung cancer, such as small cell lung cancer and non-small cells Lung cancer; esophageal cancer; gallbladder cancer; ovarian cancer; pancreatic cancer, such as exocrine pancreatic cancer; gastric cancer; cervical cancer; thyroid cancer; nasal cancer; head and neck cancer; prostate cancer; skin cancer, such as squamous cell carcinoma; lymphoid hematopoietic cells Tumors such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; myeloid hematopoietic tumors, such as
  • the cancer is selected from the group consisting of metastatic breast cancer, melanoma, non-small cell lung cancer, teratoma, neuroendocrine tumor, and liposarcoma.
  • the compound of the invention has obvious inhibitory effect on CDK (CDK4/CDK6), has obvious proliferation inhibition effect on cancer cells, and has good absorption by drug, and has obvious superior oral absorption effect.
  • the invention provides a process for the preparation of a compound of formula I, including but not limited to the following synthetic schemes:
  • Y is N
  • X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 and W are as defined above, and W is not NH,
  • the compound of formula 1-1 is reacted with a compound of formula 1-2 in the presence of a solvent such as DMSO and a base such as potassium carbonate to prepare a compound of formula 1-3, a compound of formula 1-3 in a catalyst (eg 10% Pd/C)
  • a catalyst eg 10% Pd/C
  • the compound of formula 1-4 is reacted with a compound of formula 1-5 (e.g., in tris(dibenzylideneacetone) dipalladium, binaphthyl
  • a compound of formula 1-5 e.g., in tris(dibenzylideneacetone) dipalladium, binaphthyl
  • the compound of formula 1-6 is prepared under conditions of phenylphosphine and cesium carbonate.
  • Y is N
  • X 1 , X 2 , X 3 , X 4 , R 1 , R 2 and R 3 are as defined above, and W is NH,
  • the compound of formula 1-1 is reacted with a compound of formula 1-7 in the presence of a solvent such as DMSO and a base such as potassium carbonate to prepare a compound of formula 1-8, a compound of formula 1-8 in a catalyst (eg 10% Pd/C)
  • a catalyst eg 10% Pd/C
  • Preparing a compound of formula 1-9 by reacting with a reducing agent such as hydrogen, and reacting a compound of formula 1-9 with a compound of formula 1-5 (for example, in tris(dibenzylideneacetone)dipalladium, binaphthyl
  • a compound of formula 1-5 for example, in tris(dibenzylideneacetone)dipalladium, binaphthyl
  • compounds of formula 1-10 are prepared under conditions of phenylphosphine and cesium carbonate.
  • Y is C
  • X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 and W are as defined above, and W is not NH,
  • the compound of the formula 2-1 is reacted with the compound of the formula 2-2 in the presence of a catalyst (for example, tetrakistriphenylphosphine palladium) and a base (for example, sodium carbonate) to prepare a compound of the formula 2-3, a compound of the formula 2-3 and the formula 1- 5
  • a catalyst for example, tetrakistriphenylphosphine palladium
  • a base for example, sodium carbonate
  • the compound is subjected to a reaction (for example, under the conditions of tris(dibenzylideneacetone)dipalladium, binaphthyldiphenylphosphine and cesium carbonate) to prepare a compound of the formula 2-4.
  • the compound of formula 2-1 is reacted with a compound of formula 2-5 in the presence of a catalyst (e.g., tetrakistriphenylphosphine palladium) and a base (e.g., sodium carbonate) to prepare a compound of formula 2-6, a compound of formula 2-6 in a catalyst (e.g.
  • the compound of formula 2-7 is prepared by reacting with 10% Pd/C) and a reducing agent (for example, hydrogen), and the compound of formula 2-7 is reacted with the compound of formula 1-5 (for example, in tris(dibenzylideneacetone)
  • the compound of formula 2-8 is prepared under the conditions of palladium, binaphthyldiphenylphosphonium and cesium carbonate.
  • Y is C
  • the compound of the formula 2-1 is reacted with a compound of the formula 2-9 in the presence of a catalyst such as tetrakistriphenylphosphine palladium and a base such as sodium carbonate to prepare a compound of the formula 2-10, a compound of the formula 2-10 and the formula 1- 5
  • a catalyst such as tetrakistriphenylphosphine palladium
  • a base such as sodium carbonate
  • the compound is subjected to a reaction (for example, under the conditions of tris(dibenzylideneacetone)dipalladium, binaphthyldiphenylphosphine and cesium carbonate) to prepare a compound of the formula 2-11.
  • the compound of the formula 2-1 is reacted with a compound of the formula 2-12 in the presence of a catalyst such as tetrakistriphenylphosphine palladium and a base such as sodium carbonate.
  • a catalyst eg, 10% Pd/C
  • a reducing agent eg, hydrogen
  • the compound is subjected to a reaction (for example, a compound of the formula 2-15 can be produced under the conditions of tris(dibenzylideneacetone)dipalladium, binaphthyldiphenylphosphine and cesium carbonate).
  • the compound of the formula 2-1 is reacted with a compound of the formula 2-16 in the presence of a base such as potassium carbonate to prepare a compound of the formula 2-17, and the compound of the formula 2-17 is reacted with a compound of the formula 2-18 (for example, hydroboration of acetic acid can be carried out)
  • the compound of formula 2-19 is prepared under sodium conditions, and the compound of formula 2-19 is reacted in the presence of a catalyst (for example, 10% Pd/C) and a reducing agent (for example, hydrogen) to prepare a compound of formula 2-20, formula 2-20.
  • a catalyst for example, 10% Pd/C
  • a reducing agent for example, hydrogen
  • a compound of the formula 1-5 for example, a compound of the formula 2-21 can be produced under the conditions of tris(dibenzylideneacetone)dipalladium, binaphthyldiphenylphosphine and cesium carbonate).
  • R 2 is defined as described above
  • 5-Bromo-2,6-dichloropyrimidine and a compound of the formula 3-1 are reacted in the presence of diisopropylethylamine to give a compound of the formula 3-2, which is reacted with trimethylsilylacetylene
  • a compound of the formula 3-3 can be produced under the conditions of triethylamine, bistriphenylphosphine palladium dichloride and cuprous iodide
  • the compound of the formula 3-3 is reacted with a halogenating agent (for example, N-bromosuccinimide) (for example, in the presence of silver nitrate) to prepare a compound of the formula 3-4, and the compound of the formula 3-4 is reacted (for example,
  • the compound of formula 3-5 is prepared in the presence of tetrabutylammonium fluoride trihydrate.
  • R 2 and R 4 are as defined above,
  • the compound of formula 3-5 is reacted with a compound of formula 3-6 (for example, in the presence of cuprous iodide) to prepare a compound of formula 3-7.
  • R 2 , R 5 and R 6 are as defined above,
  • the compound of the formula 4-1 is reacted with propynol (for example, it can be complexed with tetrabutylammonium fluoride trihydrate and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane
  • a compound of the formula 4-2 is prepared, and a compound of the formula 4-2 is reacted (for example, in the presence of tetrabutylammonium fluoride trihydrate) to prepare a compound of the formula 4-3, a compound of the formula 4-3
  • the compound of formula 4-5 is prepared by reacting a compound of 4-4 (for example, in the presence of manganese dioxide).
  • Compound as used in the present invention includes all stereoisomers, geometric isomers and tautomers.
  • the compounds of the invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the asymmetric carbon atom-containing compound of the present invention can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • the compounds of the invention also include tautomeric forms.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond and accompanied by a proton transfer.
  • optionally substituted alkyl as defined below means “alkyl” or “substituted alkyl”.
  • the optionally substituted group may be unsubstituted (such as CH 2 CH 3 ), fully substituted (such as CF 2 CF 3 ), monosubstituted (such as CH 2 CH 2 F) or between fully substituted and monosubstituted The degree of substitution (such as CH 2 CHF 2 , CF 2 CH 3 , CFHCHF 2, etc.).
  • a cycloalkyl group correspondingly, a cycloalkyl group is defined to include an optionally substituted alkyl group, and thus repeated).
  • substituents are generally understood to have a maximum molecular weight of about 1,000 Daltons, and more typically, up to about 500 Daltons (except where it is apparent that large molecular substituents are desired, such as polypeptides, polysaccharides, polyethylidene) Glycols, DNA and RNA, etc.).
  • heteroatom refers to an atom other than carbon and hydrogen.
  • the heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms.
  • the two or more heteroatoms may be identical to each other, or some or all of the two or more heteroatoms may be different from each other.
  • C 1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms
  • C 2-6 means that the group may have 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms
  • C 3-6 means that the group may have 3 carbon atoms , 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • hetero means a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), that is, an atom other than carbon and hydrogen or an atomic group containing the same, and the hetero atom is independently selected from the group consisting of oxygen, nitrogen, sulfur, Phosphorus, silicon, germanium, aluminum, and boron, in embodiments in which two or more heteroatoms are present, the two or more heteroatoms may be identical to each other, or a portion of the two or more heteroatoms Or all different from each other.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • cyano refers to a -CN group.
  • alkyl refers to an optionally substituted straight or optionally substituted branched monovalent saturated hydrocarbon.
  • Alkyl as used herein may have from 1 to about 18 carbon atoms, or from 1 to about 10 carbon atoms, preferably from 1 to 6 carbon atoms.
  • lower alkyl alone or in combination, refers to an alkyl group having a lower carbon number, for example, having from 1 to about 8 carbon atoms, preferably from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms.
  • alkyl groups herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-1- Butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl -1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- Dimethyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as h
  • C 1-6 alkyl means that it may be composed of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms or six carbon atoms.
  • Alkyl, the alkyl group herein also encompasses the case where no numerical range is specified.
  • C 1-4 alkyl means an alkyl group which may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, specifically, methyl, ethyl or n-propyl.
  • Base isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • alkenyl refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon having one or more carbon-carbon double bonds.
  • the alkenyl group has, for example, from 2 to about 18 carbon atoms, or from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms.
  • the double bond in these groups may be in the cis or trans configuration and should be understood to encompass both isomers.
  • C 2-6 alkenyl refers to an alkenyl group, alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • Non-limiting examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl, and the like.
  • alkynyl refers to an optionally substituted straight or optionally substituted branched monovalent hydrocarbon having one or more carbon-carbon triple bonds.
  • the alkynyl group has from 2 to about 18 carbon atoms or from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms.
  • C 2-6 alkenyl refers to an alkenyl group, alkynyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • Non-limiting examples include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), and 1, 3-butadiynyl (-C ⁇ CC ⁇ CH) and the like.
  • the term "member” refers to the number of skeletal atoms that make up the ring.
  • “3-6 yuan” means that the number of skeleton atoms constituting the ring is 3, 4, 5 or 6;
  • “5-10 yuan” means that the number of skeleton atoms constituting the ring is 5, 6 , 7, 8, 9, or 10.
  • cyclohexane, pyridine, pyran and pyrimidine are six-membered rings, while cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings.
  • the cycloalkyl group may be a monocyclic, fused polycyclic, bridged or spiro ring structure.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl, and spiro[3.3] heptyl, and the like.
  • heterocycloalkyl refers to a non-aromatic monocyclic, fused polycyclic, bridged or spiro ring system wherein some of the ring atoms are selected from the group consisting of N, O, S(O) n (where n is 0, 1 or 2) heteroatoms, the remaining ring atoms are C. Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • Examples of the 3-membered heterocycloalkyl group include, but are not limited to, an oxiranyl group, an ethylenethio group, and a cycloalkyl group
  • examples of the 4-membered heterocycloalkyl group include, but are not limited to, azetidinyl, anthranilyl
  • Examples of the thibutane group, a 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1,1-di Examples of oxoisothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl and dihydrothienyl, 6-membered heterocycloalkyl
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-10 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from the group consisting of N, O and S, the remaining ring atoms being C, and having at least one aromatic ring.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl and isodecyl.
  • solvate refers to a combination of a compound of the invention and a solvent molecule formed by solvation.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without biologically adverse effects.
  • acid including organic and inorganic acids
  • base addition salts including organic and inorganic bases
  • the pharmaceutically acceptable salt is the hydrochloride salt.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • pharmaceutically acceptable carrier refers to those carriers which have no significant irritation to the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” means an inert substance which, together with the active ingredient, which facilitates administration of the active ingredient, including, but not limited to, acceptable for human or animal use as permitted by the State Food and Drug Administration (eg Any of the glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, Isotonicity agent, solvent or emulsifier.
  • Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols, and the like.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient. Also depending on the particular active substance, a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • patient or “individual” includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.).
  • mammals eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include recombination through some recombination of bonding electrons.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atomic weight or mass number different from the atomic mass or mass number normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, respectively. 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically-labeled compounds of the present application can be used in compound and/or substrate tissue distribution assays.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for an unisotopically labeled reagent by procedures similar to those disclosed in the schemes and/or examples disclosed below.
  • substitution with heavier isotopes such as deuterium (ie, 2 H) can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • the hydrazine substitution may be partial or complete, and the partial hydrazine substitution means that at least one hydrogen is substituted by at least one hydrazine.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the asymmetric carbon atom-containing compounds of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • Boc- represents a tert-butoxycarbonyl group.
  • Step 1 Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate
  • the extract was dried with anhydrous sodium sulfate, filtered and evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 1 3-(2-Chloro-4-(cyclopentylamino)pyrimidin-5-yl)propan-2-yn-1-ol
  • Step 2 7-Cyclopentyl-6-methanesulfonyl-N-(5-(piperazin-1-yl)pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- Synthesis of amine hydrochloride
  • the sodium methylsulfinate was used in place of sodium methylsulfinate to synthesize according to the method of Example 1.
  • the intermediate 3 was used in place of 5-(4-tert-butyloxycarbonyl)piperazine-2-aminopyridine and synthesized according to Example 1.
  • the intermediate 2 and the intermediate 6 were used as a starting material, and the mixture was synthesized according to the method of the step 2 of Example 1.
  • ribociclib (100.0 mg, 0.23 mmoL) was dissolved in 50 mL of a methanolic hydrogen chloride solution (4.0 mol/L), stirred at room temperature for 2 hours, and concentrated to give ribociclib hydrochloride (108.4 mg, yield 100.0%).
  • #AM9260G were purchased from Life Technology. First, 1X Buffer A (50 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween 20 and 2 mM DTT) was placed. Compounds were dissolved in DMSO to 1 mM and diluted in DMSO gradient and then diluted 25-fold with buffer A (final concentration of DMSO 1%). CDK4/CyclinD3 and CDK6/CyclinD3 were diluted with buffer A, respectively. Finally, the substrate and ATP were configured with buffer A.
  • 1X Buffer A 50 mM HEPES, pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween 20 and 2 mM DTT
  • the compounds of the present invention have a significant inhibitory effect on the activity of CDK kinase (CDK4, CDK6).
  • Test Example 2 Determines the inhibitory effect of the compound on the proliferation of the human colon cancer cell line Colo-205 and the breast cancer cell line MCF7.
  • the compounds of the present invention have significant proliferation inhibitory activity against Colo205 cells.
  • the compounds of the present invention have significant proliferation inhibitory activity against MCF-7 cells.
  • test compound Three healthy adult male rats were used for each test compound, and the test compound was suspended in 20% sulfobutylether- ⁇ -cyclodextrin at a concentration of 1 mg/mL, and administered in a single dose. It was 5 mL/kg and the dose was 5 mg/kg.
  • the animals administered by intragastric administration were fasted overnight before the experiment. The fasting time was from 10 hours before the administration to 4 hours after the administration, and 0.25, 0.5, 1, 2, 4, 6, 8 and 24 after the intragastric administration. Blood is collected in hours.

Abstract

本发明属于药物化学领域，涉及一种取代的吡咯并嘧啶类CDK抑制剂，具体涉及式Ⅰ化合物或其药学上可接受的盐或溶剂化物、其制备方法、药物组合物，还涉及这类化合物及其药物组合物在制备治疗与CDK抑制作用相关的疾病的药物中的用途，本发明的化合物对CDK具有明显的抑制作用，且药代吸收良好，具有明显较优的口服吸收效果。

Description

取代的吡咯并嘧啶类CDK抑制剂、包含其的药物组合物以及它们的用途
相关申请的交叉引用
本申请要求于2016年3月25日向中国国家知识产权局提交的第201610180458.9号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本发明属于药物化学领域，涉及取代的吡咯并嘧啶类CDK抑制剂、其制备方法、药物组合物，还涉及这类化合物及其药物组合物在制备治疗与CDK抑制作用相关的疾病的药物中的用途。
背景技术
细胞周期蛋白激酶(CDK)属于丝氨酸/苏氨酸蛋白激酶，主要参与调控细胞周期。例如CDK1、CDK2、CDK4和CDK6参与调控细胞周期的进程和检验点，除此之外CDK8和CDK9参与调控细胞转录活性。细胞周期蛋白Cyclin通过与CDKs结合激活后者的激酶活性，对下游的底物进行磷酸化修饰参与细胞周期的调控。不同的CDKs与特定的周期蛋白结合。其中CDK4和CDK6通过与Cyclin D家族蛋白结合活化后，对下游RB蛋白磷酸化修饰，从而解除RB对转录因子E2F的抑制作用，进而激活其转录活性，引起细胞周期由G1期向S期过渡。
无论是pRB自身的缺陷还是其调节因子的异常均能引起细胞过渡增殖，这在肿瘤中非常常见。其中约80％的肿瘤细胞中存在正常的pRB。多数情况下是由于RB信号通路的调控因子异常导致肿瘤的恶性增殖。例如，在套细胞淋巴瘤和多发性骨髓瘤中，CyclinD家族蛋白过渡细胞核转移导致RB的失活，在乳腺癌和食管鳞状癌中，CyclinD过渡表达，CDK4在脂肪肉瘤中能够过渡表达，p16在黑色素瘤、非小细胞肺癌和胰腺癌等中存在缺陷等。因此，通过抑制CDK4/CDK6的激酶活性可以达到抑制肿瘤生长的目的，其有效性在很多体内和体外的肿瘤模型中得到了验证，抑制其活性能够阻滞细胞周期到G1期，进而抑制肿瘤的生长。此外，小鼠敲除模型显示敲除CDK4或者CDK6后对动物的生长发育影响较小，仅在个别的器官出现异常，而CDK1的敲除引起胚胎致死。因此，与广谱的CDKs家族抑制剂相比，选择性的靶向CDK4/CDK6抑制剂可能具有更大的治疗窗口。
WO2010020675中公开了作为CDK4/CDK6抑制剂的化合物ribociclib(又称为LEE011)，其由诺华公司开发，目前已进入III期临床试验。
Figure PCTCN2017078260-appb-000001
发明概述
一方面，本发明提供一种式I化合物或其药学上可接受的盐或溶剂化物
Figure PCTCN2017078260-appb-000002
其中，
R1选自-S(O)2R4和-C(O)NR5R6；
R4选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R5和R6独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R2选自氢、C1-6烷基和C3-6环烷基，其中所述基团任选被一种或多种Ra取代；
X1、X2、X3和X4独立地选自CH和N，且X1、X2、X3和X4中的1-2个为N，其余为CH；
基团
Figure PCTCN2017078260-appb-000003
为
Figure PCTCN2017078260-appb-000004
或者
Figure PCTCN2017078260-appb-000005
且当基团
Figure PCTCN2017078260-appb-000006
为
Figure PCTCN2017078260-appb-000007
时，Y选自CH和N，当基团
Figure PCTCN2017078260-appb-000008
为
Figure PCTCN2017078260-appb-000009
时，Y为C；
W选自O、S、CR7R8和NR9；
存在0-4个R3，且所述R3任选地相同或者不同，所述R3选自C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R7和R8独立地选自氢、-NR10R11、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R10和R11独立地选自氢、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R9选自氢、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
Ra选自卤素、氰基、-R、-OR、＝O、-SR、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-C(＝O)NRR、-C(＝O)OR、-OC(＝O)NRR、-OC(＝O)OR、-C(＝O)R、-S(＝O)2OR、-S(＝O)2R、-OS(＝O)2OR、-S(＝O)2NRR、-S(＝O)R、-NRS(＝O)2R、-NRS(＝O)2NRR、-NRS(＝O)2OR、-OP(＝O)(OR)2、-P(＝O)(OR)2、-C(＝O)R、-C(＝S)R、-C(＝O)OR、-C(＝S)OR、-C(＝O)SR、-C(＝S)SR、-C(＝O)NRR、-C(＝S)NRR、-C(＝NR)NRR和-NRC(＝NR)NRR；R独立地选自氢、C1-6烷基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基；
条件是：当R1选自-C(O)NR5R6时，基团
Figure PCTCN2017078260-appb-000010
为
Figure PCTCN2017078260-appb-000011
且Y为C。
发明详述
一方面，本发明提供一种式I化合物或其药学上可接受的盐或溶剂化物
Figure PCTCN2017078260-appb-000012
其中，
R1选自-S(O)2R4和-C(O)NR5R6；
R4选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R5和R6独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R2选自氢、C1-6烷基和C3-6环烷基，其中所述基团任选被一种或多种Ra取代；
X1、X2、X3和X4独立地选自CH和N，且X1、X2、X3和X4中的1-2个为N，其余为CH；
基团
Figure PCTCN2017078260-appb-000013
为
Figure PCTCN2017078260-appb-000014
或者
Figure PCTCN2017078260-appb-000015
且当基团
Figure PCTCN2017078260-appb-000016
为
Figure PCTCN2017078260-appb-000017
时，Y选自CH和N，当基团
Figure PCTCN2017078260-appb-000018
为
Figure PCTCN2017078260-appb-000019
时，Y为C；
W选自O、S、CR7R8和NR9；
存在0-4个R3，且所述R3任选地相同或者不同，所述R3选自C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R7和R8独立地选自氢、-NR10R11、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R10和R11独立地选自氢、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
R9选自氢、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
Ra选自卤素、氰基、-R、-OR、＝O、-SR、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-C(＝O)NRR、-C(＝O)OR、-OC(＝O)NRR、-OC(＝O)OR、-C(＝O)R、-S(＝O)2OR、-S(＝O)2R、-OS(＝O)2OR、-S(＝O)2NRR、-S(＝O)R、-NRS(＝O)2R、-NRS(＝O)2NRR、-NRS(＝O)2OR、-OP(＝O)(OR)2、-P(＝O)(OR)2、-C(＝O)R、-C(＝S)R、-C(＝O)OR、-C(＝S)OR、-C(＝O)SR、-C(＝S)SR、-C(＝O)NRR、-C(＝S)NRR、-C(＝NR)NRR和-NRC(＝NR)NRR；R独立地选自氢、C1-6烷基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基；
条件是：当R1选自-C(O)NR5R6时，基团
Figure PCTCN2017078260-appb-000020
为
Figure PCTCN2017078260-appb-000021
且Y为C。
应当理解，当W选自O、S、CR7R8和NR9时，基团
Figure PCTCN2017078260-appb-000022
相应的为
Figure PCTCN2017078260-appb-000023
Figure PCTCN2017078260-appb-000024
当Y选自CH和N时，基团
Figure PCTCN2017078260-appb-000025
相应的为
Figure PCTCN2017078260-appb-000026
当Y选自C时，基团
Figure PCTCN2017078260-appb-000027
相应的为
Figure PCTCN2017078260-appb-000028
在式I化合物的一些实施方案中，所述药学上可接受的盐为盐酸盐。
在式I化合物的一些实施方案中，当Ra为-R时，R不为氢。
在式I化合物的一些实施方案中，R4选自C1-6烷基和苯基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些实施方案中，R4选自C1-4烷基和苯基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些实施方案中，R4选自甲基、乙基和苯基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些优选实施方案中，R4选自甲基、乙基和苯基。
在式I化合物的一些实施方案中，R5和R6独立地选自C1-6烷基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些实施方案中，R5和R6独立地选自C1-4烷基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些实施方案中，R5和R6独立地选自甲基和乙基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些优选实施方案中，R5和R6独立地选自甲基。
在式I化合物的一些实施方案中，R2选自C3-6环烷基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些实施方案中，R2选自环戊基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些实施方案中，R2选自环戊基。
在式I化合物的一些实施方案中，X1、X2、X3和X4独立地选自CH和N，且X1、X2、X3和X4中的1个为N，其余为CH；在式I化合物的一些实施方案中，X1为N，X2、X3和X4为CH。在式I化合物的一些实施方案中，基团
Figure PCTCN2017078260-appb-000029
为
Figure PCTCN2017078260-appb-000030
或者
Figure PCTCN2017078260-appb-000031
且W选自CR7R8和NR9，优选为CHR8和NR9，其中R7、R8和R9的定义如前所述；在式I化合物的一些实施方案中，基团
Figure PCTCN2017078260-appb-000032
为
Figure PCTCN2017078260-appb-000033
或者
Figure PCTCN2017078260-appb-000034
且W选自CR7R8和NR9，优选为CHR8和NR9，其中R7、R8和R9的定义如前所述；在式I化合物的一些实施方案中，基团
Figure PCTCN2017078260-appb-000035
为
Figure PCTCN2017078260-appb-000036
或者
Figure PCTCN2017078260-appb-000037
其中R8和R9的定义如前所述；在式I化合物的一些优选实施方案中，基团
Figure PCTCN2017078260-appb-000038
为
Figure PCTCN2017078260-appb-000039
或者
Figure PCTCN2017078260-appb-000040
在式I化合物的一些实施方案中，R7为氢，且R8选自氢、-NR10R11、C1-6烷基和C3-6环烷基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些实施方案中，R7为氢，且R8选自-NR10R11。
在式I化合物的一些实施方案中，R10和R11独立地选自氢、C1-6烷基和C3-6环烷基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些实施方案中，R10和R11独立地选自氢和C1-4烷基，其中所 述基团任选被一种或多种Ra取代；在式I化合物的一些优选实施方案中，R10和R11独立地选自甲基。
在式I化合物的一些优选实施方案中，R7为氢，且R8为-N(CH3)2。
在式I化合物的一些实施方案中，R9选自氢和C1-4烷基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些优选实施方案中，R9选自氢。
在式I化合物的一些实施方案中，存在0-4个R3，且所述R3任选地相同或者不同，R3选自C1-6烷基，其中所述基团任选被一种或多种Ra取代；在式I化合物的一些优选实施方案中，R3不存在。
另一方面，本发明提供一种式Ⅱ化合物或其药学上可接受的盐或溶剂化物
Figure PCTCN2017078260-appb-000041
其中R1、基团
Figure PCTCN2017078260-appb-000042
和R3定义如前所述。
在式Ⅱ化合物的一些实施方案中，所述药学上可接受的盐为盐酸盐。
再一方面，本发明提供一种式Ⅲ化合物或其药学上可接受的盐或溶剂化物
Figure PCTCN2017078260-appb-000043
其中，
基团
Figure PCTCN2017078260-appb-000044
为
Figure PCTCN2017078260-appb-000045
或者
Figure PCTCN2017078260-appb-000046
且当基团
Figure PCTCN2017078260-appb-000047
为
Figure PCTCN2017078260-appb-000048
时，Y选自CH和N，当基团
Figure PCTCN2017078260-appb-000049
为
Figure PCTCN2017078260-appb-000050
时，Y为C；
W选自O、S、CR7R8和NR9；
R1、R7、R8和R9定义如前所述；
条件是：当R1选自-C(O)NR5R6时，基团
Figure PCTCN2017078260-appb-000051
为
Figure PCTCN2017078260-appb-000052
且Y为C。
在式Ⅲ化合物的一些优选实施方案中，W选自CR7R8和NR9。
在式Ⅲ化合物的一些更优选实施方案中，W选自CHR8和NR9。
在式Ⅲ化合物的一些实施方案中，基团
Figure PCTCN2017078260-appb-000053
为
Figure PCTCN2017078260-appb-000054
或者
Figure PCTCN2017078260-appb-000055
在式Ⅲ化合物的一些实施方案中，基团
Figure PCTCN2017078260-appb-000056
为
Figure PCTCN2017078260-appb-000057
或者
Figure PCTCN2017078260-appb-000058
在式Ⅲ化合物的一些优选实施方案中，基团
Figure PCTCN2017078260-appb-000059
为
Figure PCTCN2017078260-appb-000060
或者
Figure PCTCN2017078260-appb-000061
在式Ⅲ化合物的一些实施方案中，所述药学上可接受的盐为盐酸盐。
再一方面，本发明提供一种式Ⅳ化合物或其药学上可接受的盐或溶剂化物
Figure PCTCN2017078260-appb-000062
其中，
W选自CR7R8和NR9；
R5、R6、R7、R8和R9定义如前所述。
在式Ⅳ化合物的一些实施方案中，基团
Figure PCTCN2017078260-appb-000063
为
Figure PCTCN2017078260-appb-000064
在式Ⅳ化合物的一些优选实施方案中，基团
Figure PCTCN2017078260-appb-000065
为
Figure PCTCN2017078260-appb-000066
在式Ⅳ化合物的一些实施方案中，所述药学上可接受的盐为盐酸盐。
又一方面，本发明提供下列化合物或其药学上可接受的盐或溶剂化物：
Figure PCTCN2017078260-appb-000067
在本发明的一些实施方式中，所述药学上可接受的盐为盐酸盐。
还一方面，本发明提供了下列化合物：
Figure PCTCN2017078260-appb-000068
再一方面，本发明提供下列化合物或其药学上可接受的盐或溶剂化物：
7-环戊基-6-甲磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺；
7-环戊基-6-乙磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺；
7-环戊基-6-甲磺酰基-N-(5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺；
7-环戊基-6-甲磺酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺；
7-环戊基-6-甲磺酰基-N-(5-(哌啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺；
7-环戊基-6-N,N-二甲氨基甲酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺；
7-环戊基-6-苯磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺。
还一方面，本发明提供下列化合物：
7-环戊基-6-甲磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐；
7-环戊基-6-乙磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐；
7-环戊基-6-甲磺酰基-N-(5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐；
7-环戊基-6-甲磺酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐；
7-环戊基-6-甲磺酰基-N-(5-(哌啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐；
7-环戊基-6-N,N-二甲氨基甲酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐；
7-环戊基-6-苯磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐。
另一方面，本发明提供了一种药物组合物，其包含治疗有效量的式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物，以及一种或多种药学上可接受的载体或赋形剂。
本发明的药物组合物可通过将本发明的化合物或其药学上可接受的盐与适宜的药学上可接受的载体组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本发明的化合物或其药学上可接受的盐、水合物、溶剂化物或前药，或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下和静脉内给药。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法和冷冻干燥法等等。
对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂和悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、***胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用 适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本发明所述的式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物可以通过任何适用的途径和方法给药，例如通过口服或肠胃外(例如，静脉内)给药。式I、Ⅱ、Ⅲ或Ⅳ化合物的治疗有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
式I、Ⅱ、Ⅲ或Ⅳ化合物的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受式Ⅰ化合物的每日剂量，接着在若干天或更多天的期间，患者不接受式I、Ⅱ、Ⅲ或Ⅳ化合物的每日剂量。
另一方面，本发明提供了一种治疗和/或预防与CDK抑制作用相关的疾病的方法，所述方法包括给予有需要的个体治疗有效量的式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物、或者包含式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物的药物组合物；优选的，所述与CDK抑制作用相关的疾病是指与CDK4和/或CDK6抑制作用相关的疾病；在本发明的一些实施方案中，所述与CDK4和/或CDK6抑制作用相关的疾病包括癌症。
又一方面，本发明提供了式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物、或者包含式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物的药物组合物在制备用于治疗和/或预防与CDK抑制作用相关的疾病的药物中的用途；优选的，所述与CDK抑制作用相关的疾病是指与CDK4和/或CDK6抑制作用相关的疾病；在本发明的一些实施方案中，所述与CDK4和/或CDK6抑制作用相关的疾病包括癌症。
还一方面，本发明提供了一种治疗和/或预防癌症的方法，所述方法包括给予有需要的个体治疗有效量的式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物、或者包含式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物的药物组合物。
再一方面，本发明提供了式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物、或者包含式I、Ⅱ、Ⅲ或Ⅳ化合物或其药学上可接受的盐或溶剂化物的药物组合物在制备用于治疗和/或预防癌症的药物中的用途。
在本发明的一些实施方案中，所述癌症包括但不限于：膀胱癌；乳腺癌，例如转移性乳腺癌；结肠癌；肾癌；表皮癌；肝癌；肺癌，例如小细胞肺癌和非小细胞肺癌；食道癌；胆囊癌；卵巢癌；胰腺癌，例如外分泌胰腺癌；胃癌；***；甲状腺癌；鼻癌；头颈癌；***癌；皮肤癌，例如鳞状细胞癌；淋巴系的造血细胞肿瘤，例如白血病、急性淋巴性白血病、慢性淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特氏淋巴瘤；髓系造血细胞肿瘤，例如急性和慢性髓系白血病、骨髓增生异常综合征和早幼粒细胞白血病；甲状腺滤泡癌；源于***肿瘤，例如纤维肉瘤和横纹肌肉瘤；中枢或周围神经***肿瘤，例如星形细胞瘤、神经母细胞瘤、神经胶质瘤和神经鞘瘤；黑素瘤；***瘤；畸胎瘤；骨肉瘤；着色性干皮病；角化棘细胞瘤；甲状腺滤泡癌； 脂肪肉瘤；神经内分泌瘤；以及卡波西肉瘤。
在本发明的一些优选实施方案中，所述癌症选自转移性乳腺癌、黑素瘤、非小细胞肺癌、畸胎瘤、神经内分泌瘤和脂肪肉瘤。
本发明的化合物对CDK(CDK4/CDK6)具有明显的抑制作用，对癌细胞有明显的增殖抑制作用，且药代吸收良好，具有明显较优的口服吸收效果。
还一方面，本发明提供一种式I化合物的制备方法，包括但不限于以下合成方案：
合成方案1：
Figure PCTCN2017078260-appb-000069
其中，
Y为N；
X1、X2、X3、X4、R1、R2、R3和W定义如前所述，且W不是NH，
式1-1化合物与式1-2化合物在溶剂(例如DMSO)和碱(例如碳酸钾)的存在下进行反应制备式1-3化合物，式1-3化合物在催化剂(例如10％Pd/C)和还原剂(例如氢气)的存在下进行反应制备式1-4化合物，式1-4化合物与式1-5化合物进行反应(例如在三(二亚苄基丙酮)二钯、联萘二苯磷和碳酸铯的条件下)制备式1-6化合物。
合成方案2：
Figure PCTCN2017078260-appb-000070
其中，
Y为N；
X1、X2、X3、X4、R1、R2和R3定义如前所述，且W为NH，
式1-1化合物与式1-7化合物在溶剂(例如DMSO)和碱(例如碳酸钾)的存在下进行反应制备式1-8化合物，式1-8化合物在催化剂(例如10％Pd/C)和还原剂(例如氢气)的存在下进行反应制备式1-9化合物，式1-9化合物与式1-5化合物进行反应(例如在三(二亚苄基丙酮)二钯、联萘二苯磷和碳酸铯的条件下)制备式1-10化合物。
合成方案3：
Figure PCTCN2017078260-appb-000071
其中，
Y为C；
X1、X2、X3、X4、R1、R2、R3和W定义如前所述，且W不是NH，
式2-1化合物与式2-2化合物在催化剂(例如四三苯基膦钯)和碱(例如碳酸钠)的存在下进行反应制备式2-3化合物，式2-3化合物与式1-5化合物进行反应(例如在三(二亚苄基丙酮)二钯、联萘二苯磷和碳酸铯的条件下)制备式2-4化合物。
合成方案4：
Figure PCTCN2017078260-appb-000072
其中X1、X2、X3、X4、R1、R2、R3和W定义如前所述，且W不是NH，
式2-1化合物与式2-5化合物在催化剂(例如四三苯基膦钯)和碱(例如碳酸钠)的存在下进行反应制备式2-6化合物，式2-6化合物在催化剂(例如10％Pd/C)和还原剂(例如氢气)的存在下进行反应制备式2-7化合物，式2-7化合物与式1-5化合物进行反应(例如在三(二亚苄基丙酮)二钯、联萘二苯磷和碳酸铯的条件下)制备式2-8化合物。
合成方案5：
Figure PCTCN2017078260-appb-000073
其中，
Y为C；
其中X1、X2、X3、X4、R1、R2和R3定义如前所述，且W为NH，
式2-1化合物与式2-9化合物在催化剂(例如四三苯基膦钯)和碱(例如碳酸钠)的存在下进行反应制备式2-10化合物，式2-10化合物与式1-5化合物进行反应(例如在三(二亚苄基丙酮)二钯、联萘二苯磷和碳酸铯的条件下)制备式2-11化合物。
合成方案6：
Figure PCTCN2017078260-appb-000074
其中X1、X2、X3、X4、R1、R2和R3定义如前所述，且W为NH，
式2-1化合物与式2-12化合物在催化剂(例如四三苯基膦钯)和碱(例如碳酸钠)的存在下进行反应 制备式2-13化合物，式2-13化合物在催化剂(例如10％Pd/C)和还原剂(例如氢气)的存在下进行反应制备式2-14化合物，式2-14化合物与式1-5化合物进行反应(例如可以在三(二亚苄基丙酮)二钯、联萘二苯磷和碳酸铯的条件下)制备式2-15化合物。
合成方案7：
Figure PCTCN2017078260-appb-000075
其中X1、X2、X3、X4、R1、R2、R3、R10和R11定义如前所述，
式2-1化合物与式2-16化合物在碱(例如碳酸钾)的存在下进行反应制备式2-17化合物，式2-17化合物与式2-18化合物进行反应(例如可以在醋酸硼氢化钠的条件下)制备式2-19化合物，式2-19化合物在催化剂(例如10％Pd/C)和还原剂(例如氢气)的存在下进行反应制备式2-20化合物，式2-20化合物与式1-5化合物进行反应(例如可以在三(二亚苄基丙酮)二钯、联萘二苯磷和碳酸铯的条件下)制备式2-21化合物。
合成方案8：
Figure PCTCN2017078260-appb-000076
其中R2定义如前所述，
5-溴-2,6-二氯嘧啶和式3-1化合物在二异丙基乙基胺的存在下反应得到式3-2化合物，式3-2化合物与三甲基硅基乙炔反应(例如可以在三乙胺、双三苯基膦二氯化钯和碘化亚铜的条件下)制备式3-3化合物， 式3-3化合物和卤代试剂(例如N-溴代丁二酰亚胺)进行反应(例如在硝酸银的存在下)制备式3-4化合物，式3-4化合物进行反应(例如可以在三水合四丁基氟化铵的存在下)制备式3-5化合物。
合成方案9：
Figure PCTCN2017078260-appb-000077
其中R2和R4定义如前所述，
式3-5化合物与式3-6化合物反应(例如可以在碘化亚铜的存在下)制备式3-7化合物。
合成方案10：
Figure PCTCN2017078260-appb-000078
其中R2、R5和R6定义如前所述，
式4-1化合物与丙炔醇反应(例如可以在四丁基氟化胺三水合物和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物的存在下)制备式4-2化合物，式4-2化合物进行反应(例如可以在四丁基氟化铵三水合物的存在下)制备式4-3化合物，式4-3化合物与式4-4化合物进行反应(例如可以在二氧化锰的存在下)制备式4-5化合物。
上述方案表示了构成本发明的合成方法，是用于通过特定实施例描述可应用的化学方法，而不是表示本发明的范围或意在限制。不管是不是通过相同的变量名(即，R1、R2、R3等)进行标识，本文合成方案中的化学结构描绘了用本文化合物式中相应位置的化学基团定义在此进行适当限定的变量。在用于合成另一种化合物的化学结构式中化学基团的适当性在本领域普通技术人员的知识范围之内。
定义：
本发明所述的“化合物”包括所有的立体异构体、几何异构体和互变异构体。
本发明化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本发明化合物还包括互变异构体形式。互变异构体形式来源于一个单键与相邻的双键交换并一起伴随一个质子的迁移。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，下文定义的“任选取代的烷基”是指“烷基”或“取代的烷基”。此外，任选取代的基团可以是未被取代(如CH2CH3)、完全取代(如CF2CF3)、单取代(如CH2CH2F)或介于完全取代和单取代之间的取代程度(如CH2CHF2、CF2CH3、CFHCHF2等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式(例如，取代烷基包括任选取代的环烷基，相应地，环烷基被定义为包括任选取代的烷基，如此反复)。因此，所述取代基通常应被理解为最大分子量为约1,000道尔顿，更通常地，最大约500道尔顿(除显然需要大分子取代基的情况之外，例如多肽、多糖、聚乙二醇、DNA和RNA等)。
术语“杂原子”或“杂”是指除碳和氢之外的原子。杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子。在出现两个或更多杂原子的实施方式中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部彼此不同。
本文中的数字范围，是指给定范围中的各个整数。例如，“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子；“C2-6”是指该基团可具有2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子；“C3-6”是指该基团可具有3个碳原子、4个碳原子、5个碳原子或6个碳原子。术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代，酮取代不会发生在芳香基上。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，即碳和氢以外的原子或含有这些原子的原子团，杂原子独立地选自氧、氮、硫、磷、硅、锗、铝和硼，在出现两个或更多杂原子的实施方式中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的部分或全部彼此不同。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“氰基”指-CN基团。
术语“烷基”是指任选取代的直链或任选取代的支链的一价饱和烃。本文的“烷基”可具有1-约18个碳原子，或具有1-约10个碳原子，优选1-6个碳原子。本文单独或组合使用的“低级烷基”是指碳数较少的烷基，例如其具有1-约8个碳原子，优选1-约6个碳原子，或1-约4个碳原子。本文的烷基实例包括但不限于甲基、乙基、正丙基、异丙基、2-甲基-l-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-l-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-l-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-l-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基和己基，以及更长的烷基基团，如庚基和辛基等。本文中出现数字范围 时，例如“C1-6烷基”是指可由1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烷基，本文的烷基也包含未指定数字范围的情况。例如“C1-4烷基”是指可由1个碳原子、2个碳原子、3个碳原子或4个碳原子构成的烷基，具体而言，是指甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
术语“烯基”是指任选取代的直链或任选取代的支链的一价烃，其具有一个或多个碳-碳双键。所述烯基例如具有2-约18个碳原子，或具有2-约10个碳原子，更优选2-约6个碳原子。这些基团中的双键可以为顺式或反式构型，并应被理解为包含所述两种异构体。本文中出现数字范围时，例如“C2-6烯基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烯基，烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基和1,3-丁二烯基等。
术语“炔基”是指任选取代的直链或任选取代的支链的一价烃，其具有一个或多个碳-碳三键。例如所述炔基具有2-约18个碳原子或2-约10个碳原子，更优选2-约6个碳原子。本文中出现数字范围时，例如“C2-6烯基”是指可由2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子构成的烯基，炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH3)、2-丙炔基(-CH2-C≡CH)和1,3-丁二炔基(-C≡C-C≡CH)等。
术语“元”是指组成环的骨架原子的数目。例如，“3-6元”是指组成环的骨架原子的数目为3个、4个、5个或6个；“5-10元”是指组成环的骨架原子的数目为5个、6个、7个、8个、9个或10个。因此，举例而言，环己烷、吡啶、吡喃和嘧啶为六元环，而环戊烷、吡咯、四氢呋喃和噻吩为五元环。
术语“环烷基”是指由碳原子和氢原子组成的饱和的或不饱和的非芳香性的环状烃基，优选包含1或2个环。所述环烷基可以是单环、稠合多环、桥环或螺环结构。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、双环[2.2.1]庚基和螺[3.3]庚基等。
术语“杂环烷基”是指无芳香性的单环、稠合多环、桥环或螺环体系基团，其中部分环原子是选自N、O、S(O)n(其中n为0、1或2)的杂原子，其余环原子为C。这样的环可以是饱和的或不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基和环氮乙烷基，4元杂环烷基的实例包括但不限于吖丁啶基、噁丁环基和噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基、吡咯啉基、二氢呋喃基和二氢噻吩基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,2-、1,4-二噻烷基、二氢吡啶基、四氢吡啶基、二氢吡喃基、四氢吡喃基和二氢噻喃基等。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-10个碳原子。芳基的非限制性实例包括但不限于苯基、萘基和蒽基等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O和S的环原子，其余环原子为C，并且具有至少一个芳香环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、***基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基和异吲哚基等。
术语“溶剂化物”是指通过溶剂化作用形成的本发明化合物与溶剂分子的组合。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。例如酸(包括有机酸和无机酸)加成盐或碱加成盐(包括有机碱和无机碱)，在本发明的一些具体实施方案中，所述药学上可接受的盐为盐酸盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。“药学上可接受的载体”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述载体的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇等。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况， 也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“患者”或“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的中间体和化合物还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、35S、18F、123I、125I和36Cl等。
某些同位素标记的本申请化合物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.本申请引用的所有参考文献整体上并入本申请。
本发明采用下述缩略词：Boc-代表叔丁氧羰基。
实施例
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本发明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。本领域技术人员应该理解：还有形成本发明化合物的其它合成途径，下面提供的是非限制性的实施例。
凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本发明使用的原料都是市场上直接买到未经进一步纯化直接使用的。
除非另有说明，所有原料均为商业原料，并且在使用前未作进一步纯化。本发明所用柱层析采用的是青岛海洋化工所生产的硅胶(200-300目)。薄层色谱采用E.Merck公司生产的预制板(硅胶60PF254,0.25毫米)。核磁共振色谱(NMR)使用Varian VNMRS-400核磁共振仪测定，化学位移以四甲基硅烷(TMS＝δ0.00)为内标，核磁共振氢谱数据记录的格式为：质子数，峰型(s，单峰；d，双重峰；t，三重峰；q，四重峰；m，多重峰)，耦合常数(以赫兹Hz为单位)。
中间体1：4-(6-氨基吡啶-3-基)哌嗪-1-甲酸叔丁酯的合成
Figure PCTCN2017078260-appb-000079
步骤1：4-(6-硝基吡啶-3-基)哌嗪-1-甲酸叔丁酯的合成
向5-溴-2-硝基吡啶(2.03g,10.0mmoL)的二甲基亚砜(100mL)溶液中加入哌嗪-1-甲基叔丁酯(2.24g,12.0mmoL)和碳酸钾(2.76g,20.0mmoL)，混合液70℃反应4小时，冷却，倒入水中，过滤，固体用水洗涤，干燥得4-(6-硝基吡啶-3-基)哌嗪-1-甲酸叔丁酯(2.85g,收率92.5％)。
步骤2：4-(6-氨基吡啶-3-基)哌嗪-1-甲酸叔丁酯的合成
向4-(6-硝基吡啶-3-基)哌嗪-1-甲酸叔丁酯(2.85g,9.24mmoL)的甲醇(150mL)溶液中加入10％钯碳催化剂(0.50g)，该混合液在氢气氛围下(1大气压)室温搅拌24小时，硅藻土过滤，把滤液减压浓缩后得4-(6-氨基吡啶-3-基)哌嗪-1-甲酸叔丁酯(2.12g,收率82.5％)。
中间体2：6-氨基-5’,6’-二氢-[3,4’-联吡啶]-1’(2’H)-甲酸叔丁酯的合成
Figure PCTCN2017078260-appb-000080
向2-氨基-5-溴吡啶(1.73g,0.01mol)的1,4-二氧六环/水(100mL，V/V＝4:1)溶液中依次加入4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(3.40g,0.011mol)和碳酸钠(2.12g,0.02mmol)，向反应体系通氮气2分钟后加入四三苯基膦钯(0.58g,0.5mmol)，100℃反应4小时。向反应液中 加入水(50mL)，用乙酸乙酯(50mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为4:1)得6-氨基-5’,6’-二氢-[3,4’-联吡啶]-1’(2’H)-甲酸叔丁酯(2.53g,收率92.0％)。
1H NMR(400MHz,DMSO-d6):7.95(1H,d,J＝2.4Hz),7.47(1H,dd,J＝8.4Hz,2.4Hz),6.41(1H,d,J＝8.4Hz),6.98(2H,s),5.92(1H,s),3.93(2H,s),3.48(2H,t,J＝5.6Hz),2.36(2H,t,J＝5.6Hz),1.40(9H,s)。
中间体3：4-(6-氨基吡啶-3-基)哌啶-1-甲酸叔丁酯的合成
Figure PCTCN2017078260-appb-000081
向6-氨基-5’,6’-二氢-[3,4’-联吡啶]-1’(2’H)-甲酸叔丁酯(0.53g,1.92mmoL)的甲醇(50mL)溶液中加入10％钯碳催化剂(0.20g)，该混合液在氢气氛围下(1大气压)室温搅拌2小时，硅藻土过滤，把滤液减压浓缩后得4-(6-氨基吡啶-3-基)哌啶-1-甲酸叔丁酯(0.50g,收率94.0％)。
中间体4：5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-胺的合成
Figure PCTCN2017078260-appb-000082
步骤1：1-(6-硝基吡啶-3-基)哌啶-4-酮的合成
向5-溴-2-硝基吡啶(2.03g,10.0mmoL)的二甲基亚砜(100mL)溶液中加入哌啶-4-酮(1.19g,12.0mmoL)和碳酸钾(2.76g,20.0mmoL)，混合液70℃反应4小时，冷却，倒入水中，过滤，固体用水洗涤，干燥得1-(6-硝基吡啶-3-基)哌啶-4-酮(1.44g,65.2％)。
步骤2：N,N-二甲基-1-(6-硝基吡啶-3-基)哌啶-4-胺的合成
向1-(6-硝基吡啶-3-基)哌啶-4-酮(1.44g,6.51mmoL)的1，2-二氯乙烷(100mL)溶液中加入二甲胺的四氢呋喃溶液(6.5mL,2.0M)，混合液室温反应0.5小时后加入醋酸硼氢化钠(2.76g,13.02mmoL)，继续室温搅拌8小时，反应液倒入水中，用二氯甲烷(100mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩得N,N-二甲基-1-(6-硝基吡啶-3-基)哌啶-4-胺(1.32g,81.0％)。
步骤3：5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-胺的合成
向N,N-二甲基-1-(6-硝基吡啶-3-基)哌啶-4-胺(1.32g,5.27mmoL)的甲醇(150mL)溶液中加入10％钯碳催化剂(0.50g)，该混合液在氢气氛围下(1大气压)室温搅拌24小时，过滤，把滤液减压浓缩后得5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-胺(1.03g,收率88.8％)。
中间体5：6-溴-2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶的合成
Figure PCTCN2017078260-appb-000083
步骤1：5-溴-2-氯-N-环戊基嘧啶-4-胺的合成
向5-溴-2,6-二氯嘧啶(22.8g,0.1mol)和二异丙基乙基胺(19.4g,0.15mol)的乙醇(150mL)溶液中，缓慢滴加环戊胺(9.4g,0.11mol)的乙醇(100mL)溶液。滴加完毕后室温继续搅拌2小时。反应液减压浓缩后加入水(250mL)，用乙酸乙酯(250mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。残留物用石油醚重结晶得5-溴-2-氯-N-环戊基嘧啶-4-胺(23.5g,收率84.8％)。
步骤2：2-氯-N-环戊基-5-((三甲基硅基)乙炔基)嘧啶-4-胺的合成
向5-溴-2-氯-N-环戊基嘧啶-4-胺(13.8g,50.0mmol)的N-甲基吡咯烷酮(100mL)溶液中加入三乙胺(15.2g,150.0mmol)、双三苯基膦二氯化钯(1.75g,2.5mmol)、碘化亚铜(1.9g,10.0mmol)和三甲基硅基乙炔(7.4g,75.0mmol)，反应液氮气保护下，50℃反应8小时。冷却，向反应液中加入水(250mL)，用甲基叔丁基醚(250mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为10:1)得2-氯-N-环戊基-5-((三甲基硅基)乙炔基)嘧啶-4-胺(7.8g,收率53.1％)。
1H NMR(400MHz,CDCl3):8.19(1H,s),5.48(1H,d,J＝7.6Hz),4.49-4.58(1H,m),2.10-2.15(2H,m),1.66-1.78(4H,m),1.42-1.52(2H,m),0.29(9H,s)。
步骤3：2-氯-5-溴乙炔基-N-环戊基嘧啶-4-胺的合成
向2-氯-N-环戊基-5-((三甲基硅基)乙炔基)嘧啶-4-胺(7.8g,26.5mmol)的四氢呋喃(150mL)溶液中依次加入硝酸银(5.4g,31.8mmol)和N-溴代丁二酰亚胺(5.7g,31.8mmol)，室温反应2小时。向反应液中加入水(150mL)，用乙酸乙酯(150mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为10:1)得2-氯-5-溴乙炔基-N-环戊基嘧啶-4-胺(6.1g,收率76.3％)。
步骤4：6-溴-2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶的合成
向2-氯-5-溴乙炔基-N-环戊基嘧啶-4-胺(6.1g,20.3mmol)的四氢呋喃(150mL)溶液中加入三水合四丁基氟化铵(16.0g,50.8mmol)，室温反应2小时。向反应液中加入水(150mL)，用乙酸乙酯(150mL×2)萃取， 有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为5:1)得6-溴-2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶(5.2g,收率85.2％)。
1H NMR(400MHz,CDCl3):8.69(1H,s),6.64(1H,s),5.10-5.19(1H,m),2.35-2.44(2H,m),2.03-2.15(4H,m),1.68-1.78(2H.m)。
中间体6：2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的合成
Figure PCTCN2017078260-appb-000084
步骤1：3-(2-氯-4-(环戊基氨基)嘧啶-5-基)丙-2-炔-1-醇
向5-溴-2-氯-N-环戊基嘧啶-4-胺(10.0g,36.2mmol)的四氢呋喃(150mL)溶液中加入四丁基氟化胺三水合物(28.5g,90.5mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(1.3g,1.81mmol)和丙炔醇(4.1g,72.4mmol)，混合液70℃反应5小时。冷却，向反应液中加入水(500mL)，用乙酸乙酯(250mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为10:1)得3-(2-氯-4-(环戊基氨基)嘧啶-5-基)丙-2-炔-1-醇(6.0g,收率65.9％)。
1H NMR(400MHz,CDCl3):8.07(1H,s),5.56(1H,d,J＝7.2Hz),4.54(2H,s),4.38-4.47(1H,m),2.22-2.34(1H,brs),2.09-2.17(2H,m),1.62-1.77(4H,m),1.41-1.50(2H,m)。
步骤2：(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇
向3-(2-氯-4-(环戊基氨基)嘧啶-5-基)丙-2-炔-1-醇(6.0g,23.8mmol)的四氢呋喃(150mL)溶液中四丁基氟化铵三水合物(18.8g,59.6mmol)，混合液70℃反应12小时。冷却，向反应液中加入水(150mL)，用乙酸乙酯(150mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为10:1)得(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇(4.89g,收率81.5％)。
1H NMR(400MHz,CDCl3):8.65(1H,s),6.43(1H,s),4.87-4.95(1H,m),4.82(2H,s),2.35-2.43(2H,m),1.99-2.19(6H,m)。
步骤3：2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的合成
向(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇(2.0g,7.9mmol)的N,N-二甲基甲酰胺(15mL)溶液中加入二甲胺的四氢呋喃溶液(15.8mL,2.0M)和***(0.39g,7.9mmol),混合液室温搅拌反应4分钟。向反应液中分批加入活性二氧化锰(30.9g,355.5mmoL)。该混合液继续室温搅拌12小时，过滤，滤液倒入水中(100mL)，用乙酸乙酯(100mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为4:1)得2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(1.75g,收率 75.1％)。
1H NMR(400MHz,DMSO-d6):8.95(1H,s),6.78(1H,s),4.78(1H,quiv,J＝8.8Hz),3.03(3H,s),2.99(3H,s),2.16-2.26(2H,m),1.87-2.02(4H,m),1.56-1.66(2H,m)。
实施例1 7-环戊基-6-甲磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐的合成
Figure PCTCN2017078260-appb-000085
步骤1：6-甲磺酰基-2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶的合成
向6-溴-2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶(150mg,0.5mmol)的二甲基亚砜(50mL)溶液中依次加入碘化亚铜(48.6mg,0.25mmol)和甲基亚磺酸钠(61.3mg,0.6mmol)，80℃反应48小时。向反应液中加入水(50mL)，用乙酸乙酯(50mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为4:1)得6-甲磺酰基-2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶(65.2mg,收率43.5％)。
1H NMR(400MHz,CDCl3):8.97(1H,s),7.30(1H,s),5.25-5.34(1H,m),3.25(3H,s),2.48-2.57(2H,m),2.10-2.24(4H,m),1.71-1.79(2H,m)。
步骤2：7-环戊基-6-甲磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐的合成
向6-甲磺酰基-2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶(65.2mg,0.2mmol)的甲苯(50mL)溶液中依次加入5-(4-叔丁基氧甲酰基)哌嗪-2-氨基吡啶(即中间体1：4-(6-氨基吡啶-3-基)哌嗪-1-甲酸叔丁酯，83.5mg,0.3mmol)、三(二亚苄基丙酮)二钯(9.2mg,0.01mmol)、联萘二苯磷(12.5mg,0.02mmol)和碳酸铯(195.5mg,0.6mmol)，110℃反应4小时。向反应液中加入水(50mL)，用乙酸乙酯(50mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。将残留物用柱色谱纯化(石油醚：乙酸乙酯为2:1)得7-环戊基-6-甲磺酰基-N-(5-(4-叔丁基氧甲酰基哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺。
将7-环戊基-6-甲磺酰基-N-(5-(4-叔丁基氧甲酰基哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺溶于50mL氯化氢甲醇溶液中(4.0mol/L)，室温搅拌2小时，浓缩得7-环戊基-6-甲磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐(80.5mg,收率77％)。
1H NMR(400MHz,DMSO-d6):10.87-11.04(1H,brs),9.20-9.31(2H,brs),9.10(1H,s),7.95-7.99(2H,m),7.86(1H,d,J＝9.2Hz),7.32(1H,s),5.12-5.21(1H,m),3.46(3H,s),3.39-3.42(4H,m),3.20-3.29(4H,m),2.42-2.48(2H,m),2.01-2.09(4H,m),1.63-1.75(2H,m)。
实施例2 7-环戊基-6-乙磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐的合成
Figure PCTCN2017078260-appb-000086
用乙基亚磺酸钠替代甲基亚磺酸钠，按照实施例1的方法合成。
1H NMR(400MHz,DMSO-d6):11.43(1H,s),9.65(2H,s),9.15(1H,s),7.86-8.12(3H,m),7.37(1H,s),5.08-5.13(1H,m),3.39-3.56(6H,m),3.16-3.31(4H,m),2.38-2.48(2H,m),1.97-2.14(4H,m),1.59-1.74(2H,m),1.19(3H,t,J＝7.2Hz)。
实施例3 7-环戊基-6-甲磺酰基-N-(5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐的合成
Figure PCTCN2017078260-appb-000087
用中间体4代替5-(4-叔丁基氧甲酰基)哌嗪-2-氨基吡啶，按照实施例1的方法合成。
1H NMR(400MHz,DMSO-d6):11.39-11.48(1H,brs),11.09-11.39(1H,brs),9.11(1H,s),8.01-8.11(2H,m),7.91(1H,d,J＝9.2Hz),7.32(1H,s),5.15(1H,quiv,J＝8.0Hz),3.81-3.85(2H,m),3.47(3H,s),3.26-3.46(1H,m),2.72-2.79(2H,m),2.69(3H,s),2.67(3H,s),2.40-2.44(2H,m),2.15-2.18(2H,m),2.02-2.10(4H,m),1.73-1.84(2H,m),1.62-1.72(2H,m)。
实施例4 7-环戊基-6-甲磺酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐的合成
Figure PCTCN2017078260-appb-000088
用中间体2代替5-(4-叔丁基氧甲酰基)哌嗪-2-氨基吡啶，按照实施例1的方法合成。
1H NMR(400MHz,DMSO-d6):11.02-11.19(1H,brs),9.20-9.27(2H,brs),9.13(1H,s),8.43(1H,d,J＝1.6Hz),8.22(1H,dd,J＝9.6Hz,1.6Hz),8.01(1H,d,J＝9.6Hz),7.33(1H,s),6.34(1H,s),5.16-5.22(1H,m),3.74-3.80(2H,m),3.47(3H,s),3.30-3.34(2H,m),2.68-2.74(2H,m),2.45-2.52(2H,m),2.04-2.14(4H,m),1.67-1.76(2H,m)。
实施例5 7-环戊基-6-甲磺酰基-N-(5-(哌啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐的合成
Figure PCTCN2017078260-appb-000089
用中间体3代替5-(4-叔丁基氧甲酰基)哌嗪-2-氨基吡啶，按照实施例1合成。
1H NMR(400MHz,DMSO-d6):11.46-11.63(1H,brs),9.17(1H,s),9.15(2H,s),8.27(1H,d,J＝1.6Hz),8.10(1H,dd,J＝8.8Hz,1.6Hz),7.88(1H,d,J＝8.8Hz),7.37(1H,s),5.14-5.22(1H,m),3.49(3H,s),3.35-3.38(2H,m),2.95-3.01(3H,m),2.42-2.48(2H,m),2.04-2.16(4H,m),1.85-1.19(4H,m),1.61-1.74(2H,m)。
实施例6 7-环戊基-6-N,N-二甲氨基甲酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐的合成
Figure PCTCN2017078260-appb-000090
以中间体2和中间体6为原料，按照实施例1步骤2的方法合成。
1H NMR(400MHz,DMSO-d6):11.93-12.04(1H,brs),9.61(2H,s),9.07(1H,s),8.44(1H,d,J＝2.0Hz),8.37(1H,dd,J＝8.8Hz,2.0Hz),7.68(1H,d,J＝8.8Hz),6.87(1H,s),6.37(1H,s),4.76-4.83(1H,m),3.72-3.79(2H,m),3.25-3.35(2H,m),3.04(6H,s),2.66-2.74(2H,m),2.23-2.36(2H,m),1.93-2.08(4H,m),1.59-1.72(2H,m)。
实施例7 7-环戊基-6-苯磺酰基-N-(5-(哌嗪-1-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺盐酸盐的合成
Figure PCTCN2017078260-appb-000091
用苯亚磺酸钠替代甲基亚磺酸钠，按照实施例1合成。
1H NMR(400MHz,DMSO-d6):11.26-11.41(1H,brs),9.59(2H,s),9.16(1H,s),7.97-8.08(4H,m),7.77-7.82(2H,m),7.67-7.74(2H,m),7.52(1H,s),4.95-5.02(1H,m),3.37-3.48(4H,m),3.15-3.22(4H,m),2.15-2.28(2H,m),1.89-2.01(2H,m),1.44-1.62(4H,m)。
对比例1 7-环戊基-2-(5-哌嗪-1-基-吡啶-2-基氨基)-7H-吡咯并[2,3-d]嘧啶-6-甲酸二甲基酰胺(ribociclib)盐酸盐的合成
Figure PCTCN2017078260-appb-000092
将ribociclib(100.0mg,0.23mmoL)溶于50mL氯化氢甲醇溶液中(4.0mol/L)，室温搅拌2小时，浓缩得ribociclib盐酸盐(108.4mg,收率100.0％)。
1H NMR(400MHz,DMSO-d6):11.68(1H,s),9.68(2H,s),9.04(1H,s),8.12(1H,dd,J＝9.2Hz,2.8Hz),7.99(1H,d,J＝2.8Hz),7.65(1H,d,J＝9.2Hz),6.85(1H,s),4.77-4.86(1H,m),3.44-3.47(4H,m),3.21-3.30(4H,m),3.06(3H,s),2.51(3H,s),2.27-2.42(2H,m),1.93-2.09(4H,m),1.58-1.72(2H,m)。
生物学评价
测试例1本发明化合物对CDK4/CDK6激酶活性测定
CDK4/CyclinD3和CDK6/CyclinD3体外激酶活性抑制实验建立方法如下：
实验采用PerkinElmer公司LANCE方法，重组CDK4/CyclinD3(货号：04-105)和CDK6/CyclinD3(货号：04-107)激酶购自Carna Biosciences公司。底物ULight-MBP(货号：TRF0109)和Eu标记anti-MBP抗体(货号：TRF0201)购自PerkinElmer。HEPES PH7.5(货号：#15630080),DTT(货号：#D1532),MgCl2(货号：#AM9530G),EGTA(货号：#E1219),EDTA(货号：#AM9260G)购自Life Technology。首先配置1X缓冲液A(50mM HEPES,PH7.5,10mM MgCl2,1mM EGTA,0.01％Tween 20和2mM DTT)。DMSO溶解化合物到1mM，并用DMSO梯度稀释，然后用缓冲液A稀释25倍(DMSO的终浓度1％)。用缓冲液A分别稀 释CDK4/CyclinD3和CDK6/CyclinD3。最后用缓冲液A配置底物和ATP。在反应孔中加入4ul CDK4/CyclinD3(终浓度2nM)或者CDK6/CyclinD3(终浓度4nM)，2ul稀释后的化合物和4ul底物(终浓度50nM)与ATP(终浓度200uM)混合物，室温反应1小时后加入EDTA溶液终止反应，并加入Eu标记的anti-MBP抗体室温继续孵育1小时。使用EnVision读取荧光信号(激发光波长320nM，发射光波长615nM和650nM)。结果如表1。
表1本发明化合物对CDK激酶(CDK4,CDK6)活性抑制的IC50
化合物 IC50(CDK4)/nM IC50(CDK6)/nM
对比例1 2.14 26.95
实施例1 0.80 5.70
实施例2 2.12 21.04
实施例3 3.40 18.68
实施例4 2.57 11.06
实施例5 1.46 9.85
实施例6 2.37 30.62
结论：本发明化合物对CDK激酶(CDK4,CDK6)活性具有明显的抑制作用。
测试例2测定化合物对人结肠癌细胞系Colo-205和乳腺癌细胞系MCF7的增殖抑制作用
将Colo-205(中美冠科生物技术有限公司)和MCF7(北京金紫晶生物医药技术有限公司)细胞按1000个细胞每孔接种到96孔板(Corning,货号：3599)中过夜培养。第二天加入不同浓度的化合物(10000nM，3000nM，1000nM，300nM，100nM，30nM，10nM，3nM，1nM，0.3nM，0nM，DMSO终浓度为0.1％)继续培养72小时后，用真空泵吸去培养基，每孔加入50ul Cell-Titer Glo试剂(Promega，货号：G7572)震荡10分钟后，用
Figure PCTCN2017078260-appb-000093
Multilabel Reader(PerkinElmer公司)收集化学发光信号，检测细胞活力，计算化合物对细胞增殖的半数抑制浓度，结果如表2和表3。
表2本发明化合物对Colo205细胞的增殖抑制的IC50
化合物 IC50(Colo205)/nM
对比例1 2691
实施例1 270.8
实施例4 311.6
实施例5 470.3
实施例6 1255
结论：本发明化合物对Colo205细胞具有明显的增殖抑制活性。
表3本发明化合物对MCF7细胞的增殖抑制的IC50
化合物 IC50(MCF7)/nM
对比例1 325.7
实施例1 114.4
实施例4 175.3
实施例6 333.0
结论：本发明化合物对MCF-7细胞具有明显的增殖抑制活性。
药代动力学评价
每个受试化合物使用3只健康成年雄性大鼠，受试化合物混悬于20％磺丁基醚-β-环糊精中，浓度为1mg/mL，单剂量灌胃给药，给药体积为5mL/kg，剂量为5mg/kg。灌胃给药的动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时，在灌胃给药后0.25、0.5、1、2、4、6、8和24小时采血。通过眼眶静脉丛采集约0.3mL全血，放于肝素抗凝管中，样品于4℃、4000rpm，离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆样品中受试品浓度分析使用非确证的液相色谱-串联质谱联用方法(LC-MS/MS)。个体动物的血浆浓度-时间数据用WinNonlin(专业版，版本6.3；Pharsight公司)软件进行分析。非房室模型被用于浓度分析。计算受试化合物的药代动力学参数，结果如表4。
表4本发明化合物的药代动力学参数
动力学参数 对比例1 实施例1 实施例4 实施例6
T1/2(hr) 4.25 7.23 3.28 3.76
Tmax(hr) 2.67 1.33 3.0 3.33
Cmax(ng/mL) 15.8 255 90.0 74.3
AUC0-inf(hr*ng/mL) 120 1961 889 627
结论：上述结果表明，本发明化合物与对比例1相比，大鼠药代吸收良好，具有明显较优的口服吸收效果。

Claims (17)

  1. 式Ⅲ化合物或其药学上可接受的盐或溶剂化物
    Figure PCTCN2017078260-appb-100001
    其中，
    R1选自-S(O)2R4和-C(O)NR5R6；
    R4选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
    R5和R6独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
    基团
    Figure PCTCN2017078260-appb-100002
    为
    Figure PCTCN2017078260-appb-100003
    或者
    Figure PCTCN2017078260-appb-100004
    且当基团
    Figure PCTCN2017078260-appb-100005
    为
    Figure PCTCN2017078260-appb-100006
    时，Y选自CH和N，当基团
    Figure PCTCN2017078260-appb-100007
    为
    Figure PCTCN2017078260-appb-100008
    时，Y为C；
    W选自O、S、CR7R8和NR9；
    R7和R8独立地选自氢、-NR10R11、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
    R10和R11独立地选自氢、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
    R9选自氢、C1-6烷基、C3-6环烷基、5-10元芳基和5-10元杂芳基，其中所述基团任选被一种或多种Ra取代；
    Ra选自卤素、氰基、-R、-OR、＝O、-SR、-NR2、＝NR、-C(卤素)3、-CR(卤素)2、-CR2(卤素)、-OCN、-SCN、-N＝C＝O、-NCS、-NO、-NO2、-NRC(＝O)R、-NRC(＝O)OR、-NRC(＝O)NRR、-C(＝O)NRR、-C(＝O)OR、-OC(＝O)NRR、-OC(＝O)OR、-C(＝O)R、-S(＝O)2OR、-S(＝O)2R、-OS(＝O)2OR、-S(＝O)2NRR、-S(＝O)R、-NRS(＝O)2R、-NRS(＝O)2NRR、-NRS(＝O)2OR、-OP(＝O)(OR)2、-P(＝O)(OR)2、-C(＝O)R、-C(＝S)R、-C(＝O)OR、-C(＝S)OR、-C(＝O)SR、-C(＝S)SR、-C(＝O)NRR、-C(＝S)NRR、-C(＝NR)NRR和-NRC(＝NR)NRR；R独立地选自氢、C1-6烷基、C3-6环烷基、3-6元杂环烷基、5-10元芳基和5-10元杂芳基， 其中当Ra为-R时，R不为氢；
    条件是：当R1选自-C(O)NR5R6时，基团
    Figure PCTCN2017078260-appb-100009
    为
    Figure PCTCN2017078260-appb-100010
    且Y为C。
  2. 如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，其中W选自CR7R8和NR9；优选地，W选自CHR8和NR9。
  3. 如权利要求2所述的化合物或其药学上可接受的盐或溶剂化物，R4选自C1-6烷基和苯基，其中所述基团任选被一种或多种Ra取代；优选地，R4选自C1-4烷基和苯基，其中所述基团任选被一种或多种Ra取代；更优选地，R4选自甲基、乙基和苯基，其中所述基团任选被一种或多种Ra取代；最优选地，R4选自甲基、乙基和苯基。
  4. 如权利要求2所述的化合物或其药学上可接受的盐或溶剂化物，R5和R6独立地选自C1-6烷基，其中所述基团任选被一种或多种Ra取代；优选地，R5和R6独立地选自C1-4烷基，其中所述基团任选被一种或多种Ra取代；更优选地，R5和R6独立地选自甲基和乙基，其中所述基团任选被一种或多种Ra取代；最优选地，R5和R6独立地选自甲基。
  5. 如权利要求2所述的化合物或其药学上可接受的盐或溶剂化物，基团
    Figure PCTCN2017078260-appb-100011
    为
    Figure PCTCN2017078260-appb-100012
    或者
    Figure PCTCN2017078260-appb-100013
    优选地，基团
    Figure PCTCN2017078260-appb-100014
    为
    Figure PCTCN2017078260-appb-100015
    或者
    Figure PCTCN2017078260-appb-100016
  6. 如权利要求1-5中任一项所述的化合物或其药学上可接受的盐或溶剂化物，其中R7为氢，且R8选自氢、-NR10R11、C1-6烷基和C3-6环烷基，其中所述基团任选被一种或多种Ra取代；优选地，R7为氢，且R8选自-NR10R11；最优选地，R7为氢，且R8为-N(CH3)2。
  7. 如权利要求1-5中任一项所述的化合物或其药学上可接受的盐或溶剂化物，其中R9选自氢和C1-4烷基，其中所述基团任选被一种或多种Ra取代；优选地，R9选自氢。
  8. 如权利要求1-5中任一项所述的化合物或其药学上可接受的盐或溶剂化物，其中R10和R11独立地选自氢、C1-6烷基和C3-6环烷基，其中所述基团任选被一种或多种Ra取代；优选地，R10和R11独立地选自氢和C1-4烷基，其中所述基团任选被一种或多种Ra取代；更优选地，R10和R11独立地选自甲基。
  9. 如权利要求5所述的化合物或其药学上可接受的盐或溶剂化物，基团
    Figure PCTCN2017078260-appb-100017
    为
    Figure PCTCN2017078260-appb-100018
    Figure PCTCN2017078260-appb-100019
  10. 如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，所述式Ⅲ化合物为式Ⅳ化合物
    Figure PCTCN2017078260-appb-100020
    其中，
    W选自CR7R8和NR9；
    R5、R6、R7、R8和R9定义同权利要求1。
  11. 如权利要求10所述的化合物或其药学上可接受的盐或溶剂化物，其中基团
    Figure PCTCN2017078260-appb-100021
    为
    Figure PCTCN2017078260-appb-100022
    优选地，基团
    Figure PCTCN2017078260-appb-100023
    为
    Figure PCTCN2017078260-appb-100024
  12. 如权利要求1所述的化合物或其药学上可接受的盐或溶剂化物，所述式I化合物为下列化合物：
    Figure PCTCN2017078260-appb-100025
  13. 如权利要求12所述的化合物或其药学上可接受的盐或溶剂化物，所述药学上可接受的盐为盐酸盐。
  14. 药物组合物，其包含权利要求1-13任一项所述的化合物或其药学上可接受的盐或溶剂化物，以及一种或多种药学上可接受的载体或赋形剂。
  15. 权利要求1-13中任一项所述的化合物或其药学上可接受的盐或溶剂化物、或权利要求14所述的药物组合物在制备用于治疗和/或预防与CDK抑制作用相关的疾病的药物中的用途；优选地，所述与CDK抑制作用相关的疾病是指与CDK4和/或CDK6抑制作用相关的疾病；更优选地，所述与CDK4和/或CDK6抑制作用相关的疾病包括癌症。
  16. 一种治疗和/或预防与CDK抑制作用相关的疾病的方法，所述方法包括给予有需要的个体权利要求1-13任一项所述化合物或其药学上可接受的盐或溶剂化物、或者权利要求14所述的药物组合物；优选地，所述与CDK抑制作用相关的疾病是指与CDK4和/或CDK6抑制作用相关的疾病；更优选地，所述与CDK4和/或CDK6抑制作用相关的疾病包括癌症。
  17. 如权利要求15所述的用途或如权利要求16所述的方法，其中所述癌症选自膀胱癌、乳腺癌、结肠癌、肾癌、表皮癌、肝癌、小细胞肺癌、非小细胞肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、***、甲状腺癌、鼻癌、头颈癌、***癌、皮肤癌、白血病、急性淋巴性白血病、慢性淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤、伯基特氏淋巴瘤、急性和慢性髓系白血病、骨髓增生异常综合征、早幼粒细胞白血病、甲状腺滤泡癌、纤维肉瘤、横纹肌肉瘤、神经胶质瘤、神经鞘瘤、黑素瘤、***瘤、畸胎瘤、骨肉瘤、着色性干皮病、角化棘细胞瘤、甲状腺滤泡癌、脂肪肉瘤、神经内分泌瘤和卡波西肉瘤；优选地，所述癌症选自转移性乳腺癌、黑素瘤、非小细胞肺癌、畸胎瘤、神经内分泌瘤和脂肪肉瘤。
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CN107759563A (zh) * 2017-11-23 2018-03-06 上海再启生物技术有限公司 一种4‑(6‑取代胺基吡啶‑3‑基)哌啶‑1‑甲酸叔丁酯的制备方法
CN107827869A (zh) * 2017-11-23 2018-03-23 上海再启生物技术有限公司 一种4‑(6‑氨基吡啶‑3‑基)哌啶‑1‑甲酸叔丁酯的制备方法
CN110054585A (zh) * 2018-01-18 2019-07-26 新发药业有限公司 一种5-(4-叔丁氧羰基哌嗪-1-基)-2-氨基吡啶的制备方法
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WO2020052627A1 (zh) * 2018-09-13 2020-03-19 正大天晴药业集团股份有限公司 取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途
CN112888690A (zh) * 2018-09-13 2021-06-01 正大天晴药业集团股份有限公司 取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途
CN112888690B (zh) * 2018-09-13 2022-04-12 正大天晴药业集团股份有限公司 取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途
CN108822026A (zh) * 2018-09-21 2018-11-16 湖北大学 一种抗癌药帕博昔布重要中间体的合成工艺
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