WO2019036839A1 - 泊马度胺衍生物及其制备方法 - Google Patents

泊马度胺衍生物及其制备方法 Download PDF

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WO2019036839A1
WO2019036839A1 PCT/CN2017/098281 CN2017098281W WO2019036839A1 WO 2019036839 A1 WO2019036839 A1 WO 2019036839A1 CN 2017098281 W CN2017098281 W CN 2017098281W WO 2019036839 A1 WO2019036839 A1 WO 2019036839A1
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substituted
unsubstituted
group
methyl
propyl
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PCT/CN2017/098281
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English (en)
French (fr)
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刘飞
吴刚
赵欣
陈盼
廖云鹏
王晓波
祁智
杨许东
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诺瑞特国际药业股份有限公司
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Priority to US16/637,938 priority Critical patent/US20200199097A1/en
Priority to PCT/CN2017/098281 priority patent/WO2019036839A1/zh
Priority to CN201810951914.4A priority patent/CN109422727A/zh
Publication of WO2019036839A1 publication Critical patent/WO2019036839A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • the present invention relates to a pomamide amine derivative or a pharmaceutically acceptable salt thereof, and the use thereof in the preparation of a medicament for treating cancer.
  • Pomamide (formula A) was developed by the American Xaar Gene Company and was first approved for marketing in the United States in February 2013.
  • Pomodamin is the third immunoprecipitation agent listed after thalidomide, lenalidomide, which enhances T cell and natural killer cell-mediated immune responses while inhibiting monocyte production of pro-inflammatory cells.
  • Factors such as TNF- ⁇ , IL-6, etc.
  • pomicamide inhibits tumor cell proliferation and induces apoptosis, and has a strong proliferation inhibitory effect on lenalidomide-resistant multiple myeloma cell lines.
  • Common adverse reactions to pomamide include neutropenia, fatigue, anemia, constipation, diarrhea, thrombocytopenia, upper respiratory tract infections, back pain, fever, and possibly thrombosis, which can cause severe birth defects in the fetus.
  • pomamide is a poorly soluble drug, and its solubility in purified water, pH 6.8 phosphate buffer, pH 4.5 acetate buffer and 0.1 mol/L hydrochloric acid was determined to be 17.8, respectively. 17.0, 18.7 and 18.9 ⁇ g/mL.
  • the low solubility of pomicamide not only increases the difficulty of the formulation process, but also limits the dissolution and absorption process of the active ingredient in the gastrointestinal tract, thereby affecting the oral bioavailability.
  • the currently marketed pomoloproline oral capsule sold under the trade name POMALYST, is formulated with a surfactant sodium lauryl sulfate in order to increase the dissolution of the drug, but sodium lauryl sulfate has a certain Gastrointestinal irritancy.
  • the invention discloses a compound of formula (I), including stereoisomers thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2 a -6 alkynyl group, wherein the aforementioned substituted substituent is selected from a C 1-6 alkyl group, a C 1-6 alkoxy group;
  • R 2 is selected from the group consisting of H, -OR 3 , -SR 3 , -NHR 3 , a substituted or unsubstituted C 3-10 heterocyclic group, a substituted or unsubstituted C 3-10 heterocyclic aryl group, substituted or unsubstituted a C 3-10 cycloalkyl group, wherein the aforementioned substituted substituent is selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, a carbonyl group, a carboxyl group, an amino group, and a hydroxyl group;
  • R 3 is selected from -C(O)(R 4 )(R 5 ), -P(O)(OR 6 )(OR 7 ), -P(O) 2 (OR 6 )M, -P(O) 3 MY;
  • R 4 is selected from the group consisting of hydrogen, amino, hydroxy, halogen, C 1-6 alkyl
  • R 5 is selected from hydrogen, substituted or unsubstituted C 1-16 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 3-10 heterocyclyl, substituted or unsubstituted C 3-10 heterocyclyl aryl group, a substituted or unsubstituted C 3-10 cycloalkyl, phenyl, benzyl, - (CH 2) nSCH 3 , - (CH 2) mNHCH 3, - (CH 2) mN ( CH 3 ) 2 , wherein the aforementioned substituted substituent is selected from the group consisting of amino, hydroxy, carboxy, -SH, -C(O)NH 2 , C 1-6 alkyl;
  • R 6 and R 7 are each independently selected from hydrogen, C 1-6 alkyl; M and Y are each independently selected from a monovalent cation, or MY is a divalent cation;
  • n are each independently selected from 1, 2, 3, 4, 5, 6.
  • R 1 is selected from H, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted butyl, substituted or unsubstituted pentyl a substituted, unsubstituted or unsubstituted hexyl group wherein the substituents previously substituted are selected from the group consisting of methyl, ethyl or propyl.
  • R 2 is selected from the group consisting of H, -OR 3 , substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, Substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, Substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted fluorenyl, substituted or
  • R 3 is selected from -C(O)(R 4 )(R 5 ), wherein R 4 is selected from the group consisting of hydrogen, amino, methyl, ethyl, propyl; R 5 is selected from hydrogen, substituted or Unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or Non-substituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridaziny
  • n is selected from 1, 2 or 3 and m is selected from 1, 2, 3, 4 or 5.
  • R 3 is selected from the group consisting of -P(O)(OR 6 )(OR 7 ), -P(O) 2 (OR 6 )M, -P(O) 3 MY, wherein R 6 and R 7 Each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, M and Y are each independently selected from sodium ion, potassium ion, or MY is a divalent cation selected from calcium ions. Magnesium ions.
  • R 1 is selected from H, methyl, ethyl or propyl
  • R 2 is selected from H, -OR 3 , substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or not Substituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted Substituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted indenyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolin
  • R 3 is selected from -C(O)(R 4 )(R 5 ), -P(O)(OR 6 )(OR 7 ), -P(O) 2 (OR 6 )M, -P(O) 3 MY;
  • R 4 is selected from the group consisting of hydrogen, amino, methyl, ethyl, propyl;
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, tetrahydrofuranyl, tetrahydropyrrolyl, furyl, thienyl, pyrrole Base, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, fluorenyl, quinolyl, isoquinolinyl, decyl, phenyl, benzyl , -(CH 2 )nSCH 3 , -(CH 2 )mNHCH 3 , -(CH 2 )mN(CH 3 ) 2 ;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl; M and Y are each independently selected from sodium ion, potassium ion, or MY is a divalent cation selected from calcium ion, magnesium ion; And
  • n are each independently selected from 1, 2, 3, 4, 5, 6.
  • R 1 is selected from the group consisting of H, methyl
  • R 2 is selected from H, -OR 3 , Wherein the substituent is selected from the group consisting of methyl, ethyl, propyl;
  • R 3 is selected from -C(O)(R 4 )(R 5 ), -P(O)(OR 6 )(OR 7 ), -P(O) 2 (OR 6 )M, -P(O) 3 MY;
  • R 4 is selected from the group consisting of hydrogen and amino
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, decyl, tetrahydrofuranyl, tetrahydropyrrolyl, furyl, thienyl, pyrrole Base, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, fluorenyl, quinolyl, isoquinolinyl, decyl, phenyl, benzyl , -(CH 2 )nSCH 3 , -(CH 2 )mNHCH 3 , -(CH 2 )mN(CH 3 ) 2 ;
  • R 6 and R 7 are hydrogen; M and Y are each independently selected from sodium ion, potassium ion, or MY is a divalent cation selected from calcium ion, magnesium ion;
  • n are each independently selected from 1, 2, 3, 4, 5, 6.
  • compositions as described in the present invention include, but are not limited to, hydrochloride or tromethamine salts.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound (including stereoisomers thereof) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or Or an excipient.
  • the invention provides the use of a compound according to the foregoing (including stereoisomers thereof), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
  • cancers include, but are not limited to, prostate cancer.
  • the compound represented by the formula (I) according to the present invention includes stereoisomers thereof.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • Nitrogen or halogen optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include yttrium (H), yttrium (D, also known as Heavy hydrogen), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N And 15 N, the fluorine isotopes include 19 F, the chlorine isotopes include 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably a linear and branched group of 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, most preferably 1 to 2 carbon atoms;
  • examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl -2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl Benzyl
  • Alkoxy means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, undertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy.
  • Alkenyl means an alkyl group as defined herein above containing at least one carbon-carbon double bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 12 carbon atoms, more preferably 2 on the backbone Alkenyl groups may be substituted or unsubstituted to 8 carbon atoms; non-limiting examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butene , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1- Butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl- 1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
  • Alkynyl means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably containing from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably 2 on the backbone Alkynyl groups up to 4 carbon atoms; alkynyl groups may be substituted or unsubstituted; non-limiting examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl , 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexyl Alkynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl, 4-decynyl, 3-undynyl and 4-
  • Cycloalkyl means a ring of monocyclic, fused, spiro or bridged rings all carbon, including, but not limited to, cyclopropane, cyclobutane, cyclopentane, spiro[3.4]octane, bicyclic [3.1.1] Hexane, etc.
  • substitution refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom.
  • Substituted or unsubstituted refers to the case where the group may or may not be substituted, and if it is not indicated in the present invention that the group may be substituted, it means that the group is unsubstituted.
  • “Pharmaceutically acceptable salt” refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with and without a non-toxic inorganic or organic base, or the free acid. Those salts obtained by the reaction of toxic inorganic or organic acids.
  • Figure 1 shows the relationship between drug concentration and time in plasma after administration of rats to each group of compounds.
  • Step 1 Under a nitrogen atmosphere, S.M.B (20 g, 73.2 mmol, 1.00 eq) and DMF (400 ml) were added to a 1000 mL three-necked reaction flask, and stirred magnetically. Sodium hydride (3.5 g, 87.5 mmol, 1.2 eq) was then slowly added. After stirring for 30 min, potassium iodide (12 g, 72.2 mmol, 0.99 eq) and TBAB (tetrabutylammonium bromide) (3.52 g, 10.9 mmol, 0.15) were added.
  • S.M.B 20 g, 73.2 mmol, 1.00 eq
  • DMF 400 ml
  • Step 2 Under a nitrogen atmosphere, add Int 1-01 (500 mg, 1 mmol, 1.00 eq), DCM 5 ml to a 100 ml three-necked reaction flask, and stir at room temperature for 10 min, then add HCl/EA (10 ml, 10 mmol, 10.0 eq) in one time. Stirring was continued for 40 min. The reaction was quenched and dried by filtration to give 380 mg of y.
  • Int 1-01 500 mg, 1 mmol, 1.00 eq
  • DCM 5 ml 100 ml three-necked reaction flask
  • HCl/EA 10 ml, 10 mmol, 10.0 eq
  • Step 1 To a 2000 mL three-necked reaction flask was added SM2 (50 g, 285.4 mmol, 1.00 eq), H 2 O (1000 ml), sodium hydrogencarbonate (95.9 g, 1141.6 mmol, 4.00 eq), stirred for 30 min, then added DCM and Bu 4 NHSO 4 (9.7 g, 28.5 mmol, 0.1 eq). After stirring for 20 min, SMA (56.5 g, 342.5 mmol, 1.2 eq) was added and the reaction was stirred for 15 h. The reaction was stopped, and the organic layer was concentrated under reduced pressure to give 60 g of colorless oil.
  • SM2 50 g, 285.4 mmol, 1.00 eq
  • H 2 O 1000 ml
  • sodium hydrogencarbonate 95.9 g, 1141.6 mmol, 4.00 eq
  • Step 3 To a 25 ml three-necked reaction flask, Int 2-02 (0.1 g, 0.2 mmol, 1.00 eq), hydrochloric acid / 20 ml of dioxane was added under a nitrogen atmosphere, and stirred at room temperature overnight. The reaction was quenched and dried by filtration to give a product (yel. HPLC: 96.24%
  • Step 1 Add SM1 (6g, 31.7mmol, 1.00eq), H 2 O (130ml), sodium bicarbonate (10.6g, 126.8mmol, 4.00eq) to a 500mL three-necked reaction flask, stir for 30min, then add DCM And Bu 4 NHSO 4 (1.08 g, 3.2 mmol, 0.1 eq), stirred for 20 min; SMA (6.3 g, 38.0 mmol, 1.2 eq) was added and the reaction was stirred for 15 h. The reaction was quenched and the organic layer was concentrated under reduced pressure to give 7.2 g, m.
  • Step 2 Into 2250 (5.0 g, 18.3 mmol, 1.00 eq), NaI (18 g, 121 mmol), MeCN (75 ml). The reaction was quenched and the organic layer was concentrated under reduced pressure to give 9.2 g, m.
  • Step 3 Under a nitrogen atmosphere, add SMB (3g, 10.98mmol, 1.00eq), DMF 65mL to a 250ml three-neck reaction flask, cool the reaction system to below -20 °C, and add LiHMDS (11ml, 11mmol, 1.00eq). After stirring for 10 min, a solution of Int. 3-02 (4.34 g, 13.17 mmol, 1.20 eq) in DMF was added and stirring was continued.
  • Step 4 Into a 25 ml three-necked reaction flask was added Int 3-03 (0.5 g, 1.05 mmol, 1.00 eq), hydrochloric acid / dioxane 20 ml, and stirred at room temperature overnight. The reaction was quenched, filtered and dried to give 235 g, m. HPLC: 96.4%
  • Step 1 To a 500 mL three-necked reaction flask was added SM4 (6.3 g, 25.27 mmol, 1.00 eq), H 2 O (110 ml), sodium bicarbonate (8.48 g, 101.08 mmol, 4.00 eq) was added and stirred for 10 min, then After adding DCM and Bu 4 NHSO 4 (0.86 g, 2.52 mmol, 0.1 eq), and stirring for 10 min, SMA (5 g, 30.32 mmol, 1.2 eq) was added dropwise under ice bath, and the reaction was stirred at room temperature for 15 h. The reaction was quenched and the organic layer was evaporated to dryness.
  • SM4 6.3 g, 25.27 mmol, 1.00 eq
  • H 2 O 110 ml
  • sodium bicarbonate 8.48 g, 101.08 mmol, 4.00 eq
  • SMA 5 g, 30.32 mmol, 1.2 eq
  • Step 2 Under a nitrogen atmosphere, add SMB (2.7 g, 9.88 mmol, 1.00 eq), DMF 70 ml to a 250 ml three-neck reaction flask, and cool the reaction system to below -20 ° C, and add LiHMDS (9.88 ml, 9.88 mmol, 1.00 eq). Stirring was continued for 10 min, then a solution of Int. 4-01 (3.8 g, 12.84 mmol, 1.3 eq) in DMF was added and kept stirring at low temperature. The reaction was stopped, and the reaction system was poured into a 1% aqueous solution of NH 4 Cl (315 ml) in ice. The solid was separated and filtered, filtered, and then filtered and evaporated. 800mg product, yield 15%.
  • Step 3 Under a nitrogen atmosphere, into a 25 ml three-necked reaction flask, Int 4-02 (0.2 g, 0.37 mmol, 1.00 eq), 2N hydrochloric acid/EA 4 ml 4 ml was added and stirred at room temperature overnight. The reaction was quenched, filtered and dried to give a crystallite.
  • Step 1 The preparation method is the same as Step 1 of Example 4, in that S.M.4 is changed to S.M.5. Preparation 7.6 g of a colorless oil was obtained in a yield of 99.2%.
  • Step 2 The preparation method was the same as that of Step 2 of Example 4, except that Int. 4-01 was changed to Int. 5-01. Preparation 800 mg of product was obtained in a yield of 15%.
  • Step 3 The preparation method was the same as Step 3 of Example 4, except that Int. 4-02 was changed to Int. 5-02. 83.6 mg of the product product was obtained as a yellow solid, yield 52%.
  • Step 1 The preparation method is the same as Step 1 of Example 4, in that S.M.4 is changed to S.M.6. 6.3 g of a colorless oil were obtained in a yield of 94.2%.
  • Step 2 The preparation method was the same as that of Step 2 of Example 4, except that Int. 4-01 was changed to Int. 6-01. Preparation 100 mg of product was obtained in a yield of 2%.
  • Step 3 The preparation method was the same as that of Step 3 of Example 4, except that Int. 4-02 was changed to Int. 6-02. 45 mg of the product product was obtained as a yellow solid, yield 56.2%.
  • Step 1 The preparation method is the same as Step 1 of Example 4 in that S.M.4 is changed to S.M.7. 7 g of a colorless oil was obtained in a yield of 88.6%.
  • Step 2 The preparation method was the same as that of Step 2 of Example 4, except that Int. 4-01 was changed to Int. 7-01. 2.1 g of product was obtained in a yield of 40.2%.
  • Step 3 The preparation method was the same as that of Step 3 of Example 4, except that Int. 4-02 was changed to Int. 7-02. 45 mg of the product product was obtained as a yellow solid, yield 56.2%.
  • Step 1 Under a nitrogen atmosphere, add SMB (1 g, 3.66 mmol, 1.00 eq), DMF 25 mL to a 100 mL three-neck reaction flask, and cool the reaction system to below -20 ° C, and add LiHMDS (3.66 ml, 3.66 mmol, 1.00 eq). After stirring for 10 min, a solution of SM9 (1.21 g, 5.49 mmol, 1.20 eq) in DMF.
  • Step 1 Under nitrogen protection, add SM10 (15g, 107.9mmol, 1.00eq), DCM (150ml), DMF (4 drops) to a 500mL three-necked reaction flask. Continue to add oxalyl chloride (15.07) under ice bath conditions. g, 118.74 mmol, 1.1 eq), stirred at room temperature for 2 h. The reaction was stopped, and the reaction mixture was concentrated under reduced pressure to yield 14.56 g of oil.
  • Step 2 Into. 100-01 (14.56 g, 92.06 mmol, 1.00 eq), paraformaldehyde (2.78 g, 92.06 mmol, 1.00 eq), zinc chloride (2.52 g, 18.41 mmol, 0.2) was added to a 100 ml single-mouth reaction flask. Eq), the temperature of the reaction system was raised to 90 ° C and stirred. The reaction was stopped, and the reaction liquid was concentrated under reduced pressure.
  • Step 4 To a 250 ml three-necked reaction flask was added Int. 10-03 (3.33 g, 7.85 mmol, 1.00 eq), THF 66 ml, dimethylamine (1.41 g, 31.4 mmol, 4.00 eq), KI (33 mg), and stirred at room temperature. The reaction was stopped, and the system was directly dried with a reduced pressure pump to dissolve a small amount of EA, and then precipitated with 3N HCl/EA. The product was filtered to give a product (yield 15%).
  • Step 1 To a 100 mL 3-neck reaction flask was added SM11 (2.50 g, 10 mmol, 1.00 eq), sodium bicarbonate (3.78 g, 45 mmol, 4.50 eq), tetrabutylammonium hydrogen sulfate (169 mg, 0.5 mmol, 0.05 eq. After stirring for 30 min, water (12 ml) and isopropyl acetate (14 ml), SMA (2.97 g, 18 mmol, 1.80 eq) was added dropwise, and the reaction was stirred for about 13 h. The reaction was stopped, the liquid was separated, and the organic phase was concentrated under reduced pressure to give 2.20 g of colorless liquid.
  • SM11 2.50 g, 10 mmol, 1.00 eq
  • sodium bicarbonate 3.78 g, 45 mmol, 4.50 eq
  • tetrabutylammonium hydrogen sulfate 169 mg, 0.5 mmol,
  • Step 2 Under a nitrogen atmosphere, pomeloamine (1.00 g, 3.66 mmol, 1.00 eq), DMF 10 ml was added to a 100 ml three-neck reaction flask, and after stirring for 1 h, sodium hydride (60%) (175 mg, 4.39 mmol, 1.20 eq) was added. Stirring was continued for 40 min; then Int. 11.01 (0.95 g, 3.66 mmol, 1.00 eq) was added and stirring was continued for 27 h.
  • Step 3 Under a nitrogen atmosphere, into a 100 ml three-neck reaction flask, add Int11.02 (490 mg, 1 mmol, 1.00 eq), DCM 20 ml, stir at room temperature for 10 min, then add HCl/EA (20 ml, 20 mmol, 20.0 eq) and continue stirring for 45 min. . The reaction was stopped, and the hydrochloric acid in the reaction system was vacuumed for 20 minutes with a water pump, and then filtered under a nitrogen atmosphere to obtain a yellow solid product which was directly dissolved in methanol (10 ml) and used as the next material.
  • a methanol solution of the above intermediate was added to a 100 ml three-neck reaction flask, and a solution of tributylamine (243 mg, 2 mmol, 2.00 eq) in 20 ml of methanol was added dropwise with stirring at room temperature, stirred for 10 min, and 25 ml of acetone was added dropwise to the system.
  • the system has a large amount of solid precipitated and stirred for 40 minutes.
  • the filter cake was filtered and dried in vacuo to give a crystallite.
  • test sample solution 50 mg of the hydrochloride or tromethamine salt of the compound was mixed with 150 ⁇ l of water, stirred at room temperature, completely dissolved, and the supernatant was taken as a test sample solution.
  • the test sample solution was measured by HPLC, and the results are shown in Table 1.
  • the saturation solubility of the sample is not determined, but the appropriate amount of the sample is selected to determine the solubility of the sample. From the test, it was found that the compound (1 mg) or the salt (300 mg) of the present invention can be completely dissolved in 1 ml of water, the solubility of the compound is not less than 1 mg/ml, and the salt solubility is not less than 300 mg/ml.
  • the solubility of pomamide in water is about 0.01 mg/ml, which is much lower than the solubility of the compound of the present invention or a salt thereof.
  • the SD rats tested were divided into the hydrochloride group of the compound 1, the tromethamine group of the compound 11, and the possumamine group by a group design of a randomized block design. Each group was administered by intragastric administration (i.g.) at a dose of 2 mg/kg (based on posuleamine).
  • Test method Before administration, blood samples were taken at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours after administration, and collected into the anticoagulant tube containing EDTA-2K. Blood was stored on wet ice and plasma samples were obtained by centrifugation at 3500 rpm for 5 minutes at 4 ° C for 30 minutes. The plasma samples obtained by separation were immediately placed in dry ice and then transferred to a -60 to -80 ° C refrigerator. The hydrochloride salt of Compound 1 in the plasma, the tromethamine salt of Compound 11, and the possumamine were detected by LC/MS/MS. The pharmacokinetics of the rats after administration were calculated using the non-compartment model of the software WinNonlin. parameter.
  • RESULTS The pharmacokinetic parameters of the concentration of pomamide in plasma over time after administration of equimolar doses of each compound of pomamide (2 mg/kg) in rats are shown below.

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Abstract

本发明公开泊马度胺衍生物及其制备方法，具体涉及泊马度胺衍生物及其立体异构体或药学上可接受的盐，及其在制备治疗癌症的药物中的应用。

Description

泊马度胺衍生物及其制备方法 技术领域
本发明涉及泊马度胺衍生物或其药学上可接受的盐，及其在制备治疗癌症的药物中的应用。
背景技术
泊马度胺(式A结构)由美国赛尔基因公司研发，并于2013年2月首次在美国获准上市。泊马度胺是继沙利度胺，来那度胺后第三个上市的同类免疫调节剂，能够增强T细胞和自然杀伤细胞介导的免疫反应，同时抑制单核细胞产生促炎性细胞因子(如TNF-α、IL-6等)。此外，泊马度胺能够抑制肿瘤细胞增生并诱导细胞凋亡，对来那度胺耐药的多发性骨髓瘤细胞株亦具有较强的增殖抑制作用。
Figure PCTCN2017098281-appb-000001
泊马度胺常见的不良反应有中性粒细胞减少，疲乏虚弱，贫血，便秘，腹泻，血小板减少，上呼吸道感染，背痛发热，还可能引起血栓，且可能导致胎儿出现严重的出生缺陷。
根据文献报道，泊马度胺属于难溶性药物，测定其在纯化水，PH6.8磷酸盐缓冲液，PH4.5醋酸盐缓冲液和0.1mol/L盐酸中的溶解度，结果分别是17.8，17.0，18.7和18.9μg/mL。泊马度胺的低溶解度不仅增加了制剂工艺的难度，也限制了活性成分在胃肠道的溶出和吸收过程，进而影响口服生物利用度。
目前上市的泊马度胺口服胶囊剂，商品名为POMALYST，其为了增加药物的溶出度，在其处方中添加了表面活性剂十二烷基硫酸钠，但十二烷基硫酸钠有一定的胃肠道刺激性。
发明内容
本发明的目的在于提供一种新颖的具有高稳定性，良好溶解度，改善生物利用度，低毒副作用或具备长效潜力的泊马度胺前体药物。
在一方面，本发明公开一种式(Ⅰ)所示的化合物(包括其立体异构体)或其药学上可接受的盐，
Figure PCTCN2017098281-appb-000002
其中：
R1选自H，取代或非取代的C1-6烷基，取代或非取代的C1-6烷氧基，取代或非取代的C2-6烯基，取代或非取代的C2-6炔基，其中前述取代的取代基选自C1-6烷基，C1-6烷氧基；
R2选自H，-OR3，-SR3，-NHR3，取代或非取代的C3-10杂环基，取代或非取代的C3-10杂环芳基，取代或非取代的C3-10环烷基，其中前述取代的取代基选自C1-6烷基，C1-6烷氧基，羰基，羧基，氨基，羟基；
R3选自-C(O)(R4)(R5)，-P(O)(OR6)(OR7)，-P(O)2(OR6)M，-P(O)3MY；
R4选自氢，氨基，羟基，卤素，C1-6烷基；
R5选自氢，取代或非取代的C1-16烷基，取代或非取代的C1-6烷氧基，取代或非取代的C3-10杂环基，取代或非取代的C3-10杂环芳基，取代或非取代的C3-10环烷基，苯基，苄基，-(CH2)nSCH3，-(CH2)mNHCH3，-(CH2)mN(CH3)2，其中前述取代的取代基选自氨基，羟基，羧基，-SH，-C(O)NH2，C1-6烷基；
R6和R7各自独立的选自氢，C1-6烷基；M和Y各自独立选自单价阳离子，或者MY为一个二价阳离子；且
m和n各自独立的选自1，2，3，4，5，6。
在一实施例中，R1选自H，取代或非取代的甲基，取代或非取代的乙基，取代或非取代的丙基，取代或非取代的丁基，取代或非取代的戊基，取代或非取代的己基，其中前述取代的取代基选自甲基，乙基或丙基。
在一实施例中，R2选自H，-OR3，取代或非取代的四氢呋喃基，取代或非取代的四氢吡咯基，取代或非取代的呋喃基，取代或非取代的噻吩基，取代或非取代的吡咯基，取代或非取代的咪唑基，取代或非取代的吡唑基，取代或非取代的噻唑基，取代或非取代的噁唑基，取代或非取代的吡啶基，取代或非取代的嘧啶基，取代或非取代的哒嗪基，取代或非取代的吡嗪基，取代或非取代的嘌呤基，取代或非取代的喹啉基，取代或非取代的异喹啉基，取代或非取代的吲哚基，取代或非取代的环丙基，取代或非取代的环己基，取代或非取代的环丁基，取代或非取代的环戊基，
Figure PCTCN2017098281-appb-000003
其中前述取代的取代基选自甲基，乙基，丙基，羰基，羧基，氨基，羟基。
在一优选实施例中，R3选自-C(O)(R4)(R5)，其中R4选自氢，氨基，甲基，乙 基，丙基；R5选自氢，取代或非取代的四氢呋喃基，取代或非取代的四氢吡咯基，取代或非取代的呋喃基，取代或非取代的噻吩基，取代或非取代的吡咯基，取代或非取代的咪唑基，取代或非取代的吡唑基，取代或非取代的噻唑基，取代或非取代的噁唑基，取代或非取代的吡啶基，取代或非取代的嘧啶基，取代或非取代的哒嗪基，取代或非取代的吡嗪基，取代或非取代的嘌呤基，取代或非取代的喹啉基，取代或非取代的异喹啉基，取代或非取代的吲哚基，取代或非取代的环丙基，取代或非取代的环己基，取代或非取代的环丁基，取代或非取代的环戊基，苯基，苄基，-(CH2)nSCH3，-(CH2)mNHCH3，-(CH2)mN(CH3)2，
Figure PCTCN2017098281-appb-000004
其中前述取代的取代基选自氨基，羟基，羧基，-SH，-C(O)NH2，甲基，乙基，丙基。
在一更优选实施例中，n选自1，2或3，m选自1，2，3，4或5。
在一实施例中，R3选自-P(O)(OR6)(OR7)，-P(O)2(OR6)M，-P(O)3MY，其中R6和R7各自独立的选自氢，甲基，乙基，丙基，丁基，戊基，己基，M和Y各自独立选自钠离子，钾离子，或者MY为一个二价阳离子，选自钙离子，镁离子。
在一实施例中，R1选自H，甲基，乙基或丙基；R2选自H，-OR3，取代或非取代的呋喃基，取代或非取代的噻吩基，取代或非取代的吡咯基，取代或非取代的咪唑基，取代或非取代的吡唑基，取代或非取代的噻唑基，取代或非取代的噁唑基，取代或非取代的吡啶基，取代或非取代的嘧啶基，取代或非取代的哒嗪基，取代或非取代的吡嗪基，取代或非取代的嘌呤基，取代或非取代的喹啉基，取代或非取代的异喹啉基，取代或非取代的吲哚基，
Figure PCTCN2017098281-appb-000005
其中前述取代的取代基选自甲基，乙基，丙基；
R3选自-C(O)(R4)(R5)，-P(O)(OR6)(OR7)，-P(O)2(OR6)M，-P(O)3MY；
R4选自氢，氨基，甲基，乙基，丙基；
R5选自氢，甲基，乙基，丙基，丁基，戊基，己基，庚基，辛基，壬基，癸基，四氢呋喃基，四氢吡咯基，呋喃基，噻吩基，吡咯基，咪唑基，吡唑基，噻唑基，噁唑基，吡啶基，嘧啶基，哒嗪基，吡嗪基，嘌呤基，喹啉基，异喹啉基，吲哚基，苯基，苄基，-(CH2)nSCH3，-(CH2)mNHCH3，-(CH2)mN(CH3)2；
R6和R7各自独立的选自氢，甲基，乙基，丙基；M和Y各自独立选自钠离子，钾离子，或者MY为一个二价阳离子，选自钙离子，镁离子；且
m和n各自独立的选自1，2，3，4，5，6。
在一优选实施例中，其中：
R1选自H，甲基；
R2选自H，-OR3，
Figure PCTCN2017098281-appb-000006
其中取代基选自甲基，乙基，丙基；
R3选自-C(O)(R4)(R5)，-P(O)(OR6)(OR7)，-P(O)2(OR6)M，-P(O)3MY；
R4选自氢，氨基；
R5选自氢，甲基，乙基，丙基，丁基，戊基，己基，庚基，辛基，壬基，癸基，四氢呋喃基，四氢吡咯基，呋喃基，噻吩基，吡咯基，咪唑基，吡唑基，噻唑基，噁唑基，吡啶基，嘧啶基，哒嗪基，吡嗪基，嘌呤基，喹啉基，异喹啉基，吲哚基，苯基，苄基，-(CH2)nSCH3，-(CH2)mNHCH3，-(CH2)mN(CH3)2；
R6和R7为氢；M和Y各自独立选自钠离子，钾离子，或者MY为一个二价阳离子，选自钙离子，镁离子；且
m和n各自独立的选自1，2，3，4，5，6。
根据本发明，通式为式(Ⅰ)的化合物，其优选化合物包括：
Figure PCTCN2017098281-appb-000007
Figure PCTCN2017098281-appb-000008
本发明中所述的药学上可接受的盐包括但不限于盐酸盐或氨丁三醇盐。
另一方面，本发明提供一种药物组合物，其包含有治疗有效剂量的如前述的化合物(包括其立体异构体)或其药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。
又一方面，本发明提供如前述的化合物(包括其立体异构体)或其药学上可接受的盐在制备治疗癌症的药物中的用途。所述癌症包括但不限于前列腺癌。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述的式(Ⅰ)所示的化合物包括其立体异构体。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素，任选地进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“烷基”是指直链和支链的饱和脂肪族烃基团，主链包括1至20个碳原子，优选为1至12个碳原子，进一步优选为1至8个碳原子，更优选为1至6个碳原子，再进一步优选1至4个碳原子的直链与支链基团，最优选1至2个碳原子；烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2- 二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基。
“烷氧基”是指-O-烷基，其中烷基如本文上述定义。烷氧基可以是取代的或未取代的，烷氧基实施例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基和正己氧基。
“烯基”是指至少含一个碳-碳双键组成的如本文上述定义的烷基，优选含有2至20个碳原子，进一步优选2至12个碳原子，更优选在主链上有2至8个碳原子，烯基可以是取代的或未取代的；非限制性实施例包括乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯、1,4-己二烯、3-十一烯基、4-十二烯基和4,8,12-十四碳三烯基。
“炔基”是指包含至少一个碳-碳三键组成的如本文上述定义的烷基，优选含有2至20个碳原子，进一步优选2至8个碳原子，更优选在主链上有2至4个碳原子的炔基；炔基可以是取代的或未取代的；非限制性实施例包括乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基、4-癸炔基、3-十一炔基和4-十二炔基。
“环烷基”是指全部为碳的单环、稠合、螺环或桥环的环，非限制性地包括环丙烷、环丁烷、环戊烷、螺[3.4]辛烷、二环[3.1.1]己烷等。
“杂环”或“杂环基”是指取代的或未取代的饱和或不饱和的至少含有1至5个选自N、O、S、S(＝O)或S(＝O)2原子或基团的非芳香环系统，非芳香环系统包含3至20个环原子，优选3至10个环原子，更优选3至8个环原子；杂环基环中选择性取代的N、S可被氧化成各种氧化态；非限制性实施例包括氧杂环丙烷基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环己基、氧杂环辛基、氮杂环丙烷基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环丙烯基、1,3二氧环戊基、1,4-二氧环戊基、1,3-二氧环戊基、1,3-二氧环己基、1,3-二硫环己基、氮杂环庚烯基、吗啉基、哌嗪基、吡啶基、呋喃基、噻吩基、吡咯基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、硫代吗啉基、二氢吡喃、噻二唑基、噁唑基、噁二唑基、吡唑基、1,4-二氧杂环己二烯基、2H-1,2-噁嗪基或2,5-二氢噻吩基等。
“杂芳基”是指取代或未取代的5至14元芳香环，且含有1至5个选自N、O或S(＝O)n原子或基团，优选5至10元杂芳香环，进一步优选5至6元；杂芳基的非 限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并咪唑、哌叮基、苯并咪唑、苯并吡啶、吡咯并吡啶；所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。
“取代”是指基团中一个或多个氢原子被其它基团取代的情形，如果所述的基团被氢原子取代，形成的基团与被氢原子取代的基团相同。
“取代或非取代的”是指基团可以被取代或不被取代的情形，若在本发明中没有指出基团可以被取代，则表示该基团为未取代的情形。
“各自独立的选自”是指各取代基可以相同或不同，甚至在同一实施方案中用同一取代基符号表示的不同取代基也可以相同或不同。
“药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或有机碱，或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐。
附图说明
图1显示了各组化合物给药大鼠后血浆中药物浓度和时间的关系。
具体实施方式
下面将结合实施例对本发明作进一步说明，可以使本领域技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1
Compound 1的制备
Figure PCTCN2017098281-appb-000009
Step1：氮气保护下，向1000mL三颈反应瓶中加入S.M.B(20g，73.2mmol，1.00eq)和DMF(400ml)，电磁搅拌。随后缓慢加入氢化钠(3.5g，87.5mmol，1.2eq)，继续搅拌30min后，加入碘化钾(12g，72.2mmol，0.99eq)和TBAB(四丁基溴化铵)(3.52g，10.9mmol，0.15eq)，搅拌15min后，将S.M.1(23.8g，72.8mmol，0.99eq)加入，搅拌12h。停止反应，将反应体系倒入2L水中，搅拌1h，有固体析出，过滤，得到黄色固体滤饼，滤饼以500ml DCM(二氯甲烷)洗涤，分液，取有机相减压浓缩，柱层析(PE:EA＝1.5：1)，得13.20g黄色固体产品，收率35.8％.
Step2：氮气保护下，向100ml三颈反应瓶中加入Int 1-01(500mg，1mmol，1.00eq)，DCM 5ml，室温搅拌10min后，一次性加入HCl/EA(10ml，10mmol，10.0eq)，继续搅拌40min。停止反应，过滤干燥得380mg黄色固体产物，收率86.9％。
HPLC:97.05％
LCMS:403.2(M+H-HCl)
1H NMR(400MHz,DMSO)δ8.56-8.51(d,3H),7.51-7.47(dd,1H),7.06–7.04(d,1H),7.01-7.02(d,1H),6.56(bs,2H),5.91-5.85(dd,1H),5.74-5.69(t,1H),5.28-5.23(m,1H),3.92(s,1H),2.25(m,1H),2.88-2.84(d,1H),2.61-2.51(m,1H),2.16-2.10(m,2H),0.96-0.92(m,6H).
实施例2
Compound 2的制备
Figure PCTCN2017098281-appb-000010
Step 1：向2000mL三颈反应瓶中加入S.M.2(50g，285.4mmol，1.00eq)，H2O(1000ml)，碳酸氢钠(95.9g，1141.6mmol，4.00eq)，搅拌30min后，加入DCM和Bu4NHSO4(9.7g，28.5mmol，0.1eq)，继续搅拌20min后，加入S.M.A(56.5g，342.5mmol，1.2eq)，搅拌反应15h。停止反应，分液，取得有机相减压浓缩得60g无色油状物，收率93.8％。
Step2：氮气保护下，向100ml单口反应瓶中加入S.M.B(5.0g，18.3mmol，1.00eq)，DMF 50ml，冰水浴搅拌10min，随后一次性加入NaH(0.9g，22.0mmol，1.2eq)，继续搅拌20min后，加入TBAB(0.6g，1.8mmol，0.1eq)，和KI(3.0g，18.3mmol，1.00eq)加入，冰水浴下反应10min，将Int.2-01(6.2g，27.5mmol，1.50eq)加入，室温搅拌过夜。停止反应，分液，有机相减压浓缩，柱层析(DCM:EA＝5:1)得1.5g产品。
Step3：氮气保护下，向25ml三口反应瓶中加入Int 2-02(0.1g，0.2mmol，1.00eq)，盐酸/二氧六环20ml，室温搅拌过夜。停止反应，过滤干燥得73mg黄色固体产物产物，收率92.4％。HPLC:96.24％
LCMS:361.1(M+H+)
1H NMR(400MHz,DMSO)δ＝8.50(s,2H),7.49(t,1H),7.04(dd,2H),5.79(q,J＝9.7,2H),5.24(dd,4.5,1H),3.82(d,2H),3.57(s,1H),3.14–3.01(m,1H),2.85(d,1H),2.60(d,1H).
实施例3
Compound 3的制备
Figure PCTCN2017098281-appb-000011
Step 1：向500mL三颈反应瓶中加入S.M.1(6g，31.7mmol，1.00eq)，H2O(130ml)，碳酸氢钠(10.6g，126.8mmol，4.00eq)加入，搅拌30min，随后加入DCM和Bu4NHSO4(1.08g，3.2mmol，0.1eq)，搅拌20min；将S.M.A(6.3g，38.0mmol，1.2eq)加入，搅拌反应15h。停止反应，分液，有机相减压浓缩得7.2g无色油状物，收率95.5％。
Step2：向250mL单口反应瓶中加入Int 2-02(5.0g，18.3mmol，1.00eq)，NaI(18g,121mmol)，MeCN(75ml)，室温搅拌过夜。停止反应，分液，有机相减压浓缩得9.2g无色油状产物，收率92.2％。
Step 3：氮气保护下，向250ml三口反应瓶中加入S.M.B(3g，10.98mmol，1.00eq)，DMF 65mL，将反应体系温度冷却至-20℃以下，滴加LiHMDS(11ml，11mmol，1.00eq)，搅拌10min后，加入Int.3-02(4.34g，13.17mmol，1.20eq)的DMF溶液，继续搅拌。停止反应，将反应体系倒入1％的NH4Cl(300ml)冰水溶液中，搅拌析出固体，过滤，滤饼溶于EtOAc中，减压浓缩，柱层析(PE/EtOAc＝10：1-2:1)得1.6g产品，收率30％。
Step4：氮气保护下，向25ml三口反应瓶中加入Int 3-03(0.5g，1.05mmol，1.00eq)，盐酸/二氧六环20ml，室温搅拌过夜。停止反应，过滤，干燥得得235mg黄色固体产物产物，收率54.2％。HPLC:96.4％
LCMS:375.1(M+H+)
1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),7.48(t,J＝7.8Hz,1H),7.05(d,J＝8.4Hz,1H),7.01(d,J＝7.1Hz,1H),5.86(t,J＝9.1Hz,1H),5.74(d,J＝9.5Hz,1H),5.24(dd,J＝13.0,5.3Hz,1H),4.11–4.02(m,3H),3.11–3.03(m,3H),2.87–2.74(m,1H),2.68–2.57(m,1H),2.14–2.08(m,1H),1.38(d,J＝7.0Hz,3H).
实施例4
Compound 4的制备
Figure PCTCN2017098281-appb-000012
Step 1：向500mL三颈反应瓶中加入S.M.4(6.3g，25.27mmol，1.00eq)，H2O(110ml)，将碳酸氢钠(8.48g，101.08mmol，4.00eq)加入，搅拌10min，随后加入DCM和Bu4NHSO4(0.86g，2.52mmol，0.1eq)，搅拌10min后，冰浴条件下，滴加S.M.A(5g，30.32mmol，1.2eq)，室温搅拌反应15h。停止反应，分液，取得有机相减压浓缩得7.4g无色油状物，收率98.4％。
Step2：氮气保护下，向250ml三口反应瓶中加入S.M.B(2.7g，9.88mmol，1.00eq)，DMF 70ml，反应体系冷却至-20℃以下，滴加LiHMDS(9.88ml，9.88mmol，1.00eq)继续搅10min，随后加入Int.4-01(3.8g，12.84mmol，1.3eq)的DMF溶液，保持低温搅拌。停止反应，将反应体系倒入1％的NH4Cl(315ml)冰水溶液中，搅拌析出固体，过滤，滤饼以EA溶，减压浓缩，柱层析(PE:EA＝2:1)得800mg产品，收率15％。
Step3：氮气保护下，向25ml三口反应瓶中加入Int 4-02(0.2g，0.37mmol，1.00eq)，2N盐酸/EA 4ml 4ml，室温搅拌过夜。停止反应，过滤，干燥得得80mg黄色固体产物产物，收率50％。
HPLC:98.24％.
LCMS:417.4(M+H+)
1H NMR(400MHz,DMSO)δ8.43(s,2H),7.50(t,J＝7.7Hz,1H),7.09–6.95(m,2H),6.55(s,2H),5.87(d,J＝9.6Hz,1H),5.74(d,J＝9.8Hz,1H),5.24(d,J＝12.9Hz,1H),4.00(s,1H),3.09(t,J＝15.2Hz,1H),2.86(d,J＝18.2Hz,1H),1.76–1.64(m,1H),1.57(dd,J＝14.0,6.9Hz,2H),1.24(s,2H),0.89(d,J＝6.2Hz,6H).
实施例5
Compound 5的制备
Figure PCTCN2017098281-appb-000013
Step 1：制备方法同实施例4的Step 1，不同之处在于，将S.M.4改为S.M.5。制备获得7.6g无色油状物，收率99.2％。
Step2：制备方法同实施例4的Step 2，不同之处在于，将Int.4-01改为Int.5-01。制备获得800mg产品，收率15％。
Step3：制备方法同实施例4的Step 3，不同之处在于，将Int.4-02改为Int.5-02。制备得到83.6mg黄色固体产物产物,收率52％。
HPLC:99.5％
LCMS:417.4(M+H+)
1H NMR(400MHz,DMSO)δ8.47(s,3H),7.49(s,1H),7.05(d,J＝8.5Hz,2H),6.52(s,2H),5.87(d,J＝9.8Hz,1H),5.71(dd,J＝9.7,4.3Hz,1H),5.29–5.16(m,1H),3.97(s,1H),3.08(ddd,J＝18.7,12.7,6.1Hz,1H),2.86(d,J＝17.5Hz,1H),2.63(dd,J＝26.7,13.6Hz,1H),2.20–2.05(m,1H),1.41(dt,J＝13.3,6.6Hz,1H),1.32–1.07(m,2H),0.93–0.70(m,6H).
LCMS:417.4(M+H+)
实施例6
Compound 6的制备
Figure PCTCN2017098281-appb-000014
Step 1：制备方法同实施例4的Step 1，不同之处在于，将S.M.4改为S.M.6。制备得6.3g无色油状物，收率94.2％。
Step2：制备方法同实施例4的Step 2，不同之处在于，将Int.4-01改为Int.6-01。 制备获得100mg产品，收率2％。
Step3：制备方法同实施例4的Step 3，不同之处在于，将Int.4-02改为Int.6-02。制备得到45mg黄色固体产物产物,收率56.2％。
HPLC:96.53％。
LCMS:401.4(M+H+)
1H NMR(400MHz,DMSO)δ10.00(s,1H),9.00(s,1H),7.48(s,1H),7.03(dd,J＝11.8,7.8Hz,2H),6.53(s,2H),5.86(s,2H),5.24(dd,J＝13.0,5.2Hz,1H),4.40(s,1H),3.16(d,J＝32.7Hz,2H),3.13–2.98(m,1H),2.91–2.78(m,1H),2.22(dd,J＝14.8,7.1Hz,1H),2.16–2.04(m,1H),1.91(s,4H),0.85(s,0H).
实施例7
Compound 7的制备
Figure PCTCN2017098281-appb-000015
Step 1：制备方法同实施例4的Step 1，不同之处在于，将S.M.4改为S.M.7。制备得7g无色油状物，收率88.6％。
Step2：制备方法同实施例4的Step 2，不同之处在于，将Int.4-01改为Int.7-01。制备得到2.1g产品，收率40.2％。
Step3：制备方法同实施例4的Step 3，不同之处在于，将Int.4-02改为Int.7-02。制备得到45mg黄色固体产物产物,收率56.2％。
HPLC:96.41％
LCMS:451.4(M+H+)
1H NMR(400MHz,DMSO)δ8.64(s,3H),7.48(dd,J＝10.3,4.3Hz,1H),7.38–7.15(m,5H),7.14–6.92(m,2H),5.94–5.78(m,1H),5.66(dd,J＝9.6,3.1Hz,1H),5.20(d,J＝13.0Hz,1H),4.33(s,1H),3.09(dt,J＝21.8,11.7Hz,3H),2.86(d,J＝16.2Hz,1H),2.77–2.51(m,1H),2.12(d,J＝6.2Hz,1H).
实施例8
Compound 8的制备
Figure PCTCN2017098281-appb-000016
氮气保护下，向250ml三口反应瓶中加入S.M.B(2.5g，9.15mmol，1.00eq)，DMF 65mL，反应体系温度冷却至-20℃以下，滴加LiHMDS(9.15ml，9.15mmol，1.00eq)，继续低温搅拌10min，随后加入S.M.8(2.72g，11.89mmol，2.00eq)的DMF溶液，冰浴下反应。停止反应，将反应体系倒入1％的NH4Cl(300mL)冰水溶液中，搅拌析出固体，过滤，滤饼溶于EtOAc，减压浓缩，柱层析(PE:EtOAc＝2:1)得290mg产品。
HPLC:82.4％
LCMS:386.1(M+H+)
1H NMR(400MHz,DMSO)δ8.64(s,3H),7.48(dd,J＝10.3,4.3Hz,1H),7.38–7.15(m,5H),7.14–6.92(m,2H),5.94–5.78(m,1H),5.66(dd,J＝9.6,3.1Hz,1H),5.20(d,J＝13.0Hz,1H),4.33(s,1H),3.09(dt,J＝21.8,11.7Hz,3H),2.86(d,J＝16.2Hz,1H),2.77–2.51(m,1H),2.12(d,J＝6.2Hz,1H).
实施例9
Compound 9的制备
Figure PCTCN2017098281-appb-000017
Step1:氮气保护下，向100mL三口反应瓶中加入S.M.B(1g，3.66mmol，1.00eq)，DMF 25mL，将反应体系温度冷却至-20℃以下，滴加LiHMDS(3.66ml，3.66mmol，1.00eq)，搅拌10min，随后加入S.M.9(1.21g，5.49mmol，1.20eq)的DMF溶液，冰水浴下反应。停止反应，将反应体系倒入1％的NH4Cl(120mL)冰水溶液中，搅拌析出固体，过滤，滤饼以EtOAc溶，减压浓缩，柱层析(PE:EA＝2:1)得310mg产品，收率18.3％。
HPLC:98.2％
LCMS:480.2(M+Na+)
1H NMR(400MHz,DMSO)δ7.48(t,J＝7.7Hz,1H),7.02(t,J＝8.1Hz,2H),6.53(s,2H),5.64(d,J＝2.3Hz,2H),5.23(dd,J＝13.0,5.3Hz,1H),3.05(td,J＝13.9,13.4,6.9Hz,1H),2.82(dt,J＝17.8,3.2Hz,1H),2.72–2.51(m,2H),2.27(t,J＝7.3Hz, 2H),2.15–2.02(m,1H),1.49(t,J＝7.1Hz,2H),1.22(s,1H),0.84(t,J＝6.6Hz,3H).
实施例10
Compound 10的制备
Figure PCTCN2017098281-appb-000018
Step 1：氮气保护下，向500mL三颈反应瓶中加入S.M.10(15g，107.9mmol，1.00eq)，DCM(150ml)，DMF(4滴)，冰浴条件下，继续滴加草酰氯(15.07g，118.74mmol，1.1eq)，室温搅拌2h。停止反应，将反应液减压浓缩得14.56g油状物，收率86.1％。
Step2：向100ml单口反应瓶中加入Int.10-01(14.56g，92.06mmol，1.00eq)，多聚甲醛(2.78g，92.06mmol，1.00eq)，氯化锌(2.52g，18.41mmol，0.2eq)，将反应体系温度升高至90℃搅拌。停止反应，反应液减压浓缩，柱层析得4.3g产品，收率24.7％。
Step3：氮气保护下，向250ml三口反应瓶中加入S.M.B(4.48g，16.4mmol，1.00eq)，DMF 65ml，将反应体系温度冷却至-20℃以下；滴加LiHMDS(16.4ml，16.4mmol，1.00eq)，搅拌10min后，加入Int.10-02(4.0g，21.3mmol，1.3eq)的DMF溶液，冰浴下搅拌。将反应体系倒入1％的NH4Cl(360ml)冰水溶液中，搅拌析出固体，过滤，滤饼以EA溶，减压浓缩，柱层析(DCM:EA＝50:1～30:1)得3.3g产品，收率47.5％。
Step4：向250ml三口反应瓶中加入Int.10-03(3.33g，7.85mmol，1.00eq)，THF66ml，二甲胺(1.41g，31.4mmol，4.00eq)，KI(33mg)，常温搅拌。停止反应，将体系直接以减压泵旋干以少量EA溶解后再以3N的HCl/EA成盐析出，过滤得500mg产品，收率15％。
HPLC:98.6％
LCMS:451.4(M+H+)
1H NMR(400MHz,DMSO)δ10.78(s,0H),7.48(dd,J＝8.4,7.1Hz,1H),7.04(dd,J＝21.7,7.6Hz,2H),6.59(s,2H),5.81(q,J＝9.7Hz,1H),5.26(dd,J＝13.0,5.4Hz, 1H),3.61–3.18(m,1H),2.83(s,3H),2.51(dt,J＝3.8,1.9Hz,1H),2.22–1.98(m,1H).
实施例11
Compound 11的制备
Figure PCTCN2017098281-appb-000019
Step 1：向100mL三颈反应瓶中加入S.M.11(2.50g，10mmol，1.00eq)，碳酸氢钠(3.78g，45mmol，4.50eq)，四丁基硫酸氢铵(169mg，0.5mmol，0.05eq)，水(12ml)，乙酸异丙酯(14ml)，搅30min后，滴加S.M.A(2.97g，18mmol，1.80eq)，搅拌反应约13h。停止反应，分液，取得有机相减压浓缩得到无色液体2.20g，收率85.2％.
Step2：氮气保护下，向100ml三口反应瓶中加入泊马度胺(1.00g，3.66mmol，1.00eq)，DMF 10ml，搅拌1h后，加入氢化钠(60％)(175mg，4.39mmol，1.20eq)，继续搅拌40min；随后加入Int.11.01(0.95g，3.66mmol，1.00eq)，继续搅拌27h。停止反应，将体系倒入5％的氯化铵(200ml)溶液中，搅拌析出固体，过滤，滤饼以200mlDCM溶解，减压浓缩，柱层析(PE:EA＝1.5：1)得到650mg黄色固体产物。收率35.9％。
Step 3：氮气保护下，向100ml三口反应瓶中加入Int11.02(490mg，1mmol，1.00eq)，DCM 20ml，室温搅拌10min后，加入HCl/EA(20ml，20mmol，20.0eq)，继续搅拌45min。停止反应，以水泵将反应体系中盐酸真空抽20min，然后氮气氛下抽滤，得到黄色固体产物，直接以10ml甲醇溶解，用作下步原料。氮气保护下，向100ml三口反应瓶中加入上述中间体的甲醇溶液，室温搅拌下滴加三丁胺醇(243mg，2mmol，2.00eq)的20ml甲醇溶液，搅拌10min，将25ml丙酮滴加入体系中，体系有大量固体析出，搅拌40min。过滤得到滤饼，真空干燥，得到170mg黄色固体产物，收率27.2％。
HPLC:99.73
LCMS:382(M-H-2tris)
1H NMR(400MHz,DMSO),.δ7.52-7.48(t,1H),7.05-7.03(t,2H),5.92(m,2H),5.16-5.11(dd,1H),3.37(s,12H),3.03-2.95(m,1H),2.82-2.78(d,1H),2.64-2.53(m,1H),2.10-2.03(m,1H)
实施例12本发明化合物的溶解度测定
将1mg化合物1与1ml水混合，室温搅拌，完全溶解，取上清液作为供试样品溶液。通过HPLC测定供试样品溶液，结果如表1所示。
将50mg化合物的盐酸盐或氨丁三醇盐与150μl水混合，室温搅拌，完全溶解，取上清液作为供试样品溶液。通过HPLC测定供试样品溶液，结果如表1所示。
表1
样品 室温下水中的最低溶解度(mg/ml)
化合物1 1
化合物1的盐酸盐 >300
化合物2的盐酸盐 >300
化合物3的盐酸盐 >300
化合物4的盐酸盐 >300
化合物5的盐酸盐 >300
化合物6的盐酸盐 >300
化合物7的盐酸盐 >300
化合物10的盐酸盐 >300
化合物11的氨丁三醇盐 >300
本试验未测定样品的饱和溶解度，而是采用选取适量样品，判断样品的溶解能力。由试验得出，本发明化合物(1mg)或盐(300mg)能完全溶解在1ml水中，化合物溶解度不小于1mg/ml，其盐溶解度不小于300mg/ml。而泊马度胺在水中的溶解度约为0.01mg/ml，远低于本发明化合物或其盐的溶解能力。
实施例13本发明化合物的稳定性测定
取适量样品各自独立的放置于不同环境条件下，测定0天，5天，10天或30天时样品的百分含量，评价样品的稳定性。
Figure PCTCN2017098281-appb-000020
Figure PCTCN2017098281-appb-000021
注：RT＝室温，RH＝相对湿度
实施例14药动学数据
本实施例中所使用的为雄性SD大鼠(SPF级)，体重250～330g，购自北京维通利华实验动物技术有限公司，大于8周龄，动物群养在装有垫料的聚碳酸酯笼具里(最多5只动物/性别/笼)。自由饮水，每日自由采食合格饲料5CC4(同5CR4，PMI Nutrition International LLC,美国)
采用随机区组设计的分组，对试验用SD大鼠进行分组，分为化合物1的盐酸盐组、化合物11的氨丁三醇盐组、泊马度胺组。各组以灌胃(i.g.)的方式给药，给药剂量设为2mg/kg(以泊马度胺计)。
试验方法：给药前，给药后0.25、0.5、1、2、3、4、6、8、12、24、36和48小时采集血样，采入含有EDTA-2K的抗凝管中的全血于湿冰上存放，并在30分钟内于3500rpm，4℃下离心5分钟来获得血浆样品。分离取得的血浆样品立即放在干冰中暂存然后转移至-60至-80℃冰箱中。血浆中的化合物1的盐酸盐、化合物11的氨丁三醇盐和泊马度胺分析采用LC/MS/MS进行检测，采用软件WinNonlin的非室模型计算大鼠给药后的药代动力学参数。
数据结果：大鼠给予泊马度胺(2mg/kg)等摩尔剂量的各化合物后血浆中泊马度胺浓度随时间变化的药代动力学参数如下所示
Figure PCTCN2017098281-appb-000022
Figure PCTCN2017098281-appb-000023
结论：由上述试验结果可知，各组给药后，在体内均只检出泊马度胺，说明它们进入体内后均迅速代谢为泊马度胺。在2mg/kg的剂量下，给药后，本发明化合物相比泊马度胺，Cmax值升高3倍以上，AUClast升高2倍以上，化合物1和化合物11的Cmax表明本发明化合物与泊马度胺相比具有更好的口服生物利用度。

Claims (13)

  1. 一种式(Ⅰ)所示的化合物或其药学上可接受的盐，
    Figure PCTCN2017098281-appb-100001
    其中：
    R1选自H，取代或非取代的C1-6烷基，取代或非取代的C1-6烷氧基，取代或非取代的C2-6烯基，取代或非取代的C2-6炔基，其中前述取代的取代基选自C1-6烷基，C1-6烷氧基；
    R2选自H，-OR3，-SR3，-NHR3，取代或非取代的C3-10杂环基，取代或非取代的C3-10杂环芳基，取代或非取代的C3-10环烷基，其中前述取代的取代基选自C1-6烷基，C1-6烷氧基，羰基，羧基，氨基，羟基；
    R3选自-C(O)(R4)(R5)，-P(O)(OR6)(OR7)，-P(O)2(OR6)M，-P(O)3MY；
    R4选自氢，氨基，羟基，卤素，C1-6烷基；
    R5选自氢，取代或非取代的C1-16烷基，取代或非取代的C1-6烷氧基，取代或非取代的C3-10杂环基，取代或非取代的C3-10杂环芳基，取代或非取代的C3-10环烷基，苯基，苄基，-(CH2)nSCH3，-(CH2)mNHCH3，-(CH2)mN(CH3)2，其中前述取代的取代基选自氨基，羟基，羧基，-SH，-C(O)NH2，C1-6烷基；
    R6和R7各自独立的选自氢，C1-6烷基；M和Y各自独立选自单价阳离子，或者MY为一个二价阳离子；且
    m和n各自独立的选自1，2，3，4，5，6。
  2. 如权利要求1所述的化合物或其药学上可接受的盐，其中R1选自H，取代或非取代的甲基，取代或非取代的乙基，取代或非取代的丙基，取代或非取代的丁基，取代或非取代的戊基，取代或非取代的己基，其中前述取代的取代基选自甲基，乙基或丙基。
  3. 如权利要求1所述的化合物或其药学上可接受的盐，其中R2选自H，-OR3，取代或非取代的四氢呋喃基，取代或非取代的四氢吡咯基，取代或非取代的呋喃基，取代或非取代的噻吩基，取代或非取代的吡咯基，取代或非取代的咪唑基，取代或非取代的吡唑基，取代或非取代的噻唑基，取代或非取代的噁唑基，取代或非取代的吡啶基，取代或非取代的嘧啶基，取代或非取代的哒嗪基，取代或非取代的吡嗪基，取代或非取代的嘌呤基，取代或非取代的喹啉基，取代或非取代的异喹啉基，取代或非取代的吲哚基，取代或非取代的环丙基，取代或非取代的 环己基，取代或非取代的环丁基，取代或非取代的环戊基，
    Figure PCTCN2017098281-appb-100002
    其中前述取代的取代基选自甲基，乙基，丙基，羰基，羧基，氨基，羟基。
  4. 如权利要求3所述的化合物或其药学上可接受的盐，其中R3选自-C(O)(R4)(R5)，其中：
    R4选自氢，氨基，甲基，乙基，丙基；且
    R5选自氢，取代或非取代的四氢呋喃基，取代或非取代的四氢吡咯基，取代或非取代的呋喃基，取代或非取代的噻吩基，取代或非取代的吡咯基，取代或非取代的咪唑基，取代或非取代的吡唑基，取代或非取代的噻唑基，取代或非取代的噁唑基，取代或非取代的吡啶基，取代或非取代的嘧啶基，取代或非取代的哒嗪基，取代或非取代的吡嗪基，取代或非取代的嘌呤基，取代或非取代的喹啉基，取代或非取代的异喹啉基，取代或非取代的吲哚基，取代或非取代的环丙基，取代或非取代的环己基，取代或非取代的环丁基，取代或非取代的环戊基，苯基，苄基，-(CH2)nSCH3，-(CH2)mNHCH3，-(CH2)mN(CH3)2，
    Figure PCTCN2017098281-appb-100003
    其中前述取代的取代基选自氨基，羟基，羧基，-SH，-C(O)NH2，甲基，乙基，丙基。
  5. 如权利要求4所述的化合物或其药学上可接受的盐，其中n选自1，2或3，m选自1，2，3，4或5。
  6. 如权利要求1所述的化合物或其药学上可接受的盐，其中R3选自-P(O)(OR6)(OR7)，-P(O)2(OR6)M，-P(O)3MY，其中R6和R7各自独立的选自氢，甲基，乙基，丙基，丁基，戊基，己基，M和Y各自独立选自钠离子，钾离子，或者MY为一个二价阳离子，选自钙离子，镁离子。
  7. 如权利要求1所述的化合物或其药学上可接受的盐，其中：
    R1选自H，甲基，乙基或丙基；
    R2选自H，-OR3，取代或非取代的呋喃基，取代或非取代的噻吩基，取代或非取代的吡咯基，取代或非取代的咪唑基，取代或非取代的吡唑基，取代或非取代的噻唑基，取代或非取代的噁唑基，取代或非取代的吡啶基，取代或非取代的嘧啶基，取代或非取代的哒嗪基，取代或非取代的吡嗪基，取代或非取代的嘌呤基，取代或非取代的喹啉基，取代或非取代的异喹啉基，取代或非取代的吲哚基，
    Figure PCTCN2017098281-appb-100004
    其中前述取代的取代基选自甲基，乙基，丙基；
    R3选自-C(O)(R4)(R5)，-P(O)(OR6)(OR7)，-P(O)2(OR6)M，-P(O)3MY；
    R4选自氢，氨基，甲基，乙基，丙基；
    R5选自氢，甲基，乙基，丙基，丁基，戊基，己基，庚基，辛基，壬基，癸基，四氢呋喃基，四氢吡咯基，呋喃基，噻吩基，吡咯基，咪唑基，吡唑基，噻唑基，噁唑基，吡啶基，嘧啶基，哒嗪基，吡嗪基，嘌呤基，喹啉基，异喹啉基，吲哚基，苯基，苄基，-(CH2)nSCH3，-(CH2)mNHCH3，-(CH2)mN(CH3)2；
    R6和R7各自独立的选自氢，甲基，乙基，丙基；M和Y各自独立选自钠离子，钾离子，或者MY为一个二价阳离子，选自钙离子，镁离子；且
    m和n各自独立的选自1，2，3，4，5，6。
  8. 如权利要求7所述的化合物及其立体异构体或药学上可接受的盐，其中，
    R1选自H，甲基；
    R2选自H，-OR3，
    Figure PCTCN2017098281-appb-100005
    其中取代基选自甲基，乙基，丙基；
    R3选自-C(O)(R4)(R5)，-P(O)(OR6)(OR7)，-P(O)2(OR6)M，-P(O)3MY；
    R4选自氢，氨基；
    R5选自氢，甲基，乙基，丙基，丁基，戊基，己基，庚基，辛基，壬基，癸基，四氢呋喃基，四氢吡咯基，呋喃基，噻吩基，吡咯基，咪唑基，吡唑基，噻唑基，噁唑基，吡啶基，嘧啶基，哒嗪基，吡嗪基，嘌呤基，喹啉基，异喹啉基，吲哚基，苯基，苄基，-(CH2)nSCH3，-(CH2)mNHCH3，-(CH2)mN(CH3)2；
    R6和R7为氢；M和Y各自独立选自钠离子，钾离子，或者MY为一个二价阳离子，选自钙离子，镁离子；且
    m和n各自独立的选自1，2，3，4，5，6。
  9. 如权利要求1所述的化合物或其药学上可接受的盐，其中该化合物具有下列的结构之一：
    Figure PCTCN2017098281-appb-100006
    Figure PCTCN2017098281-appb-100007
  10. 如权利要求1-9任一项所述的的化合物或其药学上可接受的盐，其中该药学上可接受的盐为盐酸盐或氨丁三醇盐。
  11. 一种药物组合物，包含有治疗有效剂量的如权利要求1-9中任一项所述的化合物或其药学上可接受的盐，以及药学上可接受的载体和/或赋形剂。
  12. 如权利要求1-9中任一项所述的化合物或其药学上可接受的盐在制备治疗癌症的药物中的用途。
  13. 如权利要求12所述的用途，其中所述的癌症为前列腺癌。
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