WO2023030319A1 - 阿片受体激动剂及其制备方法和用途 - Google Patents
阿片受体激动剂及其制备方法和用途 Download PDFInfo
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- WO2023030319A1 WO2023030319A1 PCT/CN2022/115846 CN2022115846W WO2023030319A1 WO 2023030319 A1 WO2023030319 A1 WO 2023030319A1 CN 2022115846 W CN2022115846 W CN 2022115846W WO 2023030319 A1 WO2023030319 A1 WO 2023030319A1
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- WNTGVOIBBXFMLR-UHFFFAOYSA-N bicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1C2 WNTGVOIBBXFMLR-UHFFFAOYSA-N 0.000 description 1
- KVLCIHRZDOKRLK-UHFFFAOYSA-N bicyclo[4.2.1]nonane Chemical compound C1C2CCC1CCCC2 KVLCIHRZDOKRLK-UHFFFAOYSA-N 0.000 description 1
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- JGDFBJMWFLXCLJ-UHFFFAOYSA-N copper chromite Chemical compound [Cu]=O.[Cu]=O.O=[Cr]O[Cr]=O JGDFBJMWFLXCLJ-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 125000005215 cycloalkylheteroaryl group Chemical group 0.000 description 1
- KTHXBEHDVMTNOH-UHFFFAOYSA-N cyclobutanol Chemical compound OC1CCC1 KTHXBEHDVMTNOH-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
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- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- CAHCBJPUTCKATP-FAWZKKEFSA-N etorphine Chemical compound O([C@H]1[C@@]2(OC)C=C[C@@]34C[C@@H]2[C@](C)(O)CCC)C2=C5[C@]41CCN(C)[C@@H]3CC5=CC=C2O CAHCBJPUTCKATP-FAWZKKEFSA-N 0.000 description 1
- 229950004155 etorphine Drugs 0.000 description 1
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- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
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- 125000002883 imidazolyl group Chemical group 0.000 description 1
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
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- 230000003834 intracellular effect Effects 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000009191 jumping Effects 0.000 description 1
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 1
- 239000002632 kappa opiate receptor agonist Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000003399 opiate peptide Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 238000012402 patch clamp technique Methods 0.000 description 1
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- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
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- 229920001155 polypropylene Polymers 0.000 description 1
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- 238000012545 processing Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
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- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 238000012549 training Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- WNWMJFBAIXMNOF-UHFFFAOYSA-N trimethyl(propyl)silane Chemical compound CCC[Si](C)(C)C WNWMJFBAIXMNOF-UHFFFAOYSA-N 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
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Classifications
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07D405/02—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 two hetero rings
- C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicinal chemistry, and in particular relates to a class of oxaspirocyclic small molecule compounds, a preparation method thereof, a pharmaceutical composition containing the compound and its use as a therapeutic agent, especially as a MOR receptor agonist and in the preparation of therapeutic and /or use in medicines for preventing pain and other related diseases.
- Opioid receptor is a G protein coupled receptor (GPCR), which is the binding target of endogenous opioid peptides and opioids.
- GPCR G protein coupled receptor
- opioid receptors There are a variety of opioid receptors in the human body, mainly including ⁇ opioid receptors (Mu opioid receptors, MOR), delta opioid receptors (Delta opioid receptors, DOR) and ⁇ opioid receptors (Kappa opoid receptors, KOR), widely distributed in Central nervous system, heart, digestive tract, blood vessels, kidney and other peripheral tissues (Nature, 2016, 537(7619): 185).
- MOR has the strongest binding ability to morphine, and it is the receptor protein site for the main action of analgesics such as morphine and fentanyl.
- Zadina et al found that the binding ability (360pM) of MOR receptor and morphine peptide 1 is 4000 times and 15000 times of the binding ability between DOR receptor and KOR receptor and morphine peptide 1 (science, 2001, 293: 311-315; BiOChem Biophys Res Commun 235:567-570; Life Sci 61:409-415).
- the G protein signaling pathway mainly includes second messenger systems such as calcium ions, adenylate cyclase, and mitogen-activated protein kinase.
- the ⁇ -arrestin pathway has three main aspects: (1) acting as a negative regulator and interacting with GPCR kinases to cause receptor desensitization of GPCRs to stop G protein signal transduction; (2) recruiting endocytic proteins as scaffolding proteins to induce GPCR internal (3) As an adapter protein, it forms a complex with GPCR downstream signaling molecules, and activates signal transduction molecules in a G protein-independent manner.
- the present invention provides a compound with novel structure that can be used as MOR receptor agonist.
- This type of compound exhibits high activity, E max is also significantly improved, and has higher selectivity to MOR.
- the present invention provides compounds represented by formula (I), their solvates, stereoisomers, deuterated compounds or pharmaceutically acceptable salts thereof,
- Ring A is selected from
- Ring B is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 is C, and the others are independently selected from CR 2 and N;
- R 4 is independently selected from -C 1-6 alkyl or -C 1-6 alkyl-OC 1-6 alkyl;
- Any one of X 2 , X 3 , X 4 , and X 5 is C, and the others are independently selected from CR 3 , N;
- R 2 or two R 3 on adjacent two C atoms form 3 to 12 membered heterocyclyl, 3-12 membered cycloalkyl, 5 to 10 membered heteroaryl, 5 To 10-membered aryl;
- the heterocyclyl, cycloalkyl, heteroaryl, aryl can be optionally further substituted by 1 to 4 R 1 ;
- the g is selected from 0, 1, 2, 3, 4;
- the f is selected from 0, 1, 2;
- Said m is selected from 0, 1, 2.
- the compound is selected from the structures represented by formula (II) or (III);
- the R 2 and R 3 are each independently selected from 3-6 membered monoheterocyclyl, 7-10 membered heterocyclyl, 7-11 membered spiroheterocyclyl, 7-11 membered bridged heterocyclyl;
- the monoheterocyclic group may be optionally further substituted by 1 to 3 R b .
- each of R 2 and R 3 is independently selected from a 4-membered monoheterocyclic group, wherein the monoheterocyclic group is optionally further substituted by 1 to 3 R b ;
- each R 2 and R 3 are independently selected from halogen
- the ring C is selected from 3 to 12 membered heterocyclic groups, 3-12 membered cycloalkyl groups, 5 to 10 membered heteroaryl groups, and 5 to 10 membered aryl groups;
- n is selected from 0, 1, 2, 3, 4.
- the ring C is selected from 6 to 12 membered condensed heterocyclic rings; further preferably 6-12 membered heterocyclic groups and 6-12 membered spiro heterocyclic groups, and among the described heterocyclic groups and spiro heterocyclic groups at least Contains two O heteroatoms.
- X is selected from S, O, NH.
- the ring D is selected from 3 to 12 membered heterocyclic groups, 3-12 membered cycloalkyl groups, 5 to 10 membered heteroaryl groups, and 5 to 10 membered aryl groups;
- p is selected from 0, 1, 2, 3, 4.
- ring D is selected from 4 to 12 membered heterocyclic groups, and the heterocyclic group contains at least two O heteroatoms; further preferred ring D is selected from 5 to 6 membered monoheterocyclic groups, and the monoheterocyclic group The ring group contains at least two O heteroatoms.
- ring D is selected from 6 to 12 membered condensed heterocyclic rings; further preferred are 6-12 membered heterocyclic groups and 6-12 membered spiro heterocyclic groups, and the described heterocyclic groups and spiro heterocyclic groups contain at least two an O heteroatom.
- Z 1 , Z 2 , Z 3 and Z 4 are independently selected from C and N.
- Typical compounds of the present invention include but are not limited to the following structures:
- Another aspect of the present invention relates to a pharmaceutical composition, which comprises the above compound, its solvate, stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- Another aspect of the present invention provides the above-mentioned compound, its solvate, stereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of prevention and/or treatment of MOR receptor agonist-mediated Use in medicines for related diseases.
- the related diseases mediated by MOR receptor agonists are selected from pain, immune dysfunction, inflammation, esophageal reflux, neurological and mental diseases, urinary and reproductive diseases, cardiovascular diseases and respiratory diseases; the above pains are selected from postoperative pain, Pain from cancer, neuropathic pain, traumatic pain, and pain from inflammation.
- Another aspect of the present invention provides a method for the prevention and/or treatment of related diseases mediated by MOR receptor agonists, which includes administering the above compound, its solvate, stereoisomer, deuterated A compound or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.
- Another aspect of the present invention provides the above-mentioned compounds, their solvates, stereoisomers, deuterated compounds or pharmaceutically acceptable salts thereof for use as medicine or for treatment.
- the present invention found that the heterocyclic group substitution on the aryl group showed high activity, E max was also significantly improved, and hERG was also significantly improved. Further research found that the compound with a single configuration has a selectivity for MOR. Higher, lower ⁇ -arrestin-mediated side effects.
- C2-6 alkynyl used in the present invention refers to a straight chain or branched alkyne group derived from an alkyne moiety of 2 to 6 carbon atoms containing a carbon-carbon triple bond, such as ethynyl, propyne 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, etc.
- cycloalkyl in the present invention includes all possible single rings and condensed rings (including fused in the form of parallel, spiro, and bridge); for example, "3-12 membered cycloalkyl” can be a single ring , bicyclic, or multicyclic cycloalkyl systems (also known as fused ring systems).
- a monocyclic ring system is a cyclohydrocarbyl group containing 3-8 carbon atoms, examples include but are not limited to: cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexane, Cycloheptyl, cyclooctyl, etc.
- the fused ring cycloalkyl group includes parallel cycloalkyl group, bridged cycloalkyl group and spirocycloalkyl group.
- Paracycloalkyl can be 6-11 membered cyclocycloalkyl, 7-10 membered cyclocycloalkyl, representative examples of which include but are not limited to bicyclo[3.1.1]heptane, bicyclo[2.2.1] Heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane.
- Spirocycloalkyl can be 7-12 membered spirocycloalkyl, 7-11 membered spirocycloalkyl, examples include but not limited to: group.
- the above bridged cycloalkyl group can be 6-11 membered bridged cycloalkyl group, 7-10 membered bridged cycloalkyl group, examples of which include but are not limited to: group.
- heterocyclyl refers to a non-aromatic cyclic group in which at least one ring carbon atom of 3-12 members is replaced by a heteroatom selected from O, S, N, preferably 1-3 heteroatoms, while Including carbon atoms, nitrogen atoms and sulfur atoms may be substituted by oxo.
- heterocyclyl refers to monocyclic heterocyclyl, bicyclic heterocyclyl system or polycyclic heterocyclyl system (also known as fused ring system), including saturated and partially saturated heterocyclyl, but Aromatic rings are not included. Unless otherwise specified, all monocyclic rings, condensed rings (including fused in the form of parallel, spiro, and bridge), saturated, and partially saturated that may be formed are included.
- Monoheterocyclyl can be 3-8 member monoheterocyclyl, 3-6 member monoheterocyclyl, 4-7 member monoheterocyclyl, 5-7 member monoheterocyclyl, 5-6 member monoheterocyclyl , 5-6 membered oxygen-containing monoheterocyclic group, 3-8 membered nitrogen-containing monoheterocyclic group, 5-6 membered nitrogen-containing monoheterocyclic group, 5-6 membered saturated monoheterocyclic group, etc., examples of which include but not limited to: group.
- Fused heterocycles include heterocyclyls, spiroheterocyclyls, bridged heterocyclyls and may be saturated, partially saturated or unsaturated, but are not aromatic.
- the heterocyclyl can be 6-12 membered heterocyclyl, 7-10 membered heterocyclyl, 6-10 membered heterocyclyl, 6-12 membered saturated heterocyclyl, representative examples include but are not limited to : group.
- the spiroheterocyclyl can be 6-12 membered spiroheterocyclyl, 7-11 membered spiroheterocyclyl, 6-12 membered saturated spiroheterocyclyl, examples include but not limited to: group;
- the above bridged heterocyclic group can be 6-12 membered bridged heterocyclic group, 7-11 membered bridged heterocyclic group, 6-12 membered bridged heterocyclic group, examples of which include but are not limited to: group.
- aryl refers to a monovalent monocyclic or polycyclic (including fused forms) aromatic ring system consisting only of carbon and hydrogen atoms; common aryl Including, but not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.
- aryl also includes heterocyclyl and aryl, cycloalkyl and aryl;
- heteroaryl refers to a monovalent monocyclic or polycyclic (including fused forms) aromatic ring system whose ring atoms consist of carbon atoms and are selected from the group consisting of nitrogen, oxygen, and , sulfur and phosphorus heteroatoms; common heteroaryl groups include (but are not limited to) benzopyrrolyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl , azetidinyl, carbazolyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, indazolyl, indazine Base, indolyl, quinolinyl, isoquinolyl, phenazinyl, phenoxazin
- the "stereoisomer" of the compound shown in the present invention means that when the compound has an asymmetric carbon atom, it will produce enantiomers; when the compound has a carbon-carbon double bond or a ring structure, it will produce cis-trans isomerism Isomers; when compounds exist in ketones or oximes, tautomers are produced, enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomerism of all compounds Isomers, geometric isomers, epimers and mixtures thereof are included in the scope of the present invention.
- Step 3 Nitrogen-((3-(but-2-yn-1-oxyl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[ 4.5] Synthesis of decan-9-yl)ethylamine (3)
- Step 1 Synthesis of 3-((3-cyclopropyl-2-yn-1-yl)oxy)thiophene-2-carbaldehyde (4-2)
- Step 2 Nitrogen-((3-((3-cyclopropyl-2-yn-1-yl)oxy)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl) Synthesis of -6-oxaspiro[4.5]decane-9-yl)ethylamine (4)
- Step 2 Nitrogen-((3-(3,3-difluoroazetidin-1-yl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6 Synthesis of -oxaspiro[4.5]decane-9-yl)ethylamine (6)
- Step 1 Synthesis of 3-((3-(trimethylsilyl)prop-2-yn-1-yl)oxy)thiophene-2-carbaldehyde (7-2)
- Step 2 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)-nitrogen-((3-((3-(trimethylsilyl)propane Synthesis of -2-yn-1-yl)oxy)thiophen-2-yl)methyl)ethylamine (7-3)
- Step 3 Nitrogen-((3-(prop-2-yn-1-yl-oxy)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxa Synthesis of cyclo[4.5]decane-9-yl)ethylamine (7)
- 8-1 110.06mg, 1.57mmol
- 6-1 100.00mg, 523.43 ⁇ mol
- Pd(PPh 3 ) 2 Cl 2 36.74mg, 52.34 ⁇ mol
- cuprous iodide 9.97mg, 52.34 ⁇ mol
- triethylamine 118.9mg, 1.57mmol
- tetrahydrofuran 5mL
- Step 2 Nitrogen-((3-(3-methoxypropyl-1-ynyl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxa Synthesis of spiro[4.5]decane-9-yl)ethylamine (8)
- Step 2 Nitrogen-((3-(methylthio)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9- base) synthesis of ethylamine (9)
- Step 1 Synthesis of 1,3,3a,8a tetrahydrofuro[3,4-b]thieno[3,4-e][1,4]dioxin (11-3)
- Step 2 Synthesis of 1,3,3a,8a-tetrahydrofuro[3,4-b]thieno[3,4-e][1,4]dioxin-5-yl)carbaldehyde (11-4)
- Step 3 2-(9-(pyridin-2-yl)-6-oxa[4.5]decane-9-yl)-nitrogen-((1,3,3a,8a-tetrahydrofurano[3,4-b Synthesis of ]thieno[3,4-e][1,4]dioxin-5-yl)methyl)ethylamine (11)
- Step 1 Synthesis of 4a, 5, 6, 7, 8, 8a-hexahydrobenzo[b]thiophene[3,4-e][1,4]dioxin (12-2)
- Step 2 Synthesis of 4a, 5, 6, 7, 8, 8a-hexahydrobenzo[b]thiophene[3,4-e][1,4]dioxin-1-carbaldehyde (12-3)
- Step 3 Nitrogen-((4a,5,6,7,8,8a-hexahydrobenzo[b]thieno[3,4-e][1,4]dioxin-1-yl)methyl) -Synthesis of 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (12)
- Step 3 Synthesis of 2,3,5,6,8,9-hexahydrothiophene[3,4-b][1,4,7,10]tetraoxocyclododecane (13-5)
- Step 4 Synthesis of 2,3,5,6,8,9-hexahydrothiophene[3,4-b][1,4,7,10]tetraoxcyclododecane 11-carbaldehyde (13-6)
- Step 5 Nitrogen-((2,3,5,6,8,9-hexahydrothiophene[3,4-b][1,4,7,10]tetraoxocyclododec-11-yl)methanol Synthesis of yl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethylamine (13)
- Step 1 Synthesis of 3-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)thiophene-2-carbaldehyde (14-2)
- Step 2 Nitro-((3-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)thiophen-2-yl)methyl)-2-(9-(pyridine Synthesis of -2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (14)
- Step 2 Nitrogen-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-2-(9-(pyridin-2-yl)-6- Synthesis of oxaspiro[4.5]decane-9-yl)ethylamine (17)
- Step 1 Synthesis of 3-(1,4-dioxaspiro[4.5]decan-7-en-8-yl)thiophene-2-carbaldehyde (19-2)
- Step 2 Nitro-((3-(1,4-dioxaspiro[4.5]dececyl-7-en-8-yl)thiophen-2-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (19)
- Step 1 Synthesis of 3-(2-oxo-5-azabicyclo[2.2.2]octane-5-yl)thiophene-2-carbaldehyde (21-3)
- Step 2 Nitrogen-((3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)thiophen-2-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (21)
- Step 1 Synthesis of 2-((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethylamine)acetonitrile (22-2)
- Step 3 tert-butyl((2hydro-tetrazol-5-yl)methyl)(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl) Synthesis of ethyl carbamate (22-4)
- Step 4 tert-Butyl((1-methyl-1hydro-tetrazol-5-yl)methyl)(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane Synthesis of -9-yl) ethyl carbamate (22-5)
- Step 5 Nitrogen-((1-methyl-1hydro-tetrazol-5-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane- Synthesis of 9-yl)ethylamine (22)
- Step 1 tert-Butyl((2-methyl-2hydro-tetrazol-5-yl)methyl)(2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane Synthesis of -9-yl)ethylcarbamate (23-1)
- Step 2 Nitrogen-((2-methyl-2hydro-tetrazol-5-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane- Synthesis of 9-yl)ethylamine (23)
- Step 1 Synthesis of 5-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)thiophene-2-carbaldehyde (24-2)
- Step 2 Nitrogen-((5-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)thiophen-2-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (24)
- Step 1 Synthesis of tetrahydrofuran-3,4-bis(4-methylbenzenesulfonic acid) diester (25-2)
- Step 2 Synthesis of 1,3,3a,9a-tetrahydrobenzo[b]furo[3,4-e][1,4]dioxin-5-carbaldehyde (25-4)
- Step 3 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)-nitrogen-((1,3,3a,9a-benzo[b]furan Synthesis of [3,4-E][1,4]dioxin-5-yl)methyl)ethylamine (25)
- 26-1 (0.3g, 2.62mmol), 6-1 (298.79mg, 2.62mmol), potassium acetate (770.57mg, 7.85mmol), palladium acetate (117.52mg, 0.523mmol), tetrabutyl Ammonium bromide (843.5mg, 2.62mmol) was added into N,N-dimethylformamide (50mL), replaced with nitrogen three times, and heated to 80°C for 3h under nitrogen atmosphere.
- Step 2 Nitro-((3-methoxy-[2,3'-bithiophene]-2'-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro [4.5] Synthesis of decan-9-yl) ethylamine (26)
- Step 1 Synthesis of 4-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)thiophene-2-carbaldehyde (28-2)
- Step 2 Nitrogen-((4-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)thiophen-2-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (28)
- Step 1 tert-butyl((2-(2-methoxyethyl)-2-hydro-tetrazol-5-yl)methyl)(2-(9-(pyridin-2-yl)-6- Oxaspiro[4.5]decane-9-yl)ethylcarbamate & tert-butyl((1-(2-methoxyethyl)-1-hydrogen-tetrazol-5-yl)methyl) Synthesis of (2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanolate (29-1)
- Step 2 Nitrogen-((2-(2-methoxyethyl)-2-hydro-tetrazol-5-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxo Heterospiro[4.5]decane-9-yl)ethylamine & nitrogen-((1-(2-methoxyethyl)-1-hydrogen-tetrazol-5-yl)methyl)-2-(9 Synthesis of -(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethylamine (29)
- Step 2 Nitrogen-((3-(methylsulfinyl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane- Synthesis of 9-yl)ethylamine (30)
- Step 2 Nitrogen-((1-methyl-1-hydro-1,2,4-triazol-3-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxa Synthesis of spiro[4.5]decane-9-yl)ethylamine (32)
- Step 2 Nitrogen-((2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)methyl)-2-(9-(pyridin-2-yl)-6 Synthesis of -oxaspiro[4.5]decane-9-yl)ethylamine (33)
- 34-1 500mg, 2.69mmol
- 6-2 379.07mg, 2.97mmol
- cesium carbonate 2.2g, 6.76mmol
- BINAP 50.48mg, 81.07 ⁇ mol
- palladium acetate 6.07mg, 27.02 ⁇ mol
- Step 2 Nitrogen-(2-(3,3-difluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5] Synthesis of Decane-9-yl)ethylamine(34)
- 34-2 (57mg, 0.29mmol), Intermediate A (50mg, 0.19mmol), sodium sulfate (109.10mg, 0.77mmol), and dichloromethane (5mL) were sequentially added to a one-necked bottle, and stirred at room temperature for 16h , added sodium borohydride (15 mg, 0.38 mmol), stirred for 10 minutes, added methanol (0.5 mL), and stirred for 2 hours.
- Step 1 Synthesis of 2-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)nicotinaldehyde (35-1)
- Step 2 Nitrogen-((2-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)pyridin-3-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (35)
- Step 1 Synthesis of 2-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)nicotinaldehyde (36-1)
- Step 2 Nitrogen-((2-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)pyridin-3-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (36)
- Step 1 Synthesis of 2-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)benzaldehyde (37-1)
- 34-1 (600mg, 3.24mmol), 14-1 (464.33mg, 3.24mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (201.9mg, 324.29 ⁇ mol), cesium carbonate ( 3.17, 9.73mmol) and palladium acetate (72.81mg, 324.29 ⁇ mol) were sequentially added to a single-necked flask, dissolved in toluene (40mL) and replaced with nitrogen three times, heated at 100°C and stirred for 6h.
- Step 2 Nitrogen-(2-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)benzyl)-2-(9-(pyridin-2-yl)-6- Synthesis of oxaspiro[4.5]decane-9-yl)ethylamine (37)
- Step 1 Synthesis of 2-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)benzaldehyde (38-1)
- Step 2 Nitrogen-(2-(1,4-dioxaspiro[4.5]decane-7-en-8-yl)benzyl)-2-(9-(pyridin-2-yl)-6- Synthesis of oxaspiro[4.5]decane-9-yl)ethylamine (38)
- Step 1 Synthesis of (2-(1,4-dioxaspiro[4.5]decane-8-yl)pyridin-3-yl)methanol (40-2)
- Step 2 Synthesis of 2-(1,4-dioxaspiro[4.5]decane-8-yl)nicotinaldehyde (40-3)
- Step 3 Nitrogen-((2-(1,4-dioxaspiro[4.5]decane-8-yl)pyridin-3-yl)methyl)-2-(9-(pyridin-2-yl) Synthesis of -6-oxaspiro[4.5]decane-9-yl)ethylamine (40)
- Step 2 Aza-(2-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane Synthesis of alk-9-yl)ethylamine (41)
- the synthetic method of compound 41-P1 refers to the synthetic route of compound 41, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 2 Aza-(3-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane Synthesis of alk-9-yl)ethylamine (42)
- Step 1 Synthesis of 2-(3-methoxyazetidin-1-yl)nicotinaldehyde (43-1)
- Step 2 Nitrogen-((2-(3,3-difluoroazetidin-1-yl)pyridin-3-yl)methyl)-2-(9-(pyridin-2-yl)-6 Synthesis of -oxaspiro[4.5]decane-9-yl)ethylamine (43)
- Step 1 Synthesis of 5-(3-fluoroazetidin-1-yl)thiophene-2-carbaldehyde (45-3)
- Step 2 Nitrogen-((5-(3-fluoroazetidin-1-yl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxa Synthesis of spiro[4.5]decane-9-yl)ethylamine (45)
- Step 2 Nitro-((5-(2-oxo-6-azaspiro[3.3]heptan-6-yl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl) Synthesis of )-6-oxaspiro[4.5]decane-9-yl)ethylamine (46)
- Step 1 Synthesis of 5-(3-methoxyazetidin-1-yl)thiophene-2-carbaldehyde (47-1)
- Step 2 Nitrogen-((5-(3-methoxyazetidin-1-yl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6- Synthesis of oxaspiro[4.5]decane-9-yl)ethylamine (47)
- Step 1 Synthesis of 3-(3-fluoroazetidin-1-yl)thiophene-2-carbaldehyde (48-1)
- Step 2 Nitrogen-((3-(3-fluoroazetidin-1-yl)thiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxa Synthesis of spiro[4.5]decane-9-yl)ethylamine (48)
- the synthetic method of compound 48-P1 refers to the synthetic route of compound 48, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 1 Synthesis of tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (49-2)
- Step 3 Synthesis of 3-(3-hydroxy-3-methylazetidin-1-yl)thiophene-2-carbaldehyde (49-5)
- 34-1 (185mg, 1mmol), 49-3 (184mg, 1.5mmol), palladium acetate (22.45mg, 0.1mmol), BINAP (62.26mg, 0.1mmol), cesium carbonate (815mg, 2.5mmol) , dissolved in toluene (10 mL), reacted at 100°C for 16 hours.
- Step 4 3-Methyl-1-(2-((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)amino)methyl ) thiophen-3-yl) azetidin-3-ol (49) synthesis
- the synthetic method of compound 49-P1 refers to the synthetic route of compound 49, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 1 Synthesis of 3-(3-hydroxy-3-methylazetidin-1-yl)thiophene-2-carbaldehyde (50-1)
- Step 2 3-Methyl-1-(2-((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethylamine)methyl)thiophene Synthesis of -3-yl)azetidin-3-ol (50)
- Step 2 Nitro-(2-fluoro-6-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro [4.5] Synthesis of decan-9-yl) ethylamine (51)
- Step 2 Nitro-(3-fluoro-2-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro [4.5] Synthesis of decan-9-yl) ethylamine (52)
- Step 1 Synthesis of tert-butyl 3-methoxy-3-methylazetidine-1-carboxylate (53-2)
- 49-2 (900mg, 4.8mmol) was dissolved in tetrahydrofuran (15mL), and 60% NaH (385mg, 9.6mmol) was added at 0°C, and reacted at 0°C for half an hour. Add iodomethane (6.8g, 48mmol) and react at room temperature for 3 hours.
- Step 4 3-Methyl-1-(2-((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethylamine)methyl)thiophene Synthesis of -3-yl)azetidin-3-ol (53)
- Step 1 Synthesis of 3-(3-methoxy-3-methylazetidin-1-yl)thiophene-2-carbaldehyde (54-1)
- Step 2 Nitrogen-((3-(3-methoxy-3-methylazetidin-1-yl)thiophen-2-yl)methyl)-2-(9-(pyridine-2- Synthesis of yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (54)
- Step 1 Synthesis of 2,6-bis(3-methoxyazetidin-1-yl)benzaldehyde (55-1)
- Step 2 Aza-(2,6-bis(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[ 4.5] Synthesis of decan-9-yl)ethylamine (55)
- Step 1 Synthesis of 5-(1,4-dioxo-8-nitrospiro[4.5]decane-8-yl)thiophene-2-carbaldehyde (56-1)
- Step 2 Nitrogen-((5-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)thiophen-2-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (56)
- Step 1 Synthesis of 3-(5,8-dioxo-2-azaspiro[3.4]octan-2-yl)thiophene-2-carbaldehyde (57-3)
- Step 2 Nitro-((3-(5,8-dioxo-2-azaspiro[3.4]octan-2-yl)thiophen-2-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (57)
- 34-1 400mg, 2.16mmol
- 45-2 (289.38mg, 2.59mmol)
- palladium acetate 197.98mg, 216.19mmol
- BINAP 269.24mg, 0.43mmol
- cesium carbonate 2.11g, 6.49mmol
- Step 2 Nitrogen-(2-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane- Synthesis of 9-yl)ethylamine (58)
- the synthetic method of compound 58-P1 refers to the synthetic route of compound 58, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 2 Synthesis of 3-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)benzo[b]thiophene-2-carbaldehyde (59-4)
- Step 3 Nitrogen-((3-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)benzo[b]thiophen-2-yl)methyl)-2-( Synthesis of 9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethan-1-amine (59)
- 59-4 (58mg, 0.19mmol), intermediate A (45mg, 0.17mmol), sodium sulfate (50mg, 0.35mmol), dichloromethane (5mL) were sequentially added into a one-necked bottle, and stirred at room temperature for 12h.
- Sodium borohydride (20 mg, 0.52 mmol) was added, stirred for 30 minutes, methanol (1 mL) was added, and the reaction was stirred for 16 hours.
- Step 1 Synthesis of 3-formyl-2-(3-methoxyazetidin-1-yl)benzonitrile (60-3)
- Step 2 2-(3-Methoxyazetidin-1-yl)-3-(((2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane Synthesis of -9-yl)ethyl)amino)methyl)benzonitrile (60)
- Step 1 Synthesis of 2-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)thiophene-3-carbaldehyde (61-2)
- 61-1 100mg, 0.523mmol was dissolved in toluene (10mL), then BINAP (70mg, 0.112mmol) and 14-1 (98mg, 0.685mmol) and cesium carbonate (512mg, 1.571mmol) were added sequentially, Finally, palladium acetate (12mg, 0.053mmol) was added to react at room temperature overnight under the protection of nitrogen. After reacting for 16 h, the toluene was spin-dried.
- Step 2 Nitrogen-((2-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)thiophen-3-yl)methyl)-2-(9-(pyridine- Synthesis of 2-yl)-6-oxaspiro[4.5]decane-9-yl)ethanamine (61)
- Step 1 Synthesis of 4-methoxy-2-(3-methoxyazetidin-1-yl)benzaldehyde (62-3)
- Step 2 Nitro-(4-methoxy-2-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxo Synthesis of heterospiro[4.5]decane-9-yl)ethylamine (62)
- Step 2 Nitrogen-(2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxo Synthesis of heterospiro[4.5]decane-9-yl)ethylamine (63)
- 63-1 (142mg, 0.65mmol), intermediate A (170mg, 0.65mmol), sodium sulfate (923mg, 6.49mmol), and dichloromethane (10mL) were sequentially added to a one-necked bottle, and stirred at room temperature for 16h.
- Sodium borohydride (53 mg, 1.31 mmol) was added, stirred for 10 minutes, methanol (3 mL) was added, and the reaction was stirred for 2 hours.
- the synthetic method of compound 63-P1 refers to the synthetic route of compound 63, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 2 Nitro(2-(2-oxo-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[ 4.5] Synthesis of decan-9-yl)ethylamine (64)
- the synthetic method of compound 64-P1 refers to the synthetic route of compound 64, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 3 Nitrogen-(2-(1,4-dioxaspiro[4.5]decane-8-yl)phenyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[ 4.5] Synthesis of decan-9-yl)ethylamine (65)
- 66-1 200mg, 930.04 ⁇ mol
- 41-1 114.94mg, 930.04 ⁇ mol
- 1,1'-binaphthyl-2,2'-bisdiphenylphosphine 57.9mg, 93.0 ⁇ mol
- cesium carbonate 909.08mg, 2.79mmol
- palladium acetate Pd: 10%, 20.88mg, 93.0 ⁇ mol
- Step 2 Nitro-(3-methoxy-2-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxo Synthesis of heterospiro[4.5]decane-9-yl)ethylamine (66)
- Step 2 Nitro-(2-methoxy-6-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxo Synthesis of heterospiro[4.5]decane-9-yl)ethylamine (67)
- 68-1 (200mg, 930.04 ⁇ mol), 41-1 (114.94mg, 930.04 ⁇ mol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (57.9mg, 93.0 ⁇ mol), cesium carbonate ( 909.08mg, 2.79mmol) and palladium acetate (20.88mg, 93.0 ⁇ mol) were sequentially added to a single-necked bottle, dissolved in toluene (15mL) and replaced with nitrogen three times, heated to 100°C and stirred for 6h.
- Step 2 Nitro-(2-methoxy-5-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxo Synthesis of heterospiro[4.5]decane-9-yl)ethylamine (68)
- Step 1 Synthesis of 3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde (69-2)
- Step 2 Nitrogen-(3-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)benzyl)-2-(9-(pyridin-2-yl)- Synthesis of 6-oxaspiro[4.5]decane-9-yl)ethylamine (69)
- 71-1 100mg, 0.54mmol
- 57-2 68.45mg, 0.54mmol
- potassium carbonate 144.39mg, 1.08mmol
- Step 2 Nitrogen-(3-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)benzyl)-2-(9-(pyridin-2-yl)- Synthesis of 6-oxaspiro[4.5]decane-9-yl)ethylamine (71)
- Step 2 Nitrogen-(2-(1,4-dithio-8-azaspiro[4.5]decane-8-yl)benzyl)-2-(9-(pyridin-2-yl)- Synthesis of 6-oxaspiro[4.5]decane-9-yl)ethylamine (72)
- 71-1 (185 mg, 1.5 mmol), 77-2 (219 mg, 3.0 mmol), potassium carbonate (621 mg, 4.5 mmol) were dissolved in dimethyl sulfoxide (6 mL), and reacted at 120°C for 16 hours.
- the synthetic method of compound 77-P1 refers to the synthetic route of compound 77, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 3 Nitrogen-((6-(3-methoxyazetidin-1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl) Synthesis of methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9-yl)ethylamine (78)
- Step 1 Synthesis of 3-methoxy-[2,3'-phenylthiophene]-2'-carbaldehyde (79-1)
- 26-1 (0.3g, 2.62mmol), 34-1 (484.47mg, 2.62mmol), potassium acetate (770.57mg, 7.85mmol), palladium acetate (117.52mg, 0.523mmol), tetrabutyl Ammonium bromide (843.5mg, 2.62mmol) was added into N,N'dimethylformamide (50mL), replaced with nitrogen three times, and heated to 80°C for 3h under nitrogen atmosphere.
- Step 2 Nitrogen-(2-(3-methoxythiophen-2-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9- base) synthesis of ethylamine (79)
- Step 2 Nitro-(2-fluoro-4-(3-methoxyazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro [4.5] Synthesis of decan-9-yl) ethylamine (80)
- Step 2 Aza-(2-(3-(methylthio)azetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5 ]
- Step 2 Nitrogen-(2-fluoro-4-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5 Synthesis of ]decane-9-yl)ethylamine (86)
- Step 2 Nitrogen-(2-((3-cyclopropylpropynyl-1-yl)oxy)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5] Synthesis of Dec-9-yl)ethylamine(87)
- Step 2 Nitrogen-((2-(3-methoxyazetidin-1-yl)naphthalen-1-yl)methyl)-2-(9-(pyridin-2-yl)-6- Synthesis of Oxaspiro[4.5]dec-9-yl)ethylamine (89)
- Step 2 Nitro-(2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)benzyl)-2-(9-(pyridin-2-yl)-6- Synthesis of Oxaspiro[4.5]dec-9-yl)ethylamine (93)
- 61-1 200mg, 1.047mmol was dissolved in toluene (20mL), then Xphos (132mg, 0.277mmol) and 45-2 (152mg, 1.363mmol) and cesium carbonate (1024mg, 3.143mmol) were added sequentially, Finally Pd 2 (dba) 3 (96 mg, 0.105 mmol) was added. The reaction was carried out at room temperature overnight under the protection of nitrogen. After reacting for 16h, the toluene was spin-dried.
- Step 2 Nitrogen-(2-(3-fluoroazetidin-1-yl)thiophen-2-yl)methyl))-3-(9-(pyridin-2-yl)-6-oxa Synthesis of spiro[4.5]dec-9-yl)ethylamine (94)
- Step 2 Nitro-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-4-fluorobenzyl)-2-(9-(pyridin-2-yl Synthesis of )-6-oxaspiro[4.5]dec-9-yl)ethylamine (95)
- the synthetic method of compound 95-P1 refers to the synthetic route of compound 95, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 1 Synthesis of 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-fluorobenzaldehyde (96-1)
- Step 2 Nitro-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-fluorobenzyl)-2-(9-(pyridin-2-yl Synthesis of )-6-oxaspiro[4.5]dec-9-yl)ethylamine (96)
- Step 1 Synthesis of 3-fluoro-2-(3-fluoroazetidin-1-yl)benzaldehyde (97-1)
- Step 2 Nitrogen-(3-fluoro-2-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5 Synthesis of ]dec-9-yl)ethylamine (97)
- Step 2 Nitrogen-(2-(3-fluoroazetidin-1-yl)-5-methoxypyridin-3-yl)methyl)-2-(9-(pyridin-2-yl)-6 Synthesis of -oxaspiro[4.5]dec-9-yl)ethylamine (98)
- Step 2 Nitrogen-(2-fluoro-6-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5 Synthesis of ]decane-9-yl)ethylamine (103)
- Step 2 Nitrogen-(5-fluoro-2-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5 ] Decane-9-yl) ethylamine (104) synthesis
- 34-1 (100mg, 540.49 ⁇ mol), 124-1 (80.87mg, 540.49 ⁇ mol), palladium acetate (12.13mg, 54.05 ⁇ mol), cesium carbonate (528.31mg, 1.62mmol) and 1,1'-binaphthyl- 2,2'-Bisdiphenylphosphine (33.7 mg, 54.05 ⁇ mol) was successively added to toluene (5 mL) to dissolve, the gas was replaced with nitrogen three times, heated to 110° C. and stirred for 3 h.
- Step 2 2-(9-(Pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl-nitrogen-(2-(tetrahydro-1H-furo[3,4-c] Synthesis of pyrrol-5(3H)-yl)benzyl)ethylamine (124)
- the synthetic method of compound 124-P1 refers to the synthetic route of compound 124, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 2 Aza-(2-(3-cyanoazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane- Synthesis of 9-yl)ethylamine (121)
- the synthetic method of compound 121-P1 refers to the synthetic route of compound 121, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 1 Synthesis of 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-carbaldehyde (68-2)
- 68-2 (240mg, 1mmol), 41-1 (185mg, 1.5mmol), palladium acetate (23mg, 0.1mmol), BINAP (63mg, 0.1mmol) cesium carbonate (813.5mg, 2.5mmol) were dissolved in Toluene (10 mL) was reacted at 100°C for 16 hours.
- Step 3 Nitrogen-((7-(3-methoxyazetidin-1-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl) Synthesis of Methyl)-2-(9-(pyridin-2-yl)-6-oxapyridin[4.5]dec-9-yl)ethanamine (68)
- Step 2 Nitrogen-(4-chloro-2-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5 Synthesis of ]decane-9-yl)ethylamine (102)
- Step 2 Nitro-(3-cyano-2-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxa[4.5 Synthesis of ]dec-9-yl)ethylamine (105)
- 107-2 (20mg, 0.12mmol), intermediate A (32mg, 0.12mmol), magnesium sulfate (300mg, 2.5mmol), and dichloromethane (5mL) were sequentially added into a one-necked bottle, and stirred at room temperature for 16h.
- Sodium borohydride 14 mg, 0.37 mmol was added, stirred for 10 minutes, methanol (0.5 mL) was added, and the reaction was stirred for 2 hours.
- Step 1 Synthesis of 4-fluoro-2-(3-fluoroazetidin-1-yl)benzaldehyde (108-2)
- Step 2 Nitrogen-(4-fluoro-2-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxapyrrole[4.5 Synthesis of ]dec-9-yl)ethane-1-amine (108)
- Step 1 Synthesis of 2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzaldehyde (109-1)
- Step 2 Nitro-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzyl)-2-(9-(pyridin-2-yl Synthesis of )-6-oxapyrrole[4.5]dec-9-yl)ethan-1-amine (109)
- Step 1 Synthesis of 2-(3-oxo-8-azabicyclo[3.2.1]octan-8-yl)-6-fluorobenzaldehyde (110-1)
- Step 2 Nitro-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-fluorobenzyl)-2-(9-(pyridin-2-yl Synthesis of )-2-oxapyrrole[4.5]dec-9-yl)ethane-1-amine (110)
- 110-1 100mg, 0.42mmol
- intermediate A 100mg, 0.42mmol
- magnesium sulfate 504mg, 4.2mol
- dichloromethane 10mL
- Step 2 Nitro-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-chlorobenzyl)-2-(9-(pyridin-2-yl Synthesis of )-2-oxapyrrole[4.5]dec-9-yl)ethan-1-amine (111)
- Step 2 Aza-(2-(3-chloroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]dec-9 Synthesis of -yl)ethylamine (115)
- Step 2 Aza-(2-(3-methylazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane- Synthesis of 9-yl)ethylamine (116)
- Step 1 Synthesis of 3-(3-fluoroazetidin-1-yl)benzaldehyde (123-1)
- Step 3 (R)-Aza-(3-(3-fluoroazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxapyrrole[4.5 Synthesis of ]dec-9-yl)ethane-1-amine (123)
- the synthetic method of compound 123-P1 refers to the synthetic route of compound 123, the main difference is that intermediate A is replaced by intermediate A-1.
- compound 34-1 400mg, 2.16mmol
- 129-2 369.36mg, 2.16mmol
- palladium acetate 197.98mg, 216.19mmol
- BINAP 269.24mg, 0.43mmol
- cesium carbonate 2.11g, 6.49mmol
- Step 2 Aza-(2-(3-methylsulfoneazetidin-1-yl)benzyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane Synthesis of -9-yl)ethylamine (129)
- the synthetic method of compound 129-P1 refers to the synthetic route of compound 129, the main difference is that intermediate A is replaced by intermediate A-1.
- 34-1 (370 mg, 2 mmol), 136-1 (213 mg, 3 mmol), Pd(AcO) 2 (45 mg, 0.2 mmol), Xantphos (116 mg, 0.2 mmol), cesium carbonate (1.6 g, 5 mmol) were dissolved in toluene (20 mL), react at 100°C for 16 hours.
- the synthetic method of compound 136-P1 refers to the synthetic route of compound 136, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 1 Synthesis of nitrogen-(7-benzothiophene)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethylamine
- the synthetic method of compound 131-P1 refers to the synthetic route of compound 131, the main difference is that intermediate A is replaced by intermediate A-1.
- Step 1 Synthesis of 2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)-nitrogen-(quinolin-5-ylmethyl)ethylamine
- the compounds of the present invention can activate mu-opioid receptors (MOR).
- MOR mu-opioid receptors
- Activated MOR can regulate the level of intracellular cAMP, and cAMP enters the nucleus and binds to the CRE region of the reporter gene luciferase (Luciferase) to initiate the expression of the reporter gene.
- Luciferase can emit fluorescence when it reacts with its substrate, and the agonistic activity of the compound can be reflected by measuring the fluorescent signal.
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Abstract
一类氧杂螺环类小分子化合物、其制备方法及含有该化合物的药物组合物以及其作为MOR受体激动剂和在制备治疗和/或预防疼痛等相关疾病的药物中的用途。
Description
本申请要求于2021年8月31日提交中国专利局、申请号为202111010370.X发明名称为“阿片受体激动剂及其制备方法和用途”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
本发明属于药物化学领域,具体涉及一类氧杂螺环类小分子化合物、其制备方法及含有该化合物的药物组合物以及其作为治疗剂,特别是作为MOR受体激动剂和在制备治疗和/或预防疼痛等相关疾病的药物中的用途。
阿片受体是一种G蛋白偶联受体(G protein coupled receptor,GPCR),是内源性阿片肽及阿片类药物结合的靶点。人体内存在多种阿片受体,主要包括μ阿片受体(Mu opioidreceptor,MOR)、δ阿片受体(Delta opioid receptor,DOR)和κ阿片受体(Kappa opoidreceptor,KOR)三类,广泛分布在中枢神经系统,心脏,消化道,血管,肾脏等外周组织(Nature,2016,537(7619):185)。MOR与吗啡肽的结合能力最强,是吗啡、芬太尼等镇痛药主要作用的受体蛋白位点。Zadina等研究发现MOR受体与吗啡肽1的结合能力(360pM)是DOR受体、KOR受体与吗啡肽1结合力的4000倍和15000倍(science,2001,293:311-315;BiOChem Biophys Res Commun 235:567-570;Life Sci 61:409-415)。
研究发现GPCR介导及调控生理功能主要经由激活G蛋白途径和β-arrestin途径。G蛋白信号途径主要包括钙离子等第二信使系统、腺苷酸环化酶、丝裂原活化蛋白激酶等。β-arrestin途径主要有三个方面:(1)作为负性调控因子与GPCR激酶作用使GPCRs发生受体脱敏反应从而中止G蛋白信号转导;(2)作为支架蛋白募集胞吞蛋白诱导GPCR内吞;(3)作为接头蛋白与GPCR下游信号分子形成复合物,以G蛋白非依赖的方式激活信号转导分子。早期研究显示,内源性脑啡肽和阿片类药物埃托啡可以激动G蛋白并引发受体内吞,而吗啡则不引发受体内吞,这是因为吗啡通过G蛋白信号通路而不是β-arrestin途径来发挥其生理功能(Zhang等,PrOC Natl Acad Sci USA,1998,95(12):7157-7162)。研究发现给β-arrestin2基因敲除小鼠注射吗啡后,由G蛋白信号介导的镇痛效果更强且维持时间更长(Bohn等,Science,1999年)。由此可见,配体刺激G蛋白和/或β-arrestin信号的差异决定 了GPCR的配体特异性细胞生物学效应,如果此类配体的负性β-arrestin偏爱性更强,甚至可以逃脱β-arrestin介导的受体脱敏,则G蛋白信号传递时间延长,镇痛作用更强。近年来研究发现,β-arrestin通路与MOR激动剂多个副作用相关,如便秘、呼吸抑制和镇痛耐受(Science 1999,286:2495-2498;J.Pharmacol.Exp.Ther.2005,314:1195-1201)。因此,研发一种可选择性激活G蛋白信号通路的“偏向性”MOR激动剂药物,即MOR的负性β-arrestin偏爱性配体设计药物,使β-arrestin介导的副作用降低,在镇痛领域具有显著的临床价值和社会意义。
FDA于2020年8月批准了Trevena Inc公司药物Olinvyk(WO2012129495)的上市申请,目前关于G蛋白偏向性MOR激动剂的研发报道的专利有WO2017063509、WO2019205983A1、CN10920641、WO2019072235A1、CN111662284、WO2019052557A1等,虽然这些专利已经公开了一系列G蛋白偏向性MOR激动剂,但其分子结构与本发明提供的结构具有较大区别,且其药效、安全性暂未得到证实,临床上仍需要开发新的分子结构,以获得具有更好的药效、选择性、药用安全性、药物代谢结果的MOR激动剂。
发明内容
针对现有技术的需求,本发明提供了一种结构新颖的可作为MOR受体激动剂的化合物,该类化合物表现出高活性,E
max也具有明显改善,以及对MOR较高的选择性。
本发明的提供了如式(Ⅰ)所示的化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,
其中,
环B为取代的或未取代的芳基、取代的或未取代的杂芳基;
Z
1、Z
2、Z
3、Z
4、Z
5、Z
6中任一个为C,其它各自独立的选自CR
2、N;
X
1选自-S(=O)
m、O、NH或NR
4;R
4各自独立的选自-C
1-6烷基或-C
1-6烷基-O-C
1-6烷基;
X
2、X
3、X
4、X
5中任一个为C,其它各自独立的选自CR
3、N;
所述每个R
2、R
3各自独立的选自H、卤素、-OH、-CN、-C
1-6烷基、-NH
2、-NH-C
1-6烷基、-C
1-6烷基-NH-C
1-6烷基、-C
1-6烷基-O-C
1-6烷基、-O-3至12元杂环基、-O-C
1-6烷基、-(CH
2)
g-3至12元环烷基、-(CH
2)
g-3至12元杂环基、5至10元杂芳基、5至10元芳基、-S(=O)
f-C
1-6烷基、-O-C
2-6炔基、-O-C
2-6烯基、-C
2-6烯基、-C
2-6炔基;其中,所述杂环基、环烷基、杂芳基、芳基、烷基、炔基、烯基可任选进一步被1至3个R
b所取代;
所述R
b各自独立的选自H、卤素、-OH、-CN、-C
1-6烷基、氧代、-NH
2、-NH-C
1-6烷基、-S(=O)
f-C
1-6烷基、-C
1-6烷基-O-C
1-6烷基、-O-C
1-6烷基、3至6元环烷基、-O-C
2-6炔基、-O-C
2-6烯基、-C
2-6炔基、-C
2-6烯基;
或者相邻两个C原子上的两个R
2或两个R
3与其相连的C原子一起形成3至12元杂环基、3-12元环烷基、5至10元杂芳基、5至10元芳基;其中,所述杂环基、环烷基、杂芳基、芳基可任选进一步被1至4个R
1所取代;
所述R
1各自独立的选自-C
1-6烷基、-C
2-6烯基、-C
2-6炔基、卤素、-NH
2、-NH-C
1-6烷基、-OH、-O-C
1-6烷基、-O-C
2-6炔基、-O-C
2-6烯基、NR
bR
b、-S(=O)
f-C
1-6烷基、3-6元环烷基、CN、5至10元芳基;
所述g选自0、1、2、3、4;
所述f选自0、1、2;
所述m选自0、1、2。
在本发明的一个优选实施方案中,所述化合物选自式(Ⅱ)或(Ⅲ)所示结构;
其中,
所述R
2、R
3各自独立的选自3-6元单杂环基、7-10元并杂环基、7-11元螺杂环基、7-11元桥杂环基;
所述R
a选自H、卤素、-OH、-CN、-C
1-6烷基、-NH
2、-NH-C
1-6烷基、-C
1-6烷基-NH-C
1-6烷基、-C
1-6烷基-O-C
1-6烷基、-O-C
1-6烷基、-S(=O)
f-C
1-6烷基、-O-C
2-6炔基、-O-C
2-6烯基、-C
2-6烯基、-C
2-6炔基;
所述单杂环基可任选进一步被1至3个R
b所取代。
优选的,所述每个R
2、R
3各自独立的选自4元单杂环基,其中所述单杂环基任选进一步被1至3个R
b所取代;
所述每个R
b各自独立选自卤素、-C
1-6烷基、-OH、氧代、-NH
2、-NH-C
1-6烷基、-S(=O)
2-C
1-6烷基、-O-C
1-6烷基、-O-C
2-6炔基、-O-C
2-6烯基、-C
2-6炔基、-C
2-6烯基。
优先的,所述环C选自6至12元稠杂环;进一步优选6-12元并杂环基、6-12元螺杂环基,所述并杂环基、螺杂环基中至少含有两个O杂原子。
其中,X
1选自S、O、NH。
优选的,环D选自4至12元杂环基,所述杂环基中至少含有两个O杂原子;进一步优先的环D选自5至6元单杂环基,所述的单杂环基中至少含有两个O杂原子。
优选的,环D选自6至12元稠杂环;进一步优先6-12元并杂环基、6-12元螺杂环基,所述并杂环基、螺杂环基中至少含有两个O杂原子。
Z
1、Z
2、Z
3、Z
4自个独立的选自C、N。
本发明典型的化合物,包括但不限于以下结构:
本发明的另一方面涉及一种药物组合物,其包括上述化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,以及药学上可接受的载体。
本发明的另一个方面提供了上述化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,或上述药物组合物在制备预防和/或治疗MOR受体激动剂介导的相关疾病的药物中的用途。
其中,MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸疾病;上述疼痛选自术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛。
本发明的另一个方面提供了一种MOR受体激动剂介导的相关疾病的预防和/或治疗方法,其包括向有需要的对象施用上述化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,或上述药物组合物。
本发明的另一个方面提供了用作药物或用于治疗的上述化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐。
本发明在进行一系列研究后发现,芳基上进行杂环基取代后表现出高活性,E
max也显著提高,hERG也有明显改善,更进一步的研究发现单一构型的化合物对MOR的选择性更高,β-arrestin介导的副作用更低。
术语解释
本发明所用术语“C
2-6炔基”指含有碳碳叁键的2~6个碳原子的炔烃部分去除一个氢原子衍生的直链或支链的炔烃基,如乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基等。
本发明上述的“环烷基”包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)的情形;例如“3-12元环烷基”,可以是单环、双环、或者多环环烷基系统(也称为稠环系统)。在不特别指明的情况下,单环系统是含3-8个碳原子的环烃基基团,实例包括但不限于:环丙烷基、环丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基等。
稠环环烷基包括并环环烷基、桥环烷基、螺环烷基。
并环环烷基可以为6-11元并环环烷基、7-10元并环环烷基,其代表性例子包括但不限于双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环[4.2.1]壬烷。
本文所用术语“杂环基”指3-12元的至少一个环碳原子被选自O、S、N的杂原子替代的非芳香性的环状基团,优选1-3个杂原子,同时包括碳原子、氮原子和硫原子可以被氧代。“3-12元杂环基”,是指单环杂环基、双环杂环基系统或多环杂环基系统(也称为稠环系统),包括饱和、部分饱和的杂环基,但不包括芳环。在不特别指明的情况下,包括可能形成的所有单环、稠环(包括以并、螺、桥的形式稠合)、饱和、部分饱和的情形。
单杂环基可以为3-8元单杂环基、3-6元单杂环基、4-7元单杂环基、5-7元单杂环基、5-6元单杂环基、5-6元含氧单杂环基、3-8元含氮单杂环基、5-6元含氮单杂环基、5-6元饱和单杂环基等,其实例包括但不限于:
的基团。
稠杂环包括并杂环基、螺杂环基、桥杂环基,可以是饱和的、部分饱和的或不饱和的,但不是芳香性的。
本文所用术语“芳基”(或“芳环”)是指一价的单环或多环(包含稠合形式)的芳香族环系,其仅有碳原子和氢原子构成;常见的芳基包括(但不限于)苯基、萘基、蒽基、菲基、苊基、薁基、芴基、茚基、芘基等。上述芳基也包括杂环基并芳基、环烷基并芳基;
本文所用术语“杂芳基”(或“杂芳环”)是指一价的单环或多环(包含稠合形式)的芳香族环系,其环原子由碳原子及选自氮、氧、硫和磷的杂原子构成;常见的杂芳基包括(但不限于)苯并吡咯基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并噻唑基、氮杂环丁烷基、咔唑基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、吡唑基、异噁唑基、异噻唑基、吲唑基、吲嗪基、吲哚基、喹啉基、异喹啉基、吩嗪基、吩噁嗪基、 吩噻嗪基、蝶啶基、嘌呤基、吡嗪基、嘧啶基、哒嗪基、吡啶基、三唑基、四唑基等。上述杂芳基也包括杂环基并杂芳基、环烷基并杂芳基。
本发明所示化合物的“立体异构体”是指当化合物存在不对称碳原子时,会产生对映异构体;当化合物存在碳碳双键或环状结构时,会产生顺反异构体;当化合物存在酮或肟时,会产生互变异构体,所有化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物,均包括在本发明范围中。
为使本发明的目的、技术方案、及优点更加清楚明白,以下举实施例,对本发明进一步详细说明。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
氮-((3-(丁-2-炔-1-氧基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物3)的合成
步骤1:3-羟基噻吩-2-甲醛(3-2)的合成
在室温下,向50mL的单口瓶中加入3-1(1.5g,10.55mmol),三溴化硼(2.91g,11.61mmol)和二氯甲烷(15mL)。室温下搅拌反应12小时。反应完全后,向反应液加入水(50mL),二氯甲烷萃取(20mL×2),合并有机相,饱和食盐水洗涤(30mL×1),无水硫酸钠干燥,过滤,旋干滤液得到淡黄色固体3-2(900mg,产率76.57%),[M+H]
+:129.0。
步骤2:3-(丁-2-炔-1-氧基)噻吩-2-甲醛(3-4)的合成
在室温下,向10mL的单口瓶中加入3-2(50mg,390.17μmol),碳酸钾(107.85mg,780.34μmol),3-3(62.26mg,468.20μmol)和DMF(3mL)。室温下搅拌反应2小时。反 应完全后,依次向反应液加入水(10mL),二氯甲烷萃取(20mL×2),合并有机相,饱和食盐水洗涤(30mL×1),无水硫酸钠干燥,过滤,旋干滤液得到淡黄色固体3-4(60mg,产率83.55%),[M+H]
+:181.0。
步骤3:氮-((3-(丁-2-炔-1-氧基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(3)的合成
在室温下,向25mL的单口瓶中加入3-4(45.7mg,253.48μmol),中间体A(60.0mg,230.44μmol),无水硫酸钠(163.66mg,1.15mmol),二氯甲烷(5mL)。室温下搅拌反应12小时。再加入硼氢化钠(17.44mg,460.87mmol),反应0.5小时。反应完全后,减压浓缩除去溶剂。加入水(10mL),乙酸乙酯萃取(6mL×2),合并有机相,饱和食盐水洗涤(10mL×1),无水硫酸钠干燥,过滤,滤液旋干,粗品柱层析(V
二氯甲烷:V
甲醇=10:1)纯化。得到淡黄色稠状固体3(20mg,产率20.44%),[M+H]
+:425.2。
1H NMR(400MHz,CDCl
3)δ8.56-8.54(m,1H),7.63-7.59(m,1H),7.29-7.26(m,1H),7.12-7.09(m,1H),7.04-7.03(m,1H),6.84-6.82(m,1H),4.55-4.53(m,2H),3.76-3.67(m,4H),2.53-2.50(m,2H),2.49-2.41(m,1H),2.31-2.30(m,1H),2.11-2.08(m,1H),1.99-1.89(m,2H),1.84-1.83(m,2H),1.77-1.73(m,3H),1.66-1.61(m,3H),1.54-1.44(m,1H),1.25-1.24(m,2H),1.11-1.084(m,1H),0.69-0.64(m,1H)。
实施例2
氮-((3-((3-环丙基-2-炔-1-基)氧基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物4)的合成
步骤1:3-((3-环丙基-2-炔-1-基)氧基)噻吩-2-甲醛(4-2)的合成
在室温下,向25mL的单口瓶中加入3-2(0.1mg,780.34μmol),碳酸钾(215.6mg, 1.56mmol),4-1(148.91mg,936.41mmol)和DMF(5mL)。室温下搅拌反应2小时。反应完全后,依次向反应液加入水(10mL),二氯甲烷萃取(20mL×2),合并有机相,饱和食盐水洗涤(30mL×1),无水硫酸钠干燥,过滤,旋干滤液得到淡黄色固体4-2(80mg,产率49.7%),[M+H]
+:207.0。
步骤2:氮-((3-((3-环丙基-2-炔-1-基)氧基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(4)的合成
在室温下,向25mL的单口瓶中加入中间体A(90.00mg,345.66μmol),4-2(78.42mg,380.2μmol),无水硫酸钠(196.39mg,1.38mmol),二氯甲烷(5mL)。室温下搅拌反应12小时。再加入硼氢化钠(26.15mg,691.31mmol),反应0.5小时。反应完全后,减压浓缩除去溶剂。加入水(10mL),乙酸乙酯萃取(6mL×2),合并有机相,饱和食盐水洗涤(10mL×1),无水硫酸钠干燥,过滤,滤液旋干,粗品柱层析(V
二氯甲烷:V
甲醇=10:1)纯化。得到淡黄色稠状固体4(20mg,产率13%),[M+H]
+:451.2。
1H NMR(400MHz,CDCl
3)δ8.58-8.57(m,1H),7.67-7.62(m,1H),7.33-7.28(m,1H),7.15-7.13(m,1H),7.07-7.05(m,1H),6.85-6.84(m,1H),4.56-4.55(m,2H),3.79-3.71(m,4H),2.57-2.56(m,1H),2.47-2.44(m,1H),2.36-2.32(m,1H),2.15-2.13(m,1H),2.01-1.95(m,1H),1.94-1.91(m,1H),1.77-1.72(m,3H),1.70-1.63(m,3H),1.56-1.53(m,2H),1.27-1.24(m,3H),1.11-1.084(m,1H),0.81-0.77(m,2H),0.73-0.68(m,2H)。
实施例3
氮-((3-(3,3-二氟氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物6)的合成
步骤1:3-(3,3-二氟氮杂环丁烷-1-基)噻吩-2-甲醛(6-3)的合成
室温下,将6-2(163mg,1.26mmol),6-1(200mg,1.05mmol),Pd(OAc)
2(24mg, 0.105mmol),BINAP(131mg,0.209mmol)和碳酸铯(1.00g,3.14mmol)和甲苯(5mL)依次加入单口瓶,在氮气保护下,封管加热至120℃搅拌16h。反应完全后,反应液经硅藻土过滤,减压蒸馏后粗品用反相柱纯化(0-100%乙腈/水)得到白色固体6-3(200mg,产率93.8%),[M+H]
+:204.1。
步骤2:氮-((3-(3,3-二氟氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(6)的合成
氮气保护下,将中间体A(50mg,0.192mmol),6-3(58mg,0.288mmol),硫酸钠(82mg,0.576mmol),二氯甲烷(3mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(15mg,0.384mmol),搅拌10分钟,加入甲醇(0.3mL),搅拌反应1小时。反应完后,加入水(4mL),二氯甲烷萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用反相柱纯化(0-100%乙腈/水)得到无色油状液体6(20mg,产率23.27%,纯度95.00%),[M+H]
+:448.3。
1H NMR(400MHz,CDCl
3)δ8.57-8.56(m,1H),7.65-7.61(m,1H),7.31-7.29(m,1H),7.14-7.10(m,1H),7.04-7.03(m,1H),6.47-6.46(m,1H),4.18(t,J=12.0Hz,4H),3.77-3.73(m,2H),3.61-3.60(m,2H),3.41(s,3H),2.58-2.32(m,4H),2.16-2.10(m,1H),2.00-1.84(m,3H),1.78-1.67(m,4H),1.49-1.29(m,2H),1.14-1.04(m,2H)。
实施例4
氮-((3-(丙-2-炔-1-基-氧基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂环[4.5]癸烷-9-基)乙胺(化合物7)的合成
步骤1:3-((3-(三甲基硅基)丙-2-炔-1-基)氧基)噻吩-2-甲醛(7-2)的合成
在室温下,向25mL的单口瓶中加入3-2(0.1mg,780.34μmol),碳酸钾(215.6mg, 1.56mmol),7-1(148.91mg,936.41mmol)和DMF(5mL)。室温下搅拌反应2小时。反应完全后,依次向反应液加入水(10mL),二氯甲烷萃取(20mL×2),合并有机相,饱和食盐水洗涤(30mL×1),无水硫酸钠干燥,过滤,旋干滤液得到淡黄色固体7-2(80mg,产率49.7%),[M+H]
+:207.0。
步骤2:2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)-氮-((3-((3-(三甲基硅基)丙-2-炔-1-基)氧基)噻吩-2-基)甲基)乙胺(7-3)的合成
在室温下,向25mL的单口瓶中加入中间体A(0.1g,422.47μmol),7-2(0.1g,384.22μmol),无水硫酸钠(196.39mg,1.38mmol),二氯甲烷(5mL)。室温下搅拌反应12小时。加入硼氢化钠(26.15mg,691.31mmol),反应0.5小时。反应完全后,减压浓缩除去溶剂。加入水(10mL),乙酸乙酯萃取(6mL×2),合并有机相,饱和食盐水洗涤(10mL×1),无水硫酸钠干燥,过滤,滤液旋干,粗品柱层析(V
二氯甲烷:V
甲醇=10:1)纯化。得到淡黄色稠状固体7-3(80mg,产率40%)。
步骤3:氮-((3-(丙-2-炔-1-基-氧基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂环[4.5]癸烷-9-基)乙胺(7)的合成
在室温下,向25mL的单口瓶中加入7-3(80mg,165.72mmol),碳酸钾(458.1mg,331.43mmol),甲醇(5mL)。室温下反应4小时。反应完全后,加入水(10mL),乙酸乙酯(6mL×2),合并有机相,饱和食盐水(10mL×1)洗涤一次,无水硫酸钠干燥,过滤,滤液旋干,粗品柱层析(V
二氯甲烷:V
甲醇=10:1)纯化。得到淡黄色稠状固体7(20mg,产率29.4%),[M+H]
+:411.2。
1H NMR(400MHz,CDCl
3)δ8.58-8.57(m,1H),7.64-7.63(m,1H),7.32-7.30(m,1H),7.13-7.12(m,1H),7.07-7.06(m,1H),6.86-6.85(m,1H),4.61-4.60(m,2H),3.79-3.71(m,4H),2.57-2.37(m,3H),2.34-2.33(m,1H),2.01-1.99(m,1H),1.94-1.91(m,1H),1.77-1.72(m,3H),1.70-1.63(m,2H),1.56-1.53(m,1H),1.27-1.24(m,3H),1.11-1.084(m,1H),0.81-0.77(m,1H),0.73-0.68(m,1H)。
实施例5
氮-((3-(3-甲氧基丙基-1-炔-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物8)的合成
步骤1:3-(3-甲氧基丙基-1-炔基)噻吩-2-甲醛(8-2)的合成
室温下,将8-1(110.06mg,1.57mmol),6-1(100.00mg,523.43μmol),Pd(PPh
3)
2Cl
2(36.74mg,52.34μmol),碘化亚铜(9.97mg,52.34μmol),三乙胺(118.9mg,1.57mmol),四氢呋喃(5mL)依次加入单口瓶,在氮气保护下,室温搅拌12h。反应完全后,冰浴下用水(10mL)淬灭,然后用EtOAc(5mL×2)萃取,合并有机相用饱和食盐水(5mL×1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=5:1)得到黄色油状液体8-2(80mg,产率80.50%),[M+H]
+:181.22。
步骤2:氮-((3-(3-甲氧基丙基-1-炔基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(8)的合成
氮气保护下,将中间体A(80mg,307.24μmol),8-2(61mg,337.97μmol),硫酸钠(174.56mg,1.23mmol),二氯甲烷(3mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(23.25mg,614.48μmol),搅拌10分钟,加入甲醇(0.3mL),搅拌反应1小时。反应完后,加入水(4mL),二氯甲烷萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体8(80mg,产率24.64%,纯度95.00%),[M+H]
+:425.2。
1H NMR(400MHz,CDCl
3)δ8.56-8.54(m,1H),7.62-7.61(m,1H),7.30-7.28(m,1H),7.12-7.06(m,2H),6.95-6.93(m,1H),4.29(s,2H),3.89-3.76(m,2H),3.75-3.74(m,2H),3.41(s,3H),2.54-2.51(m,1H),2.49-2.41(m,1H),2.36-2.32(m,1H),2.14-2.04(m,1H),1.99-1.96(m,1H),1.94-1.89(m,1H),1.77-1.71(m,3H),1.70-1.54(m,3H),1.53-1.50(m,1H),1.27-1.25(m,2H),1.11-1.03(m,1H),0.69-0.66(m,1H)。
实施例6
氮-((3-(甲硫基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物9)的合成
步骤1:3-(甲硫基)噻吩-2-甲醛(9-1)的合成
室温下,将6-1(500.00mg,2.62mmol),甲硫醇钠(183.44mg,2.62mmol),DMF(5mL)依次加入单口瓶,在氮气保护下,室温搅拌12h。反应完全后,冰浴下用水(10mL)淬灭,然后用EtOAc(5mL×2)萃取,合并有机相用饱和食盐水(5mL×1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到黄色油状液体9-1(200mg,产率48.23%),[M+H]
+:158.99。
步骤2:氮-((3-(甲硫基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(9)的合成
氮气保护下,将中间体A(100mg,384.06μmol),9-1(61.85mg,422.47μmol),硫酸钠(174.56mg,1.23mmol),二氯甲烷(3mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(45.59mg,1.15mmol),搅拌10分钟,加入甲醇(0.3mL),搅拌反应1小时。反应完后,加入水(4mL),二氯甲烷萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体9(30mg,产率11.79%,纯度95.00%),[M+H]
+:403.6。
1H NMR(400MHz,CDCl
3)δ8.57-8.56(m,1H),7.61-7.59(m,1H),7.28-7.26(m,1H),7.16-7.08(m,2H),6.94-6.93(m,1H),3.82-3.76(m,2H),3.75-3.74(m,2H),2.52-2.42(m,1H),2.36-2.33(m,1H),2.12(s,3H),2.10-2.04(m,1H),1.97-1.93(m,1H),1.93-1.90(m,1H),1.77-1.71(m,3H),1.69-1.61(m,2H),1.49-1.48(m,3H),1.41-1.37(m,2H),1.27-1.24(m,1H)。
实施例7
2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)-氮-((1,3,3a,8a-四氢呋喃[3,4-b]噻吩[3,4-e][1,4]二噁英-5-基)甲基)乙胺(化合物11)的合成
步骤1:1,3,3a,8a四氢呋喃[3,4-b]噻吩并[3,4-e][1,4]二噁英(11-3)的合成
室温下,将11-1(1.5g,10.40mmol),11-2(2.17g,20.81mmol),甲苯(50mL)依次加入单口瓶,然后缓慢加入对甲基苯磺酸(358.28mg,2.08mmol),在氮气保护下,升温到100℃搅拌48h。反应完全后,降温到室温,反应液用水(100mL)稀释,然后用乙酸乙酯(50mL×3)萃取,合并有机相并用饱和食盐水(50mL×3)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=10:1到5:1)得到黄色油状液体11-3(400mg,产率20.87%)。
步骤2:1,3,3a,8a-四氢呋喃[3,4-b]噻吩并[3,4-e][1,4]二噁英-5-基)甲醛(11-4)的合成
将11-3(410mg,2.23mmol),氮,氮-二甲基甲酰胺(1.63g,22.26mmol),二氯甲烷(20mL)依次加入单口瓶中,在0℃下,分多次滴加三氯氧磷(682.54mg,4.45mmol),加完后在0℃下搅拌1h。反应完后,用饱和碳酸钠水溶液(5mL)淬灭反应,然后加入水(10mL)稀释,二氯甲烷萃取(25mL×2),合并有机相,有机相用饱和食盐水洗涤(10mL×3),合并有机相用无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=10:1到3:1)得到黄色油状液体11-4(450mg,产率97.65%)。
1H NMR(400MHz,CDCl
3)δ9.96(d,J=1.2Hz,1H),6.87(d,J=1.2Hz,1H),4.85(d,J=3.9Hz,1H),4.77–4.72(m,1H),4.24-4.18(m,3H),4.02-3.97(m,2H)。
步骤3:2-(9-(吡啶-2-基)-6-氧杂[4.5]癸烷-9-基)-氮-((1,3,3a,8a-四氢呋喃[3,4-b]噻吩并[3,4-e][1,4]二噁英-5-基)甲基)乙胺(11)的合成
氮气保护下,将11-4(100mg,384.06μmol),中间体A(85.58mg,403.27μmol),硫酸钠(100mg),二氯甲烷(3mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(43.59mg,1.15mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到无色稠状油11(70mg,产率32.53%,纯度97.8%),[M+H]
+: 457.3。
1H NMR(400MHz,Methanol-d
4)δ8.52-8.57(m,1H),7.74-7.80(m,1H),7.47-7.50(m,1H),7.22-7.26(m,1H),6.32-6.34(m,1H),4.66-4.74(m,2H),4.06-4.12(m,2H),3.88-3.71(m,4H),3.63-3.65(m,2H),2.56-2.37(m,3H),1.89-2.02(m,3H),1.81-1.62(m,4H),1.59-1.40(m,4H),1.17-1.07(m,1H),0.71-0.78(m,1H)。
实施例8
氮-((4a,5,6,7,8,8a-六氢苯并[b]噻吩[3,4-e][1,4]二噁英-1-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物12)的合成
步骤1:4a,5,6,7,8,8a-六氢苯并[b]噻吩[3,4-e][1,4]二噁英(12-2)的合成
室温下,将11-1(1g,6.94mmol),12-1(1.6g,13.87mmol),对甲苯磺酸(264mg,1.39mmol)加入甲苯(20mL)中,加热至100℃反应过夜。反应完成后,将反应液冷至室温,加入饱和碳酸氢钠溶液(20mL),用乙酸乙酯(20mL×2)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥后,过滤,滤液浓缩后过柱纯化(V
正己烷:V
乙酸乙酯=15:1)得白色固体12-2(1.1g,产率80.88%)。
1H NMR(400MHz,CDCl
3)δ6.30(s,2H),3.74-3.69(m,2H),2.22-2.19(m,2H),1.85-1.82(m,2H),1.47-1.32(m,4H)。
步骤2:4a、5、6、7、8、8a-六氢苯[b]噻吩[3,4-e][1,4]二噁英-1-甲醛(12-3)的合成
室温下,将12-2(1g,5.10mmol)溶于二氯甲烷(20mL),加入氮,氮-二甲基甲酰胺(2.8mL),冷至-10℃,缓慢滴加三氯氧磷(0.5mL)。将反应液移到室温反应1小时,再补加三氯氧磷(0.5mL),继续反应1小时。反应完成后,浓缩掉二氯甲烷后倒入冰水(10mL)中,用2N氢氧化钠水溶液调节pH=8,乙酸乙酯(30mL×2)萃取,有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥后,过滤,滤液浓缩后过柱纯化(V
正己烷:V
乙酸乙酯=10:1)得白色固体12-3(600mg,产率52.63%)。
1H NMR(400MHz,CDCl
3)δ9.93(s,1H),6.76(s,2H),3.91-3.85(m,1H),3.80-3.74(m,1H),2.33-2.21(m,2H),1.91-1.84(m,2H),1.54-1.37(m,4H)。
步骤3:氮-((4a,5,6,7,8,8a-六氢苯[b]噻吩并[3,4-e][1,4]二噁英-1-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(12)的合成
氮气保护下,将中间体A(100mg,384.06μmol),12-3(90.44mg,403.27μmol),硫酸钠(100mg),二氯甲烷(3mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(43.59mg,1.15mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到无色稠状油12(80mg,产率38.35%,纯度98.3%),[M+H]
+:469.4。
1H NMR(400MHz,CDCl
3)δ8.56-8.57(m,1H),7.62-7.66(td,J=7.7,1.9Hz,1H),7.31(d,J=8.1Hz,1H),7.11-7.14(m,1H),6.17(s,1H),3.76-3.78(m,2H),3.70-3.73(m,2H),3.64-3.68(m,2H),2.54-2.61(m,1H),2.42-3.47(m,1H),2.32-2.36(mHz,1H),2.13-2.21(m,6H),2.04-1.87(m,3H),1.87-1.66(m,6H),1.58-1.44(m,4H),1.08-1.17(m,1H),0.65-0.77(m,1H)。
实施例9
氮-((2,3,5,6,8,9-六氢噻吩[3,4-b][1,4,7,10]四氧环十二烷-11-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物13)的合成
步骤1:2,3,5,6,8,9-六氢噻吩[3,4-b][1,4,7,10]四氧环十二烷-11,13-二羧酸二甲酯(13-3)的合成
室温下,将13-1(4.5g,19.35mmol),13-2(8.01g,19.35mmol),碳酸钾(6.372g,46.8mmol)加入氮甲基吡咯烷酮(150mL)中,加热至120℃反应6h。反应完成后,将反应液冷至室温,加入水(200mL)稀释,用乙酸乙酯(250mL×2)萃取,有机相用饱和食 盐水(250mL×2)洗涤,无水硫酸钠干燥后,过滤,滤液浓缩后过柱纯化(V
石油醚:V
乙酸乙酯=10:1到1:1)得类白色固体13-3(2.4g,产率35.8%)。
步骤2:2,3,5,6,8,9-六氢噻吩[3,4-b][1,4,7,10]四氧环十二烷-11,13-二羧酸(13-4)的合成
0℃下,将13-3(2.4g,6.93mmol)溶于乙醇(15mL),加入5%氢氧化钠水溶液(15mL)。将反应液升温到60℃反应2小时,反应完成后,用1M HCl水溶液调节pH到6~7,固体析出,过滤收集固体,用水15mL洗涤得白色固体13-4(900mg,产率42.6%),[M+H]
+:319.0。
步骤3:2,3,5,6,8,9-六氢噻吩[3,4-b][1,4,7,10]四氧环十二烷(13-5)的合成
室温搅拌下,将13-3(400mg,1.57mmol),亚铬酸铜(262.54mg,1.44mmol),喹啉(8mL)加入单口瓶中,然后升温到160℃反应3小时。反应完成后降温到室温,用水(30mL)稀释,乙酸乙酯(50mL×3)萃取,有机相用1M HCl水溶液(50mL×3)洗涤,加入无水硫酸钠干燥,过滤浓缩。粗产品过柱纯化(V
石油醚:V
乙酸乙酯=5:1到1:1)得淡黄色固体13-4(90mg,产率31.1%)。
步骤4:2,3,5,6,8,9-六氢噻吩[3,4-b][1,4,7,10]四氧环十二烷11-甲醛(13-6)合成
室温下,将13-5(90mg,390.83μmol)溶于二氯甲烷(5mL),加入氮,氮-二甲基甲酰胺(285.67mg,3.91mmol),冷至0℃,缓慢滴加三氯氧磷(179.78mg,1.17mmol)。将反应液移到25℃反应反应2小时。反应完成后,浓缩掉二氯甲烷后倒入冰水(10mL)中,用2N氢氧化钠水溶液调节pH=8,乙酸乙酯(30mL×2)萃取,有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥后,过滤,滤液浓缩后过柱纯化(V
石油醚:V
乙酸乙酯=5:1到1:1)得到棕色固体13-6(82mg,产率81.2%)。
1H NMR(400MHz,CDCl
3)δ9.99(s,1H),6.82(s,1H),4.57-4.48(m,2H),4.25-4.17(m,2H),3.97-3.84(m,4H),3.82-3.72(m,4H)。
步骤5:氮-((2,3,5,6,8,9-六氢噻吩[3,4-b][1,4,7,10]四氧环十二烷-11-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]葵烷-9-基)乙胺(13)的合成
氮气保护下,将13-6(77mg,298.11μmol),中间体A(77.62mg,298.11μmol),硫酸钠(100mg),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(33.84mg,894.34μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤 旋干,粗品用反相中压制备得到无色稠油状产物13(40mg,产率26.7%,纯度90%),[M+H]
+:503.26。
1H NMR(400MHz,CDCl
3)δ8.63-8.53(m,1H),7.67(t,J=7.9Hz,1H),7.34(d,J=8.0Hz,1H),7.20-7.10(m,1H),6.25(d,J=2.3Hz,1H),4.25-4.14(m,2H),4.10(p,J=2.5Hz,2H),3.97-3.85(m,4H),3.84-3.71(m,8H),2.77-2.66(m,2H),2.31-2.43(m,4H),2.18-2.05(m,2H),1.99-1.89(m,2H),1.81-1.66(m,3H),1.40(s,1H),1.13(d,J=13.3Hz,1H),0.69(d,J=11.6Hz,1H)。
实施例10
氮-((3-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物14)的合成
步骤1:3-(1,4-二氧杂-8-氮杂螺环[4.5]癸烷-8-基)噻吩-2-甲醛(14-2)的合成
室温下,将6-1(400.00mg,2.09mmol),14-1(299.77mg,2.09mmol),醋酸钯(46.4mg,0.21mmol),BINAP(130.4mg,0.21mmol),碳酸铯(1.706g,5.23mmol)加入到无水甲苯(12mL)中,置换氮气后,体系升温至110℃搅拌5h。反应完全后,将反应液通过硅藻土助滤,EA(10mL*2)洗涤滤饼,浓缩滤液得到产物粗品。粗品通过柱层析纯化(V
正己烷:V
乙酸乙酯=6:1),得到黄色油状产物14-2(380mg,产率:71.74%)。
步骤2:氮-((3-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(14)的合成
室温下将14-2(35mg,0.198mmol)和中间体A(33mg,172.74μmol)加入到二氯甲烷(2mL)中,再加入无水硫酸钠(66.75mg,0.495mmol),体系在25℃下搅拌16h,TLC(V
二氯甲烷:V
甲醇=10:1)显示化合物信号消失后再加入NaBH
4(21.33mg,0.594mmol)和甲醇(1mL),体系在室温下搅拌2h。反应完全后,将反应液过滤,浓缩得到产物粗品,粗品通过反向制备分离纯化(50%ACN,H
2O)出产物。产物为淡黄色固体14(24.0mg, 产率:34.93%),[M+H]
+:498.3。
1H NMR(400MHz,Chloroform-d)δ8.54–8.42(m,1H),7.66(td,J=7.9,1.8Hz,1H),7.34(d,J=8.0Hz,1H),7.25(d,J=5.4Hz,1H),7.13(dd,J=7.5,4.8Hz,1H),7.00(d,J=5.4Hz,1H),4.27–4.16(m,2H),4.01(s,4H),3.73(d,J=11.6Hz,2H),2.90(t,J=5.6Hz,4H),2.38–2.23(m,4H),1.90(d,J=13.6Hz,1H),1.86–1.76(m,5H),1.66(dq,J=18.0,8.5,8.1Hz,3H),1.45–1.37(m,2H),1.10(d,J=13.4Hz,2H),0.88(d,J=12.1Hz,2H),0.69–0.61(m,1H)。
实施例11
氮-((2,3-二氢苯并[b][1,4]二噁英-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物17)的合成
步骤1:2,3-二氢苯并[b][1,4]二噁英-5-甲醛(17-3)的合成
室温下,将17-1(500mg,3.6mmol),17-2(717mg,7.2mmol),K
2CO
3(2.5g,18mmol),DMF(10mL)依次加入单口瓶,在氮气保护下,90℃搅拌16h。反应完全后,加入EA(100mL)淬灭,然后用Na
2CO
3溶液(50mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到无色油状液体17-3(300mg,产率51%),[M+H]
+:165.3。
步骤2:氮-((2,3-二氢苯并[b][1,4]二噁英-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(17)的合成
氮气保护下,将17-3(100mg,0.61mmol),中间体A(174mg,0.67mmol),氰基硼氢化钠(115mg,1.83mmol),二氯甲烷(3mL)甲醇(3mL)依次加入单口瓶中,室温搅拌16h。反应完后,加入EA(40mL),用(20mL×2)水洗涤,有机相用无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体产物17(20mg,产率8.1%,纯度98.3%),[M+H]
+:409.3。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=3.6Hz 1H),7.66-7.61(m,1H),7.31-7.28(m,1H),7.13(dd,J
1=4.8Hz,J
2=7.2Hz,1H),6.77-6.67(m,3H),4.26-4.23(m,4H),3.78-3.76(m,2H),3.68-3.60(m,2H),2.58-2.51(m,1H),2.45-2.42(m,1H),2.35(d,J=13.6Hz,1H),2.17-2.10(m,1H),2.07-1.98(m,1H),1.93(d,J=13.6Hz,1H),1.70-1.61(m,2H),1.56-1.39(m,3H),1.38-1.25(m,3H),1.16-1.13(m,1H),0.91-0.86(m,1H),0.75-0.67(m,1H)。
实施例12
氮-((3-(1,4-二氧杂螺[4.5]葵环-7-烯-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物19)的合成
步骤1:3-(1,4-二氧杂螺[4.5]葵环-7-烯-8-基)噻吩-2-甲醛(19-2)的合成
在室温下,将6-1(0.4g,2.09mmol),19-1(0.84g,3.14mmol),碳酸钾(868.11mg,6.28mmol),Pd(dppf)Cl
2二氯甲烷(0.4g,0.5mmol),二氧六环(12mL)和水依次加入单口瓶,在氮气保护下,110℃搅拌12h。反应结束,加入水(100mL),然后用乙酸乙酯(50mL×2)萃取,合并有机相用水(30mL×1)洗涤,饱和食盐水(50mL×1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到黄色油状液体19-2(300mg,产率56.78%),[M+H]
+:251.07。
步骤2:氮-((3-(1,4-二氧杂螺[4.5]葵环-7-烯-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(19)的合成
氮气保护下,将19-2(200mg,768.11μmol),中间体A(211.49mg,844.92μmol),硫酸钠(327.29mg,1.54mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(58.12mg,2.30mmol),搅拌10分钟,加入甲醇(0.3mL),搅拌反应1小时。反应完后,加入水(4mL),二氯甲烷萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体19(110mg,产率28.95%,纯度95.00%),[M+H]
+:495.3。
1H NMR(400MHz,CDCl
3)δ8.58-8.50(m,1H),7.65-7.61(m,1H),7.32-7.28(m,1H),7.14-7.08(m,2H),6.87-6.86(m,1H),5.50(s,1H),4.15-4.00(m,4H),3.84-3.83(m,2H),3.79-3.76(m,2H),2.52-2.34(m,8H),2.13-2.07(m,1H),1.95-1.70(m,4H),1.57-1.40(m,3H),1.28-1.20(m,2H),0.90-0.85(m,3H),0.73-0.70(m,1H)。
实施例13
氮-((3-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物21)的合成
步骤1:3-(2-氧代-5-氮杂双环[2.2.2]辛烷-5-基)噻吩-2-甲醛(21-3)的合成
在室温下,将6-1(0.3g,1.57mmol),21-1(0.31g,2.04mmol),碳酸铯(1.28g,3.93mmol),醋酸钯(35.26mg,157.03μmol),BINAP(195.57mg,314.67μmol)甲苯(5mL)依次加入单口瓶,在氮气保护下,100℃搅拌12h。反应结束,加入水(100mL),然后用乙酸乙酯(5mL×2)萃取,合并有机相用水(3mL×1)洗涤,饱和食盐水(5mL×1)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到黄色油状液体21-2(200mg,产率57%),[M+H]
+:224.07。
步骤2:氮-((3-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(21)的合成
氮气保护下,将21-2(200mg,768.11μmol),中间体A(211.49mg,844.92μmol),硫酸钠(327.29mg,1.54mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(58.12mg,2.30mmol),搅拌10分钟,加入甲醇(0.3mL),搅拌反应1小时。反应完后,加入水(4mL),二氯甲烷萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体21(110mg,产率22.27%,纯度95.00%),[M+H]
+:468.2。
1H NMR(400MHz,CDCl
3)δ8.58-8.50(m,1H),7.65-7.61(m,1H),7.32-7.28(m,1H),7.14-7.08(m,2H),6.87-6.86(m,1H),5.50(s,1H),4.15-4.00(m,4H),3.84-3.83(m,2H),3.79-3.76(m,2H),2.52-2.34(m,8H),2.13-2.07(m,1H),1.95-1.70(m,4H),1.57-1.40(m,3H),1.28-1.20(m,2H),0.90-0.85(m,3H),0.73-0.70(m,1H)。
实施例14
氮-((1-甲基-1氢-四唑-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物22)的合成
步骤1:2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺)乙腈(22-2)的合成
室温下,将中间体A(200mg,768.11μmol),溴乙腈(96.74mg,806.51μmol),三乙胺(155.45mg,1.54mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,反应完后,加入水(4mL),乙酸乙酯萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。得到粗品黄色油状物22-2(0.23g,粗品),[M+H]
+:300.42。
步骤2:叔丁基(氰甲基)(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺甲酸酯(22-3)的合成
室温下,将22-2(230mg,768.16μmol),二碳酸二叔丁酯(335.30mg,1.54mmol),三乙胺(240.56mg,2.30mmol),四氢呋喃(20mL)依次加入单口瓶中,室温搅拌12h,反应完后,加入水(40mL),乙酸乙酯萃取(50mL×2),合并有机相,有机相用饱和食盐水洗涤(80mL×1)。无水硫酸钠干燥,过滤,旋干。粗品粗品用柱层析纯化(V
石油醚:V
乙酸
乙酯=1:1)纯化。得到黄色油状物22-3(0.2g,产率:65.17%),[M+H]
+:400.42。
步骤3:叔丁基((2氢-四唑-5-基)甲基)(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺甲酸酯(22-4)的合成
室温下,将22-3(150mg,375.44μmol),叠氮化钠(26.85mg,412.98μmol),氯化铵(22.09mg,12.98μmol),DMF(5mL)依次加入单口瓶中,105℃搅拌12h,反应完后,加入水(20mL),乙酸乙酯萃取(15mL×2),合并有机相,有机相用水(15mL×3),饱和食盐水洗涤(20mL×1)。无水硫酸钠干燥,过滤,旋干,得到粗品黄色油状物22-4(0.2g,粗品),[M+H]
+:443.27。
步骤4:叔丁基((1-甲基-1氢-四唑-5-基)甲基)(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺甲酸酯(22-5)的合成
室温下,将22-4(50mg,112.98μmol),碘甲烷(169.47mg,24.05μmol),碳酸钾(31.23mg,225.96μmol),DMF(2mL)依次加入单口瓶中,室温搅拌12h,反应完后,加入水(8mL),乙酸乙酯萃取(5mL×2),合并有机相,有机相用水(5mL×3),饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=1:1)纯化。得到黄色油状物22-5(25mg,产率:48%),[M+H]
+:457.28。
步骤5:氮-((1-甲基-1氢-四唑-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(22)的合成
室温下,将22-5(25mg,54.75μmol),盐酸乙酸乙酯溶液(1mL,4N),乙酸乙酯(2mL)依次加入单口瓶中,室温搅拌0.5h,反应完后,加入饱和碳酸钠溶液调剂pH-9。乙酸乙酯萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体22(3.5mg,产率16.39%,纯度95.00%),[M+H]
+:356.2。
1H NMR(400MHz,CDCl
3)δ8.59-8.65(m,1H),7.18-7.70(m,1H),7.54-7.40(m,1H),7.19-7.02(m,1H),4.16-4.11(m,2H),3.78-3.50(m,2H),2.62-2.53(m,1H),2.45-2.23(m,6H),1.98-1.80(m,1H),1.67-1.52(m,2H),1.42-1.39(m,1H),1.35-1.26(m,6H),1.25-1.19(m,1H),0.90-0.85(m,2H),0.77-0.71(m,1H)。
实施例15
氮-((2-甲基-2氢-四唑-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物23)的合成
步骤1:叔丁基((2-甲基-2氢-四唑-5-基)甲基)(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺甲酸酯(23-1)的合成
室温下,将22-4(50mg,112.98μmol),碘甲烷(169.47mg,24.05μmol),碳酸钾(31.23mg,225.96μmol),DMF(2mL)依次加入单口瓶中,室温搅拌12h,反应完后,加入水(8mL),乙酸乙酯萃取(5mL×2),合并有机相,有机相用水(5mL×3)、饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=1:1)纯化。得到黄色油状物23-1(25mg,产率:48.46%),[M+H]
+:457.28。
步骤2:氮-((2-甲基-2氢-四唑-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(23)的合成
室温下,将23-1(25mg,54.75μmol),盐酸乙酸乙酯溶液(1mL,4N),乙酸乙酯(2mL)依次加入单口瓶中,室温搅拌0.5h,反应完后,加入饱和碳酸钠溶液调剂pH-9。乙酸乙酯萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体23(6.8mg,产率34.84%,纯度95.00%),[M+H]
+:357.24。
1H NMR(400MHz,CDCl
3)δ8.59-8.65(m,1H),7.18-7.70(m,1H),7.54-7.40(m,1H),7.19-7.02(m,1H),4.16-4.11(m,2H),3.83-3.78(m,2H),2.38-2.05(m,6H),1.98-1.80(m,1H),1.79-1.67(m,1H),1.67-1.52(m,1H),1.42-1.39(m,1H),1.35-1.26(m,6H),1.25-1.19(m,1H),0.90-0.85(m,2H),0.77-0.71(m,1H)。
实施例16
氮-((5-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物24)的合成
步骤1:5-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)噻吩-2-甲醛(24-2)的合成
室温下,将24-1(191mg,1.0mmol),19-1(293mg,1.1mmol),K
2CO
3(414mg,3.0mmol),Pd(dppf)Cl
2(82mg,0.1mmol),dioxane(5.5mL),H
2O(0.5mL),依次加入单口瓶,在氮气保护下,90℃搅拌6h。反应完全后,加入EA(100mL),然后用H
2O(50mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石
油醚:V
乙酸乙酯=10:1)得到黄色固体24-2(150mg,产率60%),[M+H]
+:251.3。
步骤2:氮-((5-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(24)的合成
氮气保护下,将24-2(150mg,0.6mmol),中间体A(156mg,0.6mmol),硫酸镁(1440mg,12mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(46mg,1.2mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应1小时。反应完后,加入水(30mL),二氯甲烷萃取(50mL×2),合并有机相,有机相用饱和食盐水洗涤(40mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体60mg,产率20%,纯度90%,取30mg过flash(A:H
2O;B:MeCN)得到产品24(20mg,纯度98%),[M+H]
+:495.2。
1H NMR(400MHz,CDCl
3)δ8.55(d,J=3.6Hz 1H),7.63-7.59(m,1H),7.28(d,J=8.4Hz 1H),7.10(dd,J
1=4.8Hz,J
2=7.2Hz,1H),6.71(d,J=3.6Hz,1H),6.60(d,J=3.6Hz,1H),5.94(t,J=4.0Hz,1H),4.00(s,4H),3.76-3.71(m,4H),2.62-2.60(m,2H),2.50-2.32(m,5H),2.11-2.04(m,1H),1.99-1.87(m,4H),1.77-1.72(m,2H),1.66-1.63(m,2H),1.55-1.37(m,5H),1.14-1.08(m,1H),0.73-0.65(m,1H)。
实施例17
2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)-氮-((1,3,3a,9a-苯并[b]呋喃并[3,4-E][1,4]二噁英-5-基)甲基)乙胺(化合物25)的合成
步骤1:四氢呋喃-3,4-二(4-甲基苯磺酸)二酯(25-2)的合成
室温下,将11-2(1.04g,10mmol),DIEA(7.74g,60mmol),DMAP(244mg,2mmol),溶于二氯甲烷(30mL),0℃下加入TsCl(5.75g,30mmol)并室温反应2小时。反应完全后,加入二氯甲烷(50mL),然后用H
2O(50mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=10:1)得到黄色液体25-2(2.0g,产率50%),[M+H]
+:413.2。
步骤2:1,3,3a,9a-四氢苯并[b]呋喃[3,4-e][1,4]二噁英-5-甲醛(25-4)的合成
氮气保护下,将25-2(1.6g,3.9mmol),17-1(536mg,3.9mmol),碳酸钾(2.7g,119.4mmol),DMF(20mL)依次加入单口瓶中,70℃搅拌16h。反应完后,加入EA(300mL),用水(100mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=10:1)得到黄色油状液体25-4(200mg,产率17%),[M+H]
+:207.2。
步骤3:2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)-氮-((1,3,3a,9a-苯并[b]呋喃并[3,4-E][1,4]二噁英-5-基)甲基)乙胺(25)的合成
氮气保护下,将25-4(80mg,0.39mmol),中间体A(101mg,0.39mmol),硫酸镁(936mg,7.80mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(30mg,0.78mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩至2mL,TLC纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体25(50mg,产率29%),[M+H]
+:451.3。
1H NMR(400MHz,CDCl
3)δ8.52(d,J=4.8Hz,1H),7.61(t,J=8.0Hz 1H),7.27(d,J=8.8Hz 1H),7.12-7.09(m,1H),6.82-6.72(m,3H),4.65-4.58(m,2H),4.13-4.08(m,2H),3.91-3.87(m,2H),3.74-3.64(m,4H),2.59-2.52(m,1H),2.41-2.30(m,3H),2.16-1.99(m,3H),1.90(d,J=13.6Hz 1H),1.83-1.61(m,4H),1.53-1.48(m,2H),1.39-1.37(m,1H),1.13-1.08(m,1H),0.71-0.63(m,1H)。
实施例18
氮-((3-甲氧基-[2,3'-联噻吩]-2'-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物26)的合成
步骤1:3-甲氧基-[2,3'-联噻吩]-2'-甲醛(26-2)的合成
室温下,依次将26-1(0.3g,2.62mmol),6-1(298.79mg,2.62mmol),乙酸钾(770.57mg,7.85mmol),醋酸钯(117.52mg,0.523mmol),四丁基溴化胺(843.5mg,2.62mmol)加入到N,N-二甲基甲酰胺(50mL)中,氮气置换三次,在氮气氛围下,加热至80℃反应3h。反应完成后,将反应液冷至室温,加入水(100mL)稀释,用乙酸乙酯(100mL×3)萃取,有机相用盐水(100mL×3)洗涤,无水硫酸钠干燥后,过滤,滤液浓缩后,粗产物经硅胶柱层析纯化(V
PE:V
EA=10:1)得淡黄色油26-2(370mg,产率67%)。
1H NMR(400MHz,CDCl
3)δ10.09(d,J=1.3Hz,1H),7.71(dd,J=5.0,1.3Hz,1H),7.38(d,J=5.5Hz,1H),7.29(d,J=5.0Hz,1H),6.99(d,J=5.5Hz,1H),3.91(s,3H)。
步骤2:氮-((3-甲氧基-[2,3'-联噻吩]-2'-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(26)的合成
氮气保护下,将26-2(100mg,445.83μmol),中间体A(116.08mg,445.83μmol),硫酸钠(100mg),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(50.60mg,1.34mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到无色稠状油26(50mg,产率23.9%,纯度95%),[M+H]
+:469.33。
1H NMR(400MHz,CDCl
3)δ8.58–8.51(m,1H),7.63(td,J=7.7,1.9Hz,1H),7.30(d,J=8.3Hz,1H),7.20(t,J=5.6Hz,2H),7.13-7.10(m,1H),7.07(d,J=5.2Hz,1H),6.90(d,J=5.6Hz,1H),3.85(d,J=1.7Hz,2H),3.80(s,3H),3.78–3.74(m,2H),2.61–2.53(m,1H),2.47–2.41(m,1H),2.35(dd,J=13.6,2.0Hz,1H),2.21–2.14 (m,1H),2.10–1.87(m,4H),1.71–1.61(m,4H),1.55–1.43(m,4H),1.18–1.11(m,1H),0.76–0.68(m,1H)。
实施例19
氮-((4-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物28)的合成
步骤1:4-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)噻吩-2-甲醛(28-2)的合成
将28-1(100mg,523.43μmol),19-1(139.31mg,523.43μmol),碳酸钾(217.02mg,1.57mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物依次加入单口瓶中,加入二氧六环溶液(10mL)和水(2mL)并用氮气置换气体三次,加热到100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到棕色油28-2(130mg,产率99.2%)。
1H NMR(400MHz,CDCl
3)δ9.92(d,J=1.3Hz,1H),7.88(d,J=1.5Hz,1H),7.58-7.52(m,1H),6.15-6.11(m,1H),4.04(s,4H),2.68-2.63(m,2H),2.51-2.47(m,2H),1.98–1.92(m,2H)。
步骤2:氮-((4-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(28)的合成
氮气保护下,将28-2(65mg,259.67μmol),中间体A(67.61mg,259.67μmol),硫酸钠(100mg),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(29.47mg,779.01μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油28(28mg,产率27.9%,纯度95%),[M+H]
+:495.39。
1H NMR(400MHz,CD
3OD)δ8.54-8.49(m,1H),7.76(td,J=7.8,1.9Hz,1H),7.51–7.45(m,1H),7.27-7.20(m,1H),7.09-7.01(m,2H),6.01-5.95(m,1H),4.03-3.95 (m,4H),3.81–3.74(m,3H),3.61–3.57(m,1H),2.59–2.41(m,6H),2.09–1.98(m,2H),1.93–1.85(m,3H),1.79–1.46(m,9H),1.14-1.07(m,1H),0.77–0.69(m,1H)。
实施例20
氮-((2-(2-甲氧基乙基)-2-氢-四唑-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺&氮-((1-(2-甲氧基乙基)-1-氢-四唑-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物29)的合成
步骤1:叔丁基((2-(2-甲氧基乙基)-2-氢-四唑-5-基)甲基)(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺甲酸酯&叔丁基((1-(2-甲氧基乙基)-1-氢-四唑-5-基)甲基)(2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺甲酸酯(29-1)合成
室温下,将22-4(150mg,338.93μmol),1-溴-2-甲氧基乙烷(70.56mg,508.40μmol),碳酸铯(220.86mg,677.97μmol),DMF(2mL)依次加入单口瓶中,室温搅拌12h,反应完后,加入水(8mL),乙酸乙酯萃取(5mL×2),合并有机相,有机相用水(5mL×3),饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品粗品用柱层析纯化(V
石
油醚:V
乙酸乙酯=1:1)纯化。得到黄色油状物29-1(100mg,产率:58.93%),[M+H]
+:501.31。
步骤2:氮-((2-(2-甲氧基乙基)-2-氢-四唑-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺&氮-((1-(2-甲氧基乙基)-1-氢-四唑-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(29)的合成
室温下,将29-2(100mg,199.74μmol),盐酸乙酸乙酯溶液(1mL,4N),乙酸乙酯(2mL)依次加入单口瓶中,室温搅拌2h,反应完后,加入饱和碳酸钠溶液调剂pH-9。乙酸乙酯萃取(5mL×2),合并有机相,有机相用饱和食盐水洗涤(8mL×1)。无水硫酸钠干燥,过滤,旋干。粗品用柱层析纯化(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液29(30mg,产率37.5%,纯度95.00%),[M+H]
+:401.53。
1H NMR(400MHz,CDCl
3)δ8.55-8.53(m,1H),7.66-7.64(m,1H),7.15-7.13(m,1H),7.13-7.12(m,1H),4.75-4.72(m,2H),4.12-4.10(m,2H),3.90-3.71(m,4H),3.90-3.71(s,3H),2.80-2.75(m,1H),2.41-2.30(m,3H),1.92-1.89(m,2H),1.78-1.67(m,4H),1.49-1.38(m,3H),1.25-1.12(m,1H),0.87-0.68(m,1H),0.67-0.61(m,1H)。
实施例21
氮-((3-(甲基亚磺酰基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物30)的合成
步骤1:3-(甲基亚磺酰基)噻吩-2-甲醛(30-1)的合成
室温下,依次将9-1(0.2g,1.26mmol),间氯过苯甲酸(256.0mg,1.26mmol),二氯甲烷(5mL),室温下反应3h。反应完成后,加入水(10mL)稀释,二氯甲烷(10mL×3)萃取,有机相用盐水(10mL×1)洗涤,无水硫酸钠干燥后,过滤,滤液浓缩后,得到淡黄色油状物30-1(150mg,产率81.74%)。
步骤2:氮-((3-(甲基亚磺酰基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(30)的合成
氮气保护下,将中间体A(50mg,192.03μmol),30-1(36.80mg,211.23μmol),硫酸钠(100mg),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(14.53mg,384.05μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到无色稠状油30(30mg,产率22.50%,纯度95%),[M+H]
+:419.61。
1H NMR(400MHz,CDCl
3)δ8.59-8.57(m,1H),7.66-7.62(m,1H),7.36-7.34(m,1H),7.32-7.30(m,2H),7.15-7.12(m,1H),3.98-3.86(m,2H),3.78-3.51(m,2H),2.78(s,3H),2.55-2.36(m,4H),2.13-2.00(m,2H),1.97-1.91(m,2H),1.77-1.73(m,3H),1.69-1.63(m,2H),1.42-1.40(m,1H),1.27-1.24(m,1H),0.90-0.88(m, 1H),0.75-0.71(m,1H)。
实施例22
氮-((1-甲基-1氢-1,2,4-三唑-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物32)的合成
步骤1:1-甲基-1-氢-1,2,4-三唑-3-甲醛(32-2)的合成
室温下,依次将32-1(0.3g,2.65mmol),TEMPO(41.44mg,265.21μmol),DAIB(935.64mg,3.92mmol),二氯甲烷(10mL),室温下反应12h。反应完成后,旋干溶剂,粗品经柱层析纯化(V
石油醚:V
乙酸乙酯=1:2),无水硫酸钠干燥后,过滤,滤液浓缩后,得到白色固体32-2(150mg,产率50.91%)。
步骤2:氮-((1-甲基-1-氢-1,2,4-三唑-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(32)的合成
氮气保护下,将中间体A(50mg,192.03μmol),32-2(22.40mg,201.63μmol),硫酸钠(100mg),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(14.53mg,384.05μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到无色稠状油32(20mg,产率12.50%,纯度95%),[M+H]
+:356.24。
1H NMR(400MHz,CDCl
3)δ8.59-8.57(m,1H),7.92(s,1H),7.65-7.61(m,1H),7.39-7.30(m,1H),7.16-7.10(m,1H),3.90(s,3H),3.86-3.67(m,4H),2.54(s,1H),2.46-2.43(m,1H),2.37-2.26(m,1H),2.01-1.97(m,1H),1.95-1.90(m,2H),1.58-1.51(m,4H),1.39-1.32(m,2H),1.27-1.24(m,2H),0.97-0.86(m,2H),0.73-0.67(m,1H)。
实施例23
氮-((2-(3,3-二氟氮杂环丁烷-1-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧 杂螺[4.5]癸烷-9-基)乙胺(化合物33)的合成
步骤1:2-(3,3-二氟氮杂环丁烷-1-基)烟醛(33-2)的合成
室温下,将33-1(500mg,2.69mmol),6-2(379.07mg,2.97mmol),DIEA(1.04g,8.06mmol)溶于DMF(6mL),100℃反应16小时。反应完全后,加入H
2O(20mL),然后用乙酸乙酯(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体33-2(400mg,产率75.09%),[M+H]
+:199.06。
步骤2:氮-((2-(3,3-二氟氮杂环丁烷-1-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(33)的合成
氮气保护下,将33-2(58mg,0.29mmol),中间体A(50mg,0.19mmol),硫酸钠(109.10mg,0.77mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(15mg,0.38mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相制备分离(A:水;B:乙腈)得到黄色油状液体33(19mg,产率28.6%),[M+H]
+:443.3。
1H NMR(400MHz,CDCl
3)δ8.59(d J=5.2Hz,1H),8.11-8.09(m,1H),7.66-7.62(m,1H),7.36-7.27(m,1H),7.15-7.12(m,1H),6.75-6.72(m,1H),4.41-4.35(m,4H),3.79-3.77(m,2H),3.73-3.71(m,2H),3.45(s,2H),2.52-2.25(m,3H),2.14-2.08(m,1H),2.07-1.98(m,1H),1.97-1.89(m,1H),1.81-1.69(m,4H),1.55-1.51(m,2H),1.43-1.41(m,1H),1.17-1.13(m,1H),0.89-0.76(m,1H),0.76-0.68(m,1H)。
实施例24
氮-(2-(3,3-二氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物34)的合成
步骤1:2-(3,3-二氟氮杂环丁烷)苯甲醛(34-2)的合成
室温下,将34-1(500mg,2.69mmol),6-2(379.07mg,2.97mmol),碳酸铯(2.2g,6.76mmol),BINAP(50.48mg,81.07μmol),醋酸钯(6.07mg,27.02μmol)溶于甲苯(10mL),100℃反应12小时。反应完全后,加入H
2O(20mL),然后用乙酸乙酯(10mL×2)萃取,合并有机相,有机相用饱和食盐水(8mL×1)洗涤一次,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体34-2(150mg,产率28.15%),[M+H]
+:198.06。
步骤2:氮-(2-(3,3-二氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(34)的合成
氮气保护下,将34-2(57mg,0.29mmol),中间体A(50mg,0.19mmol),硫酸钠(109.10mg,0.77mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(15mg,0.38mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相制备分离(A:水;B:乙腈)得到黄色油状液体34(23mg,产率27.13%),[M+H]
+:442.3。
1H NMR(400MHz,CDCl
3)δ8.59-8.57(m,1H),7.65-7.62(m,1H),7.32-7.27(m,1H),7.19-7.08(m,3H),6.87-6.83(m,1H),6.52(d,J=8,1H),4.23-4.11(m,4H),3.79-3.69(m,2H),3.51(s,2H),2.54-2.52(m,1H),2.51-2.50(m,1H),2.48-2.46(m,1H),2.14-2.08(m,2H),2.07-1.98(m,1H),1.97-1.89(m,1H),1.81-1.69(m,2H),1.57-1.51(m,2H),1.17-1.14(m,2H),0.89-0.85(m,1H),0.76-0.68(m,1H)。
实施例25
氮-((2-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物35)的合成
步骤1:2-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)烟醛(35-1)的合成
室温下,将33-1(400mg,2.2mmol),14-1(472mg,3.3mmol),DIEA(1.7g,13mmol),溶于H
2O(6mL),100℃反应16小时。反应完全后,加入H
2O(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石
油醚:V
乙酸乙酯=2:1)得到黄色液体35-1(400mg,产率75%),[M+H]
+:249.2。
步骤2:氮-((2-(1,4-二氧-8-氮螺环[4.5]癸烷-8-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(35)的合成
氮气保护下,将35-1(80mg,0.32mmol),中间体A(83.2mg,0.32mmol),硫酸镁(768mg,6.4mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(24mg,0.64mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过flash(A:H
2O;B:MeCN)得到黄色油状液体35(20mg,产率13%),[M+H]
+:493.3。
1H NMR(400MHz,CDCl
3)δ8.55(dd,J1=1.2Hz,J2=4.8Hz,1H),8.14(dd,J1=1.6Hz,J2=4.8Hz,1H),7.61(dt,J1=2.0Hz,J2=7.6Hz,1H),7.47(dd,J1=1.6Hz,J2=7.6Hz,1H),7.27(d,J=7.6Hz,1H),7.12-7.09(m,1H),6.83(dd,J1=4.8Hz,J2=7.6Hz,1H),3.98(S,4H),3.75(dd,J1=2.8Hz,J2=7.6Hz,2H),3.58(s,2H),3.17(d,J=5.6Hz,4H),2.48-2.40(m,2H),2.33(dd,J1=1.6Hz,J2=13.6Hz,1H),2.06-2.00(m,2H),1.97-1.89(m,2H),1.81-1.78(m,4H),1.70-1.67(m,2H),1.54-1.37(m,5H),1.13-1.08(m,1H),0.73-0.66(m,1H)。
实施例26
氮-((2-(1,4-杂螺[4.5]癸烷-7-烯-8-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物36)的合成
步骤1:2-(1,4-二氧杂螺[4.5]葵烷-7-烯-8-基)烟醛(36-1)的合成
室温下,将33-1(200mg,1.1mmol),19-1(324mg,1.2mmol),K
2CO
3(445mg,3.2mmol),Pd(dppf)Cl
2(82mg,0.1mmol),dioxane(5.5mL),H
2O(0.5mL),依次加入单口瓶,在氮气保护下,100℃搅拌16h。反应完全后,加入EA(100mL),然后用H
2O(50mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石
油醚:V
乙酸乙酯=10:1)得到黄色固体36-1(250mg,产率95%),[M+H]
+:246.3。
步骤2:氮-((2-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(36)的合成
氮气保护下,将36-1(80mg,0.33mmol),中间体A(85mg,0.33mmol),硫酸镁(792mg,6.6mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(25mg,0.66mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相制备分离(A:水;B:乙腈)纯化,得到黄色油状液体36(15mg,产率9.4%),[M+H]
+:490.3。
1H NMR(400MHz,CDCl
3)δ8.52(dd,J1=1.2Hz,J2=4.8Hz,1H),8.41(dd,J1=1.6Hz,J2=4.8Hz,1H),7.61(dt,J1=2.0Hz,J2=8.0Hz,1H),7.54(dd,J1=1.6Hz,J2=7.6Hz,1H),7.27(d,J=7.6Hz,1H),7.11-7.06(m,2H),5.59-5.57(m,1H),4.01(S,4H),3.76-3.73(m,2H),3.64(s,2H),2.52-2.51(m,2H),2.43-2.32(m,5H),2.04-1.89(m,5H),1.70-1.65(m,3H),1.54-1.37(m,5H),1.13-1.08(m,1H),0.69-0.66(m,1H)。
实施例27
氮-(2-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物37)的合成
步骤1:2-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)苯甲醛(37-1)的合成
将34-1(600mg,3.24mmol),14-1(464.33mg,3.24mmol),1,1'-联萘-2,2'-双二苯膦(201.9mg,324.29μmol),碳酸铯(3.17,9.73mmol)和醋酸钯(72.81mg,324.29μmol)依次加入单口瓶中,加入甲苯(40mL)溶解并用氮气置换气体三次,加热100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1)纯化得到淡黄色油371(120mg,产率15.0%),[M+H]
+:248.20。
步骤2:氮-(2-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(37)的合成
氮气保护下,将37-1(120mg,485.26μmol),中间体A(126.35mg,485.26μmol),硫酸钠(120mg),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(55.08mg,1.46mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备(A:水;B:乙腈)纯化得到淡黄色稠状油37(20mg,产率8.38%,纯度95%),[M+H]
+:492.39。
1H NMR(400MHz,CD
3OD)δ8.58-8.46(m,1H),7.78-7.71(m,1H),7.49-7.43(m,1H),7.29-7.19(m,2H),7.17-7.10(m,2H),7.06-6.97(m,1H),4.05-3.90(m,4H),3.82-3.72(m,2H),3.68(s,2H),2.97-2.80(m,4H),2.49-2.37(m,3H),2.10-1.84(m,4H),1.80-1.48(m,11H),1.15-1.09(m,1H),0.78-0.70(m,1H)。
实施例28
氮-(2-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物38)的合成
步骤1:2-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)苯甲醛(38-1)的合成
将34-1(200mg,1.08mmol),19-1(287.69mg,1.08mmol),碳酸钾(448.19mg,3.24mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(87.6mg,108.1μmol)依次加入单口瓶中,加入二氧六环溶解(5mL)和水(1mL)溶解并用氮气置换气体三次,加热到100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油38-1(190mg,产率71.9%)。
1H NMR(400MHz,CDCl
3)δ10.19(d,J=0.8Hz,1H),7.93(dd,J=7.8,1.5Hz,1H),7.56(td,J=7.5,1.5Hz,1H),7.43-7.34(m,2H),5.58-5.52(m,1H),4.08-4.01(m,4H),2.67-2.57(m,2H),2.52-2.44(m,2H),2.00-1.92(m,2H)。
步骤2:氮-(2-(1,4-二氧杂螺[4.5]癸烷-7-烯-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(38)的合成
氮气保护下,将38-1(80mg,327.49μmol),中间体A(85.27mg,327.49μmol),硫酸钠(80mg),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(37.17mg,982.46μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油38(35mg,产率21.9%,纯度95%),[M+H]
+:489.39。
1H NMR(400MHz,CD
3OD)δ8.54-8.48(m,1H),7.78-7.71(m,1H),7.49-7.43(m,1H),7.28-7.13(m,4H),7.09-7.04(m,1H),5.45-5.34(m,1H),4.03(s,4H),3.79-3.70(m,2H),3.65(s,2H),2.49-2.33(m,6H),2.05-1.84(m,5H),1.79-1.44(m,9H),1.13-1.07(m,1H),0.77-0.69(m,1H)。
实施例29
氮-(4-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物39)的合成
室温下,将中间体A(50mg,0.192mmol)用二氯甲烷(5mL)溶解,然后依次加入硫酸钠(136mg,0.96mmol)和39-1(62mg,0.251mmol),反应在氮气保护下室温过夜。反应16h后,加入硼氢化钠(15mg,0.397mmol)和甲醇(2mL)继续搅拌30分钟。反应完全后,用15mL水进行淬灭,加入乙酸乙酯(15×2mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
二
氯甲烷:V
甲醇=10:1)得到淡黄色油状液体39(53mg,产率56.2%),[M+H]
+:492.2。
1H NMR(400MHz,Chloroform-d)δ8.53(d,J=4.8Hz,1H),7.64(d,J=1.9Hz,1H),7.31(d,J=8.1Hz,1H),7.14(d,J=7.5Hz,3H),6.86(d,J=8.6Hz,2H),4.01(s,4H),3.76(d,J=6.1,3.4Hz,2H),3.65–3.59(m,2H),3.30(t,J=5.8Hz,4H),2.65–2.59(m,1H),2.37(d,J=15.5Hz,2H),2.20(td,J=11.1,4.8Hz,2H),2.06(d,J=4.1Hz,1H),1.92(d,J=13.7Hz,3H),1.85–1.81(m,5H),1.78–1.66(m,5H),1.12(s,1H),0.74–0.68(m,1H)。
实施例30
氮-((2-(1,4-二氧杂螺[4.5]癸烷-8-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物40)的合成
步骤1:(2-(1,4-二氧杂螺[4.5]癸烷-8-基)吡啶-3-基)甲醇(40-2)的合成
室温下,将36-1(160mg,0.65mmol),Pd/C(Pd:10%,50mg),甲醇(3mL),乙 酸乙酯(3mL),依次加入单口瓶,在氢气下,室温搅拌16h。反应完全后,过滤浓缩得到无色液体体40-2(160mg,产率98%),[M+H]
+:250.3。
步骤2:2-(1,4-二氧杂螺[4.5]癸烷-8-基)烟醛(40-3)的合成
将40-2(160mg,0.65mmol),二氧化锰(546mg,6.5mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌3h。反应完全后,过滤浓缩得到黄色液体40-3(100mg,产率77%),[M+H]
+:248.2。
步骤3:氮-((2-(1,4-二氧杂螺[4.5]癸烷-8-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(40)的合成
氮气保护下,将40-3(100mg,0.40mmol),中间体A(104mg,0.40mmol),硫酸镁(960mg,8.0mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(30mg,0.80mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:H
2O;B:MeCN)纯化得到黄色油状液体40(25mg,产率13%),[M+H]
+:492.3。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=4.4Hz,1H),8.42(d,J=4.8Hz,1H),7.62(t,J=8.0Hz,1H),7.42(d,,J=7.6Hz,1H),7.28(d,J=8.0Hz 1H),7.11(dd,J1=4.8Hz,J2=7.2Hz,1H),7.00(dd,J1=5.2Hz,J2=7.6Hz,1H),3.97(S,4H),3.76(dd,J1=2.8Hz,J2=7.6Hz,2H),3.61(s,2H),2.86-2.80(m,1H),2.53-2.42(m,2H),2.36(d,J=13.6Hz,1H),2.15-2.07(m,2H),2.01-1.84(m,4H),1.78-1.62(m,9H),1.53-1.38(m,5H),1.13-1.08(m,1H),0.73-0.65(m,1H)。
实施例31
氮-(2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物41)和(R)-氮-(2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物41-P1)的合成
步骤1:2-(3-甲氧基氮杂环丁烷-1-基)苯甲醛(41-2)的合成
将34-1(200mg,1.08mmol),41-1(154.78mg,1.08mmol),1,1'-联萘-2,2'-双二苯膦(67.3mg,108.1μmol),碳酸铯(1.06g,3.24mmol)和醋酸钯(24.27mg,108.1μmol)依次加入单口瓶中,加入甲苯(10mL)溶解并用氮气置换气体三次,加热到100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油41-2(85mg,纯度95%,产率41.1%),[M+H]
+:192.15。
步骤2:氮-(2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(41)的合成
氮气保护下,将41-2(85mg,444.50μmol),中间体A(115.74mg,444.50μmol),硫酸钠(85mg),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(50.45mg,1.33mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油41(55mg,产率28.4%,纯度95%),[M+H]
+:436.37。
1H NMR(400MHz,CD
3OD)δ8.55-8.49(m,1H),7.79-7.73(m,1H),7.50-7.45(m,1H),7.26-7.22(m,1H),7.18-7.13(m,1H),7.04-6.99(m,1H),6.82-6.75(m,1H),6.64-6.59(m,1H),4.30-4.23(m,1H),4.07-3.99(m,2H),3.80-3.71(m,2H),3.65-3.56(m,4H),3.36(d,J=10.6Hz,3H),2.53-2.40(m,3H),2.06-2.00(m,2H),1.91(d,J=13.7Hz,1H),1.78-1.49(m,8H),1.15-1.08(m,1H),0.78-0.71(m,1H)。
化合物41-P1的合成方法参考化合物41的合成路线,主要区别为将中间体A替换成中间 体A-1。
实施例32
氮-(3-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物42)的合成
步骤1:3-(3-甲氧基氮杂环丁烷-1-基)苯甲醛(42-2)的合成
将42-1(200mg,1.08mmol),41-1(154.78mg,1.08mmol),1,1'-联萘-2,2'-双二苯膦(67.3mg,108.1μmol),碳酸铯(1.06g,3.24mmol)和醋酸钯(24.27mg,108.1μmol)依次加入单口瓶中,加入甲苯(10mL)溶解并用氮气置换气体三次,加热到100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油42-2(60mg,产率29.0%),[M+H]
+:192.1。
步骤2:氮-(3-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(42)的合成
氮气保护下,将42-2(60mg,313.76μmol),中间体A(81.70mg,313.76μmol),硫酸钠(60mg),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(35.61mg,941.29μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油42(55mg,产率40.2%,纯度93%),[M+H]
+:436.38。
1H NMR(400MHz,CD
3OD)δ8.59-8.51(m,1H),7.82-7.74(m,1H),7.55-7.47(m,1H),7.29-7.22(m,1H),7.13(t,J=7.7Hz,1H),6.60(d,J=7.5Hz,1H),6.49-6.30(m,2H),4.40-4.32(m,1H),4.12-4.01(m,2H),3.82-3.70(m,2H),3.68-3.59(m,3H),3.35(d,J=8.2Hz,3H),2.66-2.57(m,1H),2.53-2.40(m,2H),2.16-2.03(m,2H),1.93-1.88(m,1H),1.82-1.43(m,8H),1.14-1.08(m,1H),0.77-0.69(m,1H)。
实施例33
氮-((2-(3,3-二氟氮杂环丁烷-1-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧 杂螺[4.5]癸烷-9-基)乙胺(化合物43)的合成
步骤1:2-(3-甲氧基氮杂环丁烷-1-基)烟醛(43-1)的合成
室温下,将33-1(150mg,0.81mmol),41-1(147.05mg,1.21mmol),DIEA(312.68mg,0.24mmol)溶于DMF(6mL),100℃反应16小时。反应完全后,加入H
2O(20mL),然后用乙酸乙酯(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体43-1(60mg,产率38.71%)。
步骤2:氮-((2-(3,3-二氟氮杂环丁烷-1-基)吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(43)的合成
氮气保护下,将43-1(55mg,0.29mmol),中间体A(50mg,0.19mmol),硫酸钠(109.10mg,0.77mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(15mg,0.38mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相制备分离(A:水;B:乙腈)纯化得到黄色油状液体43(15mg,产率17.9%),[M+H]
+:443.2。
1H NMR(400MHz,CDCl
3)δ8.59-8354(m,1H),8.14-8.13(m,1H),8.08-8.06(m,1H),7.62-7.58(m,1H),7.26-7.20(m,1H),7.18-7.12(m,1H),6.68-6.67(m,1H),6.60-6.58(m,1H),4.30-4.20(m,1H),4.18-4.14(m,2H),3.93-3.91(m,2H),3.75-3.68(m,4H),3.49(s,1H),3.32(s,3H),2.68-2.65(m,1H),2.41-2.32(m,1H),2.24-2.08(m,2H),2.04-1.81(m,3H),1.49-1.38(m,3H),1.18-1.10(m,2H),0.87-0.84(m,2H),0.69-0.67(m,1H)。
实施例34
氮-((5-(3-氟氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物45)的合成
步骤1:5-(3-氟氮杂环丁烷-1-基)噻吩-2-甲醛(45-3)的合成
室温下,将24-1(191mg,1mmol),45-2(167mg,1.5mmol),醋酸钯(22.45mg,0.1mmol),BINAP(62.26mg,0.1mmol),碳酸铯(815mg,2.5mmol),溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)纯化得到黄色液体45-3(100.9mg,产率54%),[M+H]
+:186.2。
步骤2:氮-((5-(3-氟氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(45)的合成
氮气保护下,将45-3(83.4mg,0.45mmol),中间体A(62.4mg,0.23mmol),硫酸镁(1g,8mmol),1,2-二氯乙烷(10mL)依次加入单口瓶中,65℃搅拌16h,加入硼氢化钠(35.2mg,0.93mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:水;B:乙腈)得到黄色油状液体45(20mg,产率17%)。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=5.2Hz,1H),7.62(dt,J1=2.0Hz,J2=8.0Hz,1H),7.29(d,J=8.0Hz,1H),7.11(dd,J1=5.2Hz,J2=6.8Hz,1H),6.43(d,J=3.6Hz,1H),5.69(d,J=3.6Hz,1H),5.44-5.39(m,0.5H),5.28-5.24(m,0.5H),4.15-4.07(m,2H),3.96-3.87(m,2H),3.77-3.74(m,2H),3.65(d,J=6.8Hz,2H),2.52-2.32(m,4H),2.13-2.06(m,1H),2.00-1.89(m,2H),1.75-1.62(m,4H),1.63-1.49(m,4H),1.13-1.08(m,1H),0.73-0.68(m,1H)。
实施例35
氮-((5-(2-氧-6-氮杂螺[3.3]庚烷-6-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物46)的合成
步骤1:5-(2-氧代-6-氮杂螺环[3.3]庚烷-6-基)噻吩-2-甲醛(46-3)的合成
室温下,将24-1(200mg,1mmol),46-2(149mg,1.5mmol),醋酸钯(22.45mg,0.1mmol),BINAP(62.26mg,0.1mmol),碳酸铯(815mg,2.5mmol),溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体46-3(80mg,产率37%),[M+H]
+:210.2。
步骤2:氮-((5-(2-氧-6-氮杂螺[3.3]庚烷-6-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(46)的合成
氮气保护下,将46-3(80mg,0.38mmol),中间体A(89mg,0.34mmol),硫酸镁(1g,8mmol)二氯甲烷(10mL)依次加入单口瓶中,40℃搅拌72h,加入硼氢化钠(43mg,1.14mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:水;B:乙腈)得到黄色油状液体46(10mg,产率6%)。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=4.8Hz,1H),7.62(dt,J1=2.0Hz,J2=7.6Hz,1H),7.29(d,J=8.0Hz 1H),7.11(dd,J1=4.8Hz,J2=6.4Hz,1H),6.41(d,J=3.6Hz,1H),5.65(d,J=3.6Hz,1H),4.79(s,4H),3.96(s,4H),3.75(dd,J1=3.2Hz,J2=7.6Hz,2H),3.63(d,J=4.0Hz,2H),2.54-2.32(m,4H),2.14-2.04(m,1H),1.99-1.89(m,2H),1.78-1.68(m,4H),1.54-1.31(m,4H),1.13-1.08(m,1H),0.73-0.66(m,1H)。
实施例36
氮-((5-(3-甲氧基氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物47)的合成
步骤1:5-(3-甲氧基氮杂环丁烷-1-基)噻吩-2-甲醛(47-1)的合成
室温下,将24-1(200mg,1mmol),41-1(186mg,1.5mmol),醋酸钯(22.45mg,0.1mmol),BINAP(62.26mg,0.1mmol),碳酸铯(815mg,2.5mmol),溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体47-1(80mg,产率40%),[M+H]
+:198.2。
步骤2:氮-((5-(3-甲氧基氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(47)的合成
氮气保护下,将47-1(80mg,0.40mmol),中间体A(89mg,0.34mmol),硫酸镁(1g,8mmol),二氯甲烷(10mL)依次加入单口瓶中,40℃搅拌72h,加入硼氢化钠(46mg,1.21mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:水;B:乙腈)得到黄色油状液体47(15mg,产率8%)。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=4.0Hz,1H),7.62(t,,J=7.6Hz,1H),7.29(d,J=8.0Hz 1H),7.11(m,1H),6.42(d,J=3.2Hz,1H),5.65(d,J=3.2Hz,1H),4.29-4.27(m,1H),4.03(t,,J=7.2Hz,1H),3.76-3.64(m,6H),3.31(s,3H),2.52-2.36(m,4H),2.14-2.08(m,1H),1.96-1.90(m,2H),1.74-1.63(m,4H),1.56-1.38(m,4H),1.13-1.08(m,1H),0.74-0.67(m,1H)。
实施例37
氮-((3-(3-氟氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物48)和(R)-氮-((3-(3-氟氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(48-P1)的合成
步骤1:3-(3-氟氮杂环丁烷-1-基)噻吩-2-甲醛(48-1)的合成
室温下,将6-1(191mg,1mmol),45-2(167mg,1.5mmol),醋酸钯(22.45mg,0.1mmol),BINAP(62.26mg,0.1mmol),碳酸铯(815mg,2.5mmol),溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体48-1(80mg,产率43%),[M+H]
+:186.2。
步骤2:氮-((3-(3-氟氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(48)的合成
氮气保护下,将48-1(80mg,0.43mmol),中间体A(89mg,0.34mmol),硫酸镁(1g,8mmol),二氯甲烷(10mL)依次加入单口瓶中,40℃搅拌72h,加入硼氢化钠(49mg,1.29mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:水;B:乙腈)得到黄色油状液体48(10mg,产率5%)。
1H NMR(400MHz,CDCl
3)δ8.57-8.56(m,1H),7.62(dt,J1=1.6Hz,J2=7.6Hz,1H),7.29(d,J=8.0Hz,1H),7.12-7.10(m,1H),7.00(d,J=5.6Hz,1H),6.48-6.47(m,1H),5.45(d,J=5.2Hz,1H),5.39-5.34(m,0.5H),5.24-5.19(m,0.5H),4.16-4.10(m,2H),3.95-3.86(m,2H),3.77-3.74(m,2H),3.59(d,J=1.6Hz,2H),2.52-2.32(m,4H),2.15-2.08(m,1H),2.00-1.90(m,2H),1.76-1.64(m,4H),1.50-1.37(m,3H),1.13-1.08(m,1H),0.74-0.66(m,1H)。
化合物48-P1的合成方法参考化合物48的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例38
3-甲基-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)噻吩-3-基)氮杂环丁烷-3-醇(化合物49)和(R)-3-甲基-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)噻吩-3-基)氮杂环丁烷-3-醇(化合物49-P1)的合成
步骤1:3-羟基-3-甲基氮杂环丁烷-1-羧酸叔丁酯(49-2)的合成
将49-1(1.71g,10mmol),溶于四氢呋喃(20mL),0℃下加入3M甲基溴化镁(10mL,30mmol),0℃反应2小时。反应完全后,加入饱和氯化铵溶液(50mL),然后用乙酸乙酯(40mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石
油醚:V
乙酸乙酯=1:1)得到无色透明液体49-2(1.5g,产率80%)。
步骤2:3-甲基氮杂环丁醇盐酸盐(49-3)的合成
将49-2(600g,3.2mmol),溶于4M的盐酸乙酸乙酯中(10mL),室温反应3小时。反应完全后,室温浓缩得到无色透明液体49-3(400mg,产率100%)。
步骤3:3-(3-羟基-3-甲基氮杂环丁烷-1-基)噻吩-2-甲醛(49-5)的合成
室温下,将34-1(185mg,1mmol),49-3(184mg,1.5mmol),醋酸钯(22.45mg,0.1mmol),BINAP(62.26mg,0.1mmol),碳酸铯(815mg,2.5mmol),溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到黄色固体49-5(100mg,产率52%),[M+H]
+:192.2。
步骤4:3-甲基-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)噻吩-3-基)氮杂环丁烷-3-醇(49)的合成
氮气保护下,将49-5(80mg,0.42mmol),中间体A(109mg,0.42mmol),硫酸镁(1g,8mmol),二氯甲烷(10mL)依次加入单口瓶中,40°搅拌72h,加入硼氢化钠(48mg,1.26mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:水;B:乙腈)得到黄色油状液体49(25mg,产率16%),[M+H]
+:436.2。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=4.8Hz,1H),7.61(dt,J1=2.0J=7.6Hz,1H),7.29(d,J=8.0Hz,1H),7.12-7.09(m,2H),7.01(dd,J1=1.6Hz,J2=7.6Hz,1H),6.75(dt,J1=0.8Hz,J2=7.2Hz,1H),6.47(d,J=8.0Hz,1H),3.79-3.71(m,6H),3.50(s,2H),2.49-2.43(m,2H),2.32(dd,J1=2.0Hz,J=12.8Hz,1H),2.13-1.97(m,2H),1.92(d,J=13.6Hz,1H),1.76-1.59(m,8H),1.49-1.41(m,4H),1.13-1.08(m,1H),0.72-0.65(m,1H)。
化合物49-P1的合成方法参考化合物49的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例39
3-甲基-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)噻吩-3-基)氮杂环丁烷-3-醇(化合物50)的合成
步骤1:3-(3-羟基-3-甲基氮杂环丁烷-1-基)噻吩-2-甲醛(50-1)的合成
室温下,将6-1(300mg,1.6mmol),49-3(290mg,2.4mmol),醋酸钯(Pd:10%,36mg,0.16mmol),BINAP(100mg,0.16mmol),碳酸铯(1.3g,4.0mmol),溶于甲苯(15mL),100℃反应16小时。反应完全后,加入水(30mL),然后用二氯甲烷(30mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到黄色固体50-1(100mg,产率32%),[M+H]
+:198.2。
步骤2:3-甲基-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺)甲基)噻吩-3-基)氮杂环丁烷-3-醇(50)的合成
氮气保护下,将50-1(100mg,0.51mmol),中间体A(133mg,0.51mmol),硫酸镁(1g,8mmol),1,2-二氯乙烷(10mL)依次加入单口瓶中,40℃搅拌72h,加入硼氢化钠(58mg,1.53mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:水;B:乙腈)得到黄色油状液体50(10mg,产率4.5%)。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=3.6Hz,1H),7.65-7.61(m,1H),7.30(d,J=8.0Hz 1H),7.11(dd,J1=4.8Hz,J2=7.6Hz,1H),6.99(d,J=5.6Hz,1H),6.43(d,J=5.2Hz,1H),3.83-3.69(m,6H),3.64-3.54(m,2H),2.56-2.53(m,1H),2.45-2.31(m,2H),2.17-2.13(m,1H),2.00-1.90(m 2H),1.80-1.74(m,4H),1.55(s,3H),1.54-1.38(m,4H),1.13-1.08(m,1H),0.74-0.66(m,1H)。
实施例40
氮-(2-氟-6-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物51)的合成
步骤1:2-氟-6-(3-甲氧基氮杂环丁烷-1-基)苯甲醛(51-2)的合成
室温下,将51-1(203mg,1.0mmol),41-1(185mg,1.5mmol),醋酸钯(22mg,0.1mmol),BINAP(62mg,0.1mmol),碳酸铯(813mg,2.5mmol),溶于甲苯(10mL), 100℃反应16小时。反应完全后,加入水(30mL),然后用二氯甲烷(30mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=5:1)得到黄色固体51-2(120mg,产率57%),[M+H]
+:210.2。
步骤2:氮-(2-氟-6-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(51)的合成
氮气保护下,将51-2(80mg,0.39mmol),中间体A(100mg,0.38mmol),硫酸镁(1g,8mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(44mg,1.15mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=15:1)得到黄色油状液体51(30mg,产率17%),[M+H]
+:454.2。
1H NMR(400MHz,CDCl
3)δ8.56-8.54(m,1H),7.62-7.58(m,1H),7.27(d,J=8.0Hz,1H),7.11-7.00(m,2H),6.46(t,J=8.8Hz,1H),6.23(d,J=8.0Hz,1H),4.26-4.20(m,1H),4.12-4.08(m,2H),3.76-3.72(m,4H),3.56(d,J=1.6Hz,2H),3.32(s,3H),2.47-2.40(m,2H),2.34-2.30(m,1H),2.07-1.89(m,3H),1.78-1.65(m,4H),1.52-1.37(m,4H),1.13-1.08(m,1H),0.74-0.66(m,1H)。
实施例41
氮-(3-氟-2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物52)的合成
步骤1:3-氟-2-(3-甲氧基氮杂环丁烷-1-基)苯甲醛(52-2)的合成
室温下,将52-1(203mg,1.0mmol),41-1(185mg,1.5mmol),醋酸钯(22mg,0.1mmol),BINAP(62mg,0.1mmol),碳酸铯(813mg,2.5mmol),溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(30mL),然后用二氯甲烷(30mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=5:1)得到黄色固体52-2(180mg,产率86%),[M+H]
+:210.2。
步骤2:氮-(3-氟-2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(52)的合成
氮气保护下,将52-2(80mg,0.39mmol),中间体A(100mg,0.38mmol),硫酸镁(1g,8mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(44mg,1.15mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=15:1)得到黄色油状液体52(20mg,产率12%),[M+H]
+:454.2。
1H NMR(400MHz,CDCl
3)δ8.56-8.55(m,1H),7.60(dt,J1=2.0Hz J2=7.6Hz 1H),7.27(d,J=8.0Hz,1H),7.11-7.08(m,1H),6.84-6.75(m,2H),6.64-6.59(m,1H),4.30-4.25(m,2H),4.18-4.13(m,1H),4.00-3.96(m,2H),3.77-3.74(m,2H),3.52(s,2H),3.48(s,1H),3.30(s,3H),2.47-2.32(m,3H),2.07-1.89(m,3H),1.79-1.68(m,4H),1.49-1.37(m,4H),1.13-1.08(m,1H),0.74-0.66(m,1H)。
实施例42
3-甲基-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)噻吩-3-基)氮杂环丁烷-3-醇(化合物53)的合成
步骤1:3-甲氧基-3-甲基氮杂环丁烷-1-羧酸叔丁酯(53-2)的合成
将49-2(900mg,4.8mmol),溶于四氢呋喃(15mL),0℃下加入60%NaH(385mg,9.6mmol),0℃反应半小时。加入碘甲烷(6.8g,48mmol)并室温反应3小时,反应完全后,加入冰水(100mL),然后用乙酸乙酯(50mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到无色透明液体53-2(950mg,产率98%)。
步骤2:3-甲氧基-3-甲基氮芥盐酸盐(53-3)的合成
将53-2(950mg,4.7mmol),溶于4M的盐酸乙酸乙酯中(15mL),室温反应2小时。反应完全后,室温浓缩得到无色透明液体53-3(600mg,产率93%)。
步骤3:2-(3-甲氧基-3-甲基氮杂环丁烷-1-基)苯甲醛(53-5)的合成
室温下,将34-1(185mg,1mmol),53-3(206mg,1.5mmol),醋酸钯(Pd:10%,22.45mg,0.1mmol),BINAP(62.26mg,0.1mmol),碳酸铯(815mg,2.5mmol),溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=5:1)得到黄色固体53-5(150mg,产率73%),[M+H]
+:206.2。
步骤4:3-甲基-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺)甲基)噻吩-3-基)氮杂环丁烷-3-醇(53)的合成
氮气保护下,将53-5(80mg,0.39mmol),中间体A(101mg,0.39mmol),硫酸镁(1g,8mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(44mg,1.17mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=15:1)得到黄色油状液体53(30mg,产率17%),[M+H]
+:450.2。
1H NMR(400MHz,CDCl
3)δ8.54(dd,J1=0.8Hz,J2=7.2Hz,1H),7.60(dt,J1=2.0J=8.0Hz,1H),7.27(d,J=8.4Hz 1H),7.15-7.08(m,2H),7.03(d,J=7.2Hz,1H),6.76(t,J=7.2Hz,1H),6.52(d,J=8.0Hz,1H),3.80-3.73(m,4H),3.66(d,J=7.6Hz,2H),3.61-3.53(m,2H),3.25(s,3H),2.53-2.46(m,1H),2.42-2.38(m,1H),2.32(dd,J1=1.6Hz,J=13.6Hz,1H),2.14-2.07(m,1H),2.03-1.97(m,1H),1.90(d,J=14Hz1H),1.81-1.60(m,4H),1.54(s,3H),1.53-1.37(m,4H),1.13-1.08(m,1H),0.74-0.66(m,1H)。
实施例43
氮-((3-(3-甲氧基-3-甲基氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物54)的合成
步骤1:3-(3-甲氧基-3-甲基氮杂环丁烷-1-基)噻吩-2-甲醛(54-1)的合成
室温下,将6-1(250mg,1.3mmol),53-3(269mg,2.0mmol),醋酸钯(Pd:10%,29mg,0.13mmol),BINAP(81mg,0.13mmol),碳酸铯(1056mg,3.3mmol),溶于甲苯(15mL),100℃反应16小时。反应完全后,加入水(30mL),然后用二氯甲烷(30mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到黄色固体54-1(180mg,产率66%),[M+H]
+:212.2。
步骤2:氮-((3-(3-甲氧基-3-甲基氮杂环丁烷-1-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(54)的合成
氮气保护下,将54-1(100mg,0.47mmol),中间体A(104mg,0.40mmol),硫酸镁(1g,8mmol),1,2-二氯乙烷(10mL)依次加入单口瓶中,65℃搅拌16h,加入硼氢化钠(54mg,1.41mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体54(20mg,产率9%)。
1H NMR(400MHz,CDCl
3)δ8.55(dd,J1=1.2Hz,J2=8.8Hz,1H),7.61(dt,J1=2.0Hz,J2=8.0Hz,1H),7.29(d,J=8.0Hz 1H),7.12-7.09(m,1H),6.99(d,J=5.2Hz,1H),6.45(d,J=5.2Hz,1H),3.80-3.73(m,4H),3.70-3.65(m,4H),3.24(s,3H),2.58-2.51(m,1H),2.44-2.41(m,1H),2.34-2.31(m,1H),2.19-2.19(m,1H),2.01-1.92(m1H),1.91(d,J=13.6Hz,1H),1.72-1.64(m,4H),1.52(s,3H),1.52-1.36(m,4H),1.13-1.08(m,1H),0.74-0.66(m,1H)。
实施例44
氮-(2,6-二(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物55)的合成
步骤1:2,6-双(3-甲氧基氮杂环丁烷-1-基)苯甲醛(55-1)的合成
室温下,将51-1(203mg,1.0mmol),41-1(185mg,1.5mmol),醋酸钯(22mg,0.1mmol),BINAP(62mg,0.1mmol),碳酸铯(813mg,2.5mmol),溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(30mL),然后用二氯甲烷(30mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=5:1)得到黄色固体55-1(60mg,产率22%),[M+H]
+:277.2。
步骤2:氮-(2,6-二(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(55)的合成
氮气保护下,将55-1(60mg,0.22mmol),中间体A(57mg,0.22mmol),硫酸镁(1g,8mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(25mg,0.65mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体55(7mg,产率6%),[M+H]
+:521.2。
1H NMR(400MHz,CDCl
3)δ8.43(d,J=3.6Hz 1H),7.60(dt,J1=1.6Hz,J2=7.6Hz,1H),7.20(d,J=8.0Hz 1H),7.16(t,J=8.0Hz,1H),7.11-7.08(m,1H),6.34(d,J=8.4Hz,2H),4.28-4.23(m,2H),4.06-4.03(m,6H),3.66-3.63(m,6H),3.31(s,6H),2.48-2.43(m,1H),2.21-2.08(m,3H),2.06-1.98(m,2H),1.87-1.71(m,4H),1.47-1.35(m,4H),1.13-1.08(m,1H),0.68-0.60(m,1H)。
实施例45
氮-((5-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物56)的合成
步骤1:5-(1,4-二氧-8-氮螺环[4.5]癸烷-8-基)噻吩-2-甲醛(56-1)的合成
室温下,将24-1(192mg,1mmol),14-1(143mg,1mmol),醋酸钯(23mg,0.1mmol),BINAP(63mg,0.1mmol),碳酸铯(813.5mg,2.5mmol)溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体56-1(79.5mg,产率32%),[M+H]
+:254.2。
步骤2:氮-((5-(1,4-二氧-8-氮螺环[4.5]癸烷-8-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(56)的合成
氮气保护下,将56-1(79.5mg,0.32mmol),中间体A(70mg,0.27mmol),硫酸镁(768mg,6.4mol),1,2-二氯乙烷(10mL)依次加入单口瓶中,65℃搅拌16h,加入硼氢化钠(45mg,1.2mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:H
2O;B:MeCN)得到黄色油状液体56(5mg,产率4%)。
1H NMR(400MHz,CDCl
3)δ8.55(d,J=4.8Hz,1H),7.63(dt,J1=2.0Hz,J2=7.6Hz,1H),7.29(d,J=8.4Hz 1H),7.12(dd,J1=4.0Hz,J2=6.4Hz,1H),6.47(d,J=3.6Hz,1H),5.87(d,J=4.0Hz,1H),3.97(s,3H),3.76-3.68(m,4H),3.22(t,J=6.0Hz,4H),2.55-2.31(m,6H),2.20-2.13(m,1H),2.01-1.89(m,3H),1.84-1.80(m,4H),1.58-1.36(m,4H),1.13-1.08(m,1H),0.73-0.66(m,1H)。
实施例46
氮-((3-(5,8-二氧-2-氮杂螺[3.4]辛烷-2-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物57)的合成
步骤1:3-(5,8-二氧-2-氮杂螺[3.4]辛烷-2-基)噻吩-2-甲醛(57-3)的合成
室温下,将6-1(0.2g,1.05mmol),57-2(238.05mg,1.57mmol),DIEA(361.87mg,3.14mmol),水(5mL)加入到25mL的单口瓶,100℃反应12小时。反应完全后,加入水(10mL),然后用二氯甲烷(10mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到黄色液体57-3(150mg,产率42.4%),[M+H]
+:226.1。
步骤2:氮-((3-(5,8-二氧-2-氮杂螺[3.4]辛烷-2-基)噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(57)的合成
氮气保护下,将中间体A(50mg,192.03μmol),57-3(51.91mg,230.43μmol),硫酸钠(109.10mg,766.11μmol),二氯甲烷(5mL)依次加入单口瓶中,室温下搅拌12h,加入硼氢化钠(14.53mg,384.05μmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:H
2O;B:MeCN)得到黄色油状液体57(19mg,产率19.19%),[M+H]
+:470.2。
1H NMR(400MHz,CDCl
3)δ8.55(d,J=5.2Hz,1H),7.70-7.65(m,1H),7.55-7.54(m,1H),7.34-7.12(m,2H),6.53(d,J=5.6Hz,1H),4.11-4.07(m,2H),4.03-3.98(m,4H),3.86-3.75(m,2H),3.39-3.36(m,1H),2.81-2.75(m,1H),2.39-2.35(m,1H),2.23-2.20(m,1H),2.09-2.08(m,1H),2.06-1.96(m,1H),1.87-1.76(m,7H),1.73-1.71(m,2H),1.49-1.43(m,2H),1.24-1.11(m,2H),0.69-0.67(m,1H)。
实施例47
氮-(2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物58)和(R)-氮-(2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物58-P1)的合成
步骤1:2-(3-氟氮杂环丁烷-1-基)苯甲醛(58-1)的合成
室温下,将34-1(400mg,2.16mmol),45-2(289.38mg,2.59mmol),醋酸钯(197.98mg,216.19mmol),BINAP(269.24mg,0.43mmol),碳酸铯(2.11g,6.49mmol)溶于甲苯(10mL),100℃反应12小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体58-1(150mg,产率38.2%)。
步骤2:氮-(2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(58)的合成
氮气保护下,将中间体A(50mg,0.19mmol),58-1(41.29mg,0.23mmol),硫酸钠(81.82mg,0.57mmol),二氯甲烷(5mL)依次加入单口瓶中,室温下搅拌12h,加入硼氢化钠(14.53mg,0.38mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,滤液旋干,室温浓缩过反相(A:H
2O;B:MeCN)得到黄色油状液体58(8mg,产率6.7%),[M+H]
+:424.2。
1H NMR(400MHz,CDCl
3)δ8.53(d,J=5.2Hz,1H),7.66-7.62(m,1H),7.31-7.29(m,1H),7.29-7.28(m,1H),7.23-7.21(m,2H),6.85(t,J=8.0Hz,1H),6.59(d,J=8.0Hz,1H),5.31-5.25(m,1H),4.19-4.16(m,2H),3.97-3.89(m,2H),3.77-3.62(m,4H),2.59-2.58(m,1H),2.41-2.21(m,3H),2.19-2.15(m,3H),2.09-1.91(m,2H),1.88-1.82(m,1H),1.77-1.66(m,4H),1.49-1.43(m,1H),1.24-1.11(m,1H),0.69-0.67(m,1H)。
化合物58-P1的合成方法参考化合物58的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例48
氮-((3-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)苯并[b]噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙-1-胺(化合物59)的合成
步骤1:3-溴苯并[b]噻吩-2-甲醛(59-2)的合成
25mL单口瓶中加入双三甲基硅基胺基锂(471mg,2.82mmol),冰浴条件下缓慢加入化合物59-1(300mg,1.41mmol),反应30min后加入氮,氮-二甲基甲酰胺(196mg,2.67mmol),继续在冰浴条件下反应3.5h。反应完成后,滴加饱和NH
4Cl水溶液5mL淬灭反应,加入正己烷30mL萃取,有机相用饱和食盐水洗涤,无水硫酸镁干燥,过滤,旋干,得到棕黄色固体59-2(312mg,产率91.9%)。
1H NMR(400MHz,CDCl
3)δ10.29(s,1H),8.03(d,J=7.2Hz,1H),7.88(d,J=7.6Hz,1H),7.59–7.51(m,2H)。
步骤2:3-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)苯并[b]噻吩-2-甲醛(59-4)的合成
在25mL单口瓶中加入59-2(100mg,0.42mmol),14-1(90mg,0.63mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(24mg,42μmol),碳酸铯(270mg,0.83mmol)和醋酸钯(Pd:10%,10mg,42μmol),加入甲苯(5mL)溶解并用氮气置换气体三次,100℃加热搅拌反应12h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙
酸乙酯=10:1到1:1)纯化得到红棕色固体59-4(61mg,产率48.41%),[M+H]
+:304.15。
步骤3:氮-((3-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)苯并[b]噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙-1-胺(59)的合成
氮气保护下,将59-4(58mg,0.19mmol),中间体A(45mg,0.17mmol),硫酸钠(50mg,0.35mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(20 mg,0.52mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应16小时。反应完后,加入水(10mL),二氯甲烷20mL萃取两次,有机相饱和食盐水洗涤,无水硫酸镁干燥,过滤旋干,粗品用反相中压制备得到淡黄色稠状油59(17mg,产率16.34%,纯度95%),[M+H]
+:548.32。
1H NMR(400MHz,CDCl
3)δ8.50(d,J=3.8Hz,1H),7.77(d,J=7.4Hz,1H),7.70(d,J=6.8Hz,1H),7.58–7.53(m,1H),7.32–7.27(m,2H),7.23(d,J=5.0Hz,1H),7.05(dd,J=7.0,5.0Hz,1H),4.02(s,4H),3.96(s,2H),3.77–3.71(m,2H),3.22(s,4H),2.55(dd,J=11.2,5.4Hz,1H),2.41(d,J=13.6Hz,1H),2.35–2.31(m,1H),2.21–2.13(m,1H),2.03(d,J=14.8Hz,2H),1.91(d,J=13.4Hz,2H),1.83(t,J=5.4Hz,4H),1.78(dd,J=5.6,2.8Hz,2H),1.74(d,J=7.2Hz,2H),1.72–1.70(m,2H),0.88–0.86(m,2H)。
实施例49
2-(3-甲氧基氮杂环丁烷-1-基)-3-(((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)苄腈(化合物60)的合成
步骤1:3-甲酰基-2-(3-甲氧基氮杂环丁烷-1-基)苯腈(60-3)的合成
在25mL单口瓶中加入60-1(100mg,0.48mmol),41-1(118mg,0.96mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(28mg,48μmol),碳酸铯(465mg,1.44mmol)和醋酸钯(11mg,48μmol),加入甲苯(5mL)溶解并用氮气置换气体三次,100℃加热搅拌反应12h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到4:1)纯化得到红棕色固体60-3(63mg,产率61.16%),[M+H]
+:217.19。
步骤2:2-(3-甲氧基氮杂环丁烷-1-基)-3-(((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)氨基)甲基)苄腈(60)的合成
氮气保护下,将60-3(63mg,0.25mmol),中间体A(60mg,0.23mmol),硫酸钠(100mg,0.70mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(26 mg,0.69mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(10mL),二氯甲烷萃取(20mL×2),有机相饱和食盐水洗涤,无水硫酸镁干燥,过滤旋干,粗品用反相中压制备得到淡黄色稠状油60(25mg,产率21.45%,纯度95%),[M+H]
+:461.35。
1H NMR(400MHz,CDCl
3)δ8.56–8.51(m,1H),7.66–7.58(m,1H),7.31(dd,J=7.8,1.6Hz,1H),7.27(s,1H),7.16–7.10(m,2H),6.63(t,J=7.6Hz,1H),4.59–4.52(m,2H),4.22–4.15(m,3H),3.78–3.71(m,2H),3.57(s,2H),3.32(s,3H),2.83(s,2H),2.50–2.43(m,1H),2.40–2.29(m,2H),2.08–1.96(m,2H),1.88(d,J=13.6Hz,1H),1.81–1.73(m,2H),1.72–1.63(m,2H),0.87(d,J=7.2Hz,2H)。
实施例50
氮-((2-(1,4-二氧杂-8-氮杂螺环[4.5]癸烷-8-基)噻吩-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物61)的合成
步骤1:2-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)噻吩-3-甲醛(61-2)的合成
室温下,将61-1(100mg,0.523mmol)用甲苯(10mL)溶解,然后依次加入BINAP(70mg,0.112mmol)和14-1(98mg,0.685mmol)和碳酸铯(512mg,1.571mmol),最后加入醋酸钯(12mg,0.053mmol)反应在氮气保护下室温过夜。反应16h后,将甲苯旋干。加入20mL水,加入乙酸乙酯(20mL×2)进行萃取然后用饱和碳酸钠溶液洗涤(10mL×2),有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色油状液体61-2(62mg,产率46.0%)。
步骤2:氮-((2-(1,4-二氧-8-氮杂螺[4.5]癸烷-8-基)噻吩-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(61)的合成
室温下,将61-2(50mg,0.197mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(67mg,0.256mmol)和硫酸钠(140mg,0.984mmol),反应在氮气保护下室温过夜。反应16h后,加入硼氢化钠(15mg,0.393mmol)反应半小时,再加入无水甲醇(2.5 mL)再搅拌半小时。反应完全后,加入15mL水进行淬灭处理,加入乙酸乙酯(20mL×2)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色稠状固体61(28mg,产率28.6%,纯度96.00%),[M+H]
+:498.69。
1H NMR(400MHz,CDCl
3)δ8.46(d,J=4.8Hz,1H),7.71(s,1H),7.36(d,J=7.7Hz,1H),7.19(s,1H),7.16(d,J=5.8Hz,1H),7.03–6.97(m,1H),4.02(s,4H),3.79–3.68(m,2H),3.51(s,1H),2.96(s,4H),2.48–2.21(m,4H),1.90–1.79(m,4H),1.50(s,4H),1.28(s,4H),1.11(s,2H),0.92–0.84(m,2H),0.67(d,J=9.7Hz,1H)。
实施例51
氮-(4-甲氧基-2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物62)的合成
步骤1:4-甲氧基-2-(3-甲氧基氮杂环丁烷-1-基)苯甲醛(62-3)的合成
室温下,将62-1(100mg,0.465mmol)用甲苯(10mL)溶解,然后依次加入BINAP(58mg,0.093mmol)和41-1(69mg,0.558mmol)和碳酸铯(455mg,1.396mmol),最后加入醋酸钯(11mg,0.049mmol),反应在氮气保护下室温过夜。反应16h后,将甲苯旋干。加入20mL水,加入乙酸乙酯(20mL×2)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色油状液体62-3(50mg,产率48.60%)。
步骤2:氮-(4-甲氧基-2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(62)的合成
室温下,将62-3(50mg,0.486mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(46mg,0.177mmol)和硫酸钠(124mg,0.873mmol)反应在氮气保护下室温过 夜。反应16h后,加入硼氢化钠(14mg,0.370mmol)反应半小时,再加入无水甲醇(2.5mL)再搅拌半小时。反应完全后,加入15mL水进行淬灭处理,加入乙酸乙酯(20mL×2)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色稠状固体62(28mg,产率26.61%,纯度97.00%),[M+H]
+:466.6。
1H NMR(400MHz,CDCl
3)δ8.58(s,1H),7.69(d,J=7.7Hz,1H),7.19(d,J=7.8Hz,2H),7.11(s,1H),6.95(d,J=8.4Hz,1H),6.69(s,1H),4.01(s,3H),3.86(s,2H),3.74(s,3H),3.40(s,3H),3.01(s,2H),2.79(s,2H),2.36(d,J=9.9Hz,3H),1.90–1.79(m,4H),1.66(s,4H),1.50(s,4H),1.24-1.11(m,1H),0.69-0.67(m,1H)。
实施例52
氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物63)和(R)-氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物63-P1)的合成
步骤1:2-(3-氧-8-氮杂双环[3.2.1]辛烷-8-基)苯甲醛(63-1)的合成
室温下,将34-1(200mg,1.1mmol),21-1(243mg,1.6mmol),Pd
2(dba)
3(50mg,0.05mmol),BINAP(67mg,0.1mmol),碳酸铯(881mg,2.7mmol),溶于甲苯(6mL),氮气保护,100℃反应16小时。反应完全后,反应液用滤膜过滤,旋干拌样,用柱层析纯化(V
石油醚:V
乙酸乙酯=15:1)得到黄色油状物63-1(159mg,产率67%),[M+H]
+:218.2。
步骤2:氮-(2-(3-氧-8-氮杂双环[3.2.1]辛烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(63)的合成
氮气保护下,将63-1(142mg,0.65mmol),中间体A(170mg,0.65mmol),硫酸钠(923mg,6.49mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(53mg,1.31mmol),搅拌10分钟,加入甲醇(3mL),搅拌反应2小时。反应完后,向反应体系中加入30mL水,用二氯甲烷萃取(40mL×3),合并有机液,用饱和食盐水洗涤,再用无水硫酸钠干燥,过滤,滤液旋干,通过制备硅胶板分离纯化,得黄色油状物63(96mg,产率32%)。
1H NMR(400MHz,CDCl
3)δ8.56-8.54(m,1H),7.64-7.59(m,1H),7.29-7.27(m,1H),7.16-7.09(m,3H),6.94-6.90(m,1H),6.81-6.79(m,1H),3.80-3.73(m,6H),3.66-3.53(m,4H),2.57-2.50(m,1H),2.42-2.38(m,1H),2.35-2.31(m,1H),2.14-1.97(m,7H),1.82-1.38(m,11H)。
化合物63-P1的合成方法参考化合物63的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例53
氮(2-(2-氧-6-氮杂螺[3.3]庚烷-6-基)苯基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物64)和(R)氮(2-(2-氧-6-氮杂螺[3.3]庚烷-6-基)苯基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物64-P1)的合成
步骤1:2-(2-氧-6-氮杂螺[3.3]庚烷-6-基)苯甲醛(64-1)的合成
将34-1(200mg,1.08mmol),46-2(107.16mg,1.08mmol),1,1'-联萘-2,2'-双二苯膦(67.3mg,108.1μmol),碳酸铯(1.06g,3.24mmol)和醋酸钯(24.27mg,108.1μmol)依次加入单口瓶中,加入甲苯(10mL)溶解并用氮气置换气体三次,加热到100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油64-1(120mg,产率54.6%),[M+H]
+:204.15。
步骤2:氮(2-(2-氧-6-氮杂螺[3.3]庚烷-6-基)苯基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(64)的合成
氮气保护下,将64-1(120mg,590.44μmol),中间体A(153.74mg,590.44μmol),硫酸钠(120mg,0.845mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(35.61mg,941.29μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应16小时。反应完后,加入水(5mL),过滤旋干,滤液旋干,粗品用反相中压制备得到淡黄色稠状油64(20mg,产率7.56%,纯度95%),[M+H]
+:448.34。
1H NMR(400MHz,CDCl
3)δ8.63-8.56(m,1H),7.68-7.61(m,1H),7.33-7.29(m,1H),7.17–7.09(m,2H),7.07-6.99(m,1H),6.81-6.73(m,1H),6.50-6.41(m,1H),4.82(s,4H),4.00(s,4H),3.81-3.74(m,2H),3.56-3.46(m,2H),2.55–2.41(m,2H),2.39-2.34(m,1H),2.13-1.98(m,2H),1.97-1.92(m,1H),1.81-1.59(m,6H),1.47–1.37(m,2H),1.19-1.11(m,1H),0.78-0.68(m,1H)。
化合物64-P1的合成方法参考化合物64的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例54
氮-(2-(1,4-二氧杂螺[4.5]癸烷-8-基)苯基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物65)的合成
步骤1:2-(1,4-二氧杂螺[4.5]癸烷-8-基)苯甲醇(65-2)的合成
将38-1(200mg,818.71μmol)和50%湿钯碳(163.7mg,818.71μmol)溶解于乙酸 乙酯(5mL)中,氢气置换3次,反应液在氢气(15Psi)下25℃反应16小时。反应完后,用硅藻土过滤,滤液集中旋干得到粗产品淡黄色油65-2(0.2g,收率98.3%),[M-OH+H]
+:231.18。
步骤2:2-(1,4-二氧杂螺[4.5]癸烷-8-基)苯甲醛(65-3)的合成
向溶解有65-2(200mg,805.42μmol)的二氯甲烷(20mL)中加入二氧化锰(700.21mg,805.42μmol),搅拌反应3小时。反应完后,用硅藻土过滤,滤液集中旋干得到粗产品无色油65-3(140mg,70.6%),产品未进一步纯化直接用于下一步反应。
步骤3:氮-(2-(1,4-二氧杂螺[4.5]癸烷-8-基)苯基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(65)的合成
氮气保护下,将65-3(140mg,568.41μmol),中间体A(148mg,568.41μmol),硫酸钠(140mg,0.985mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(64.51mg,1.71mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油65(50mg,产率17.9%,纯度95%),[M+H]
+:491.33。
1H NMR(400MHz,CDCl
3)δ8.59-8.54(m,1H),7.65(td,J=7.7,1.9Hz,1H),7.34-7.29(m,2H),7.24-7.20(m,1H),7.18-7.15(m,1H),7.15-7.09(m,2H),4.06-3.96(m,4H),3.80-3.74(m,2H),3.68(s,2H),2.80-2.71(m,1H),2.62-2.53(m,1H),2.49-2.42(m,1H),2.39-2.34(m,1H),2.23-2.15(m,1H),1.97-1.90(m,2H),1.85-1.67(m,13H),1.55-1.46(m,3H),1.18-1.12(m,1H),0.76-0.68(m,1H)。
实施例55
氮-(3-甲氧基-2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物66)的合成
步骤1:3-甲氧基-2-(3-甲氧基氮杂环丁烷-1-基)苯甲醛(66-2)的合成
将66-1(200mg,930.04μmol),41-1(114.94mg,930.04μmol),1,1'-联萘-2,2'- 双二苯膦(57.9mg,93.0μmol),碳酸铯(909.08mg,2.79mmol)和醋酸钯(Pd:10%,20.88mg,93.0μmol)依次加入单口瓶中,加入甲苯(15mL)溶解并用氮气置换气体三次,加热到100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正
己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油66-2(60mg,产率29.1%),[M+H]
+:222.13。
步骤2:氮-(3-甲氧基-2-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(66)的合成
氮气保护下,将66-2(60mg,271.18μmol),中间体A(70.61mg,271.18μmol),硫酸钠(60mg,0.422mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(30.78mg,813.55μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油66(30mg,产率23.8%,纯度95%),[M+H]
+:466.35。
1H NMR(400MHz,CDCl
3)δ8.58-8.50(m,1H),7.66-7.60(td,J=7.7,1.9Hz,1H),7.32-7.29(m,1H),7.15-7.09(m,1H),6.92-6.86(m,1H),6.83-6.78(m,1H),6.70-6.63(m,1H),4.24-4.10(m,3H),4.04-3.96(m,2H),3.83(s,3H),3.78-3.69(m,4H),3.33(s,3H),2.59-2.55(m,1H),2.40-2.32(m,2H),2.18-2.06(m,2H),1.95-1.61(m,6H),1.56-1.46(m,3H),1.17-1.10(m,1H),0.75-0.67(m,1H)。
实施例56
氮-(2-甲氧基-6-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物67)的合成
步骤1:2-甲氧基-6-(3-甲氧基氮杂环丁烷-1-基)苯甲醛(67-2)的合成
将67-1(200mg,930.04μmol),41-1(114.94mg,930.04μmol),1,1'-联萘-2,2'-双二苯膦(57.9mg,93.0μmol),碳酸铯(909.08mg,2.79mmol)和醋酸钯(Pd:10%,20.88mg,93.0μmol)依次加入单口瓶中,加入甲苯(15mL)溶解并用氮气置换气体三次,加热到100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正
己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油67-2(60mg,产率58.3%),[M+H]
+:222.09。
步骤2:氮-(2-甲氧基-6-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(67)的合成
氮气保护下,将67-2(120mg,542.37μmol),中间体A(141.22mg,542.37μmol),硫酸钠(120mg,0.849mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(61.56mg,1.63mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油67(30mg,产率11.9%,纯度95%),[M+H]
+:466.35。
1H NMR(400MHz,CDCl
3)δ8.56-8.50(m,1H),7.67-7.59(m,1H),7.31-7.28(m,1H),7.17-7.07(m,2H),6.42(d,J=8.2Hz,1H),6.24(d,J=8.2Hz,1H),4.27-4.21(m,1H),4.15-4.08(m,2H),3.79-3.69(m,9H),3.33(s,3H),2.54-2.51(m,1H),2.41-2.37(m,1H),2.31-2.27(m,1H),2.18-2.11(m,1H),2.05-1.98(m,1H),1.92-1.60(m,6H),1.54-1.45(m,3H),1.17-1.10(m,1H),0.75-0.66(m,1H)。
实施例57
氮-(2-甲氧基-5-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物68)的合成
步骤1:2-甲氧基-5-(3-甲氧基氮杂环丁烷-1-基)苯甲醛(68-2)的合成
将68-1(200mg,930.04μmol),41-1(114.94mg,930.04μmol),1,1'-联萘-2,2'-双二苯膦(57.9mg,93.0μmol),碳酸铯(909.08mg,2.79mmol)和醋酸钯(20.88mg,93.0μmol)依次加入单口瓶中,加入甲苯(15mL)溶解并用氮气置换三次,加热到100℃搅拌6h,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油68-2(60mg,产率29.2%),[M+H]
+:222.1。
步骤2:氮-(2-甲氧基-5-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂 螺[4.5]癸烷-9-基)乙胺(68)的合成
氮气保护下,将68-2(60mg,271.18μmol),中间体A(70.61mg,271.18μmol),硫酸钠(60mg,0.422mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(30.78mg,813.55μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油68(20mg,产率15.8%,纯度95%),[M+H]
+:466.32。
1H NMR(400MHz,CD
3OD)δ8.57-8.48(m,1H),7.77(td,J=7.8,1.9Hz,1H),7.48(dt,J=8.1,1.0Hz,1H),7.27-7.20(m,1H),6.84-6.78(m,1H),6.77-6.67(m,2H),4.28-4.19(m,1H),4.01-3.91(m,2H),3.81-3.71(m,5H),3.68(s,2H),3.59-3.50(m,2H),3.35(s,3H),2.65-2.56(m,1H),2.51-2.39(m,2H),2.16-2.02(m,2H),1.91(d,J=13.7Hz,1H),1.81-1.43(m,8H),1.16-1.09(m,1H),0.77-0.69(m,1H)。
实施例58
氮-(3-(1,4-二氧杂-8-氮杂螺环[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物69)的合成
步骤1:3-(1,4-二氧杂-8-氮杂螺环[4.5]癸-8-基)苯甲醛(69-2)的合成
室温下,将69-1(185mg,1mmol),14-1(215mg,1.5mmol),醋酸钯(23mg,0.1mmol),BINAP(63mg,0.1mmol),碳酸铯(813.5mg,2.5mmol)溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=5:1)得到黄色液体69-2(150mg,产率61%),[M+H]
+:248.2。
步骤2:氮-(3-(1,4-二氧杂-8-氮杂螺环[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(69)的合成
氮气保护下,将69-2(80mg,0.32mmol),中间体A(84mg,0.32mmol),硫酸镁(768mg,6.4mol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(45 mg,1.2mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,滤液旋干,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到黄色稠状物69(40mg,产率25%),[M+H]
+:492.2。
1H NMR(400MHz,CDCl
3)δ8.53(dd,J1=0.8Hz,J2=4.8Hz,1H),7.61(dt,J1=1.6Hz,J2=7.6Hz,1H),7.27(d,J=8.0Hz 1H),7.15-7.08(m,2H),6.83-6.78(m,2H),6.64(d,J=7.6Hz,1H),3.98(s,4H),3.75-3.73(m,2H),3.58(s,2H),3.31-3.27(m,4H),2.57-2.50(m,1H),2.42-2.39(m,1H),2.2.35-2.31(m,1H),2.19-2.10(m,2H),1.92-1.89(m,1H),1.83-1.61(m,8H),1.54-1.37(m,4H),1.13-1.09(m,1H),0.72-0.64(m,1H)。
实施例59
氮-(3-(1,4-二氧杂-8-氮杂螺环[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物71)的合成
步骤1:2-(5,8-二氧杂-2-氮杂螺环[3.4]辛烷-2-基)苯甲醛(71-2)的合成
室温下,将71-1(100mg,0.54mmol),57-2(68.45mg,0.54mmol),碳酸钾(144.39mg,1.08mmol)溶于N,N-二甲基甲酰胺(6mL),120℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体71-2(50mg,产率28.3%),[M+H]
+:220.1。
步骤2:氮-(3-(1,4-二氧杂-8-氮杂螺环[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(71)的合成
氮气保护下,将71-2(50mg,0.19mmol),中间体A(50.5mg,0.23mmol),硫酸钠(109mg,0.76mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(14mg,0.76mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后, 加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物71(20mg,产率18.92%),[M+H]
+:464.2。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=5.2Hz,1H),7.64-7.62(m,1H),7.15-7.02(m,4H),6.81(t,J=7.6Hz,1H),6.56(d,J=8Hz,1H),4.02-4.00(m,6H),3.78-3.75(m,2H),3.61-3.60(m,2H),2.53-2.30(m,4H),2.14-1.80(m,6H),1.66-1.51(m,3H),1.50-1.40(m,2H),1.21-1.17(m,2H),0.75-0.67(m,1H)。
实施例60
氮-(2-(1,4-二硫代-8-氮杂螺环[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物72)的合成
步骤1:2-(1,4-二硫代-8-氮杂螺环[4.5]癸-8-基)苯甲醛(72-3)的合成
室温下,将71-1(100mg,0.80mmol),72-2(155.45mg,0.88mmol),碳酸钾(227mg,1.61mmol)溶于N,N-二甲基甲酰胺(6mL),120℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体72-3(80mg,产率35.54%),[M+H]
+:280.1。
步骤2:氮-(2-(1,4-二硫代-8-氮杂螺环[4.5]癸烷-8-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(72)的合成
氮气保护下,将72-3(50mg,0.19mmol),中间体A(64.39mg,0.23mmol),硫酸钠(109mg,0.76mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(14mg,0.76mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物72(20mg,产率21.43%),[M+H]
+:524.8。
1H NMR(400MHz,CDCl
3)δ8.53-8.51(m,1H),7.67-7.62(m,1H),7.31-7.30 (m,1H),7.29-7.28(m,1H),7.25-7.20(m,4H),3.83(s,2H),3.77-3.75(m,2H),3.36(s,4H),2.96-2.93(m,4H),2.63-2.61(m,1H),2.37-2.35(m,3H),2.23-2.11(m,5H),1.93-1.90(m,2H),1.87-1.55(m,6H),1.21-1.17(m,1H),0.75-0.67(m,1H)。
实施例61
1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)氨基)甲基)苯基)氮杂环丁-3-醇(化合物77)和(R)-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)氨基)甲基)苯基)氮杂环丁-3-醇(化合物77-P1)的合成
步骤1:2-(3-羟基氮杂环丁烷-1-基)苯甲醛(77)的合成
室温下,将71-1(185mg,1.5mmol),77-2(219mg,3.0mmol),碳酸钾(621mg,4.5mmol)溶于二甲基亚砜(6mL),120℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体77-3(20mg,产率7.5%),[M+H]
+:178.2。
步骤2:1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)氨基)甲基)苯基)氮杂环丁-3-醇(77)的合成
氮气保护下,将77-3(20mg,0.11mmol),中间体A(29mg,0.11mmol),硫酸镁(271mg,2.3mol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(13mg, 0.34mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物77(22mg,产率46%),[M+H]
+:422.2。
1H NMR(400MHz,CDCl
3)δ8.51(dd,J1=0.8Hz,J2=4.8Hz,1H),7.62(dt,J1=2.0Hz,J2=8.0Hz,1H),7.28-7.21(m,2H),7.14-7.11(m,1H),6.95(dd,J1=1.6Hz,J2=7.6Hz,1H),6.79(t,J=7.6Hz,1H),6.62(d,J=8.0Hz,1H),4.55-4.53(m,1H),4.10-4.04(m,2H),3.90-3.71(m,6H),2.69-2.61(m,1H),2.34-2.30(m,2H),2.21-2.06(m,2H),1.99-1.87(m,2H),1.79-1.60(m,4H),1.53-1.43(m,3H),1.12-1.09(m,1H),0.70-0.62(m,1H)。
化合物77-P1的合成方法参考化合物77的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例62
氮-((6-(3-甲氧基氮杂环丁烷-1-基)-2,3-二氢苯并[b][1,4]二恶英-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物78)的合成
步骤1:6-溴-2,3-二氢苯并[b][1,4]二恶英-5-碳醛(78-2)的合成
-78℃下,将78-1(213mg,1mmol)溶于四氢呋喃(5mL),加入2N的LDA(0.75mL,1.5mmol)并反应5分钟。-78℃下,加入DMF(146mg,2mmol)并反应10分钟,然后用NH
4Cl(10mL)淬灭,用乙酸乙酯(10mL×2)萃取。有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=10:1)得到黄色液体78-2(125mg,产率51%)。
步骤2:6-(3-甲氧基氮杂环丁烷-1-基)-2,3-二氢苯并[b][1,4]二恶英-5-碳醛(78-4)的合成
室温下,将78-2(100mg,0.41mmol),41-1(76mg,0.62mmol),Pd
2(dba)
3(38mg,0.04mmol),Xphos(39mg,0.08mmol)碳酸铯(333mg,1.0mmol) 溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石
油醚:V
乙酸乙酯=3:1)得到78-4(40mg,产率31%),[M+H]
+:250.2。
步骤3:氮-((6-(3-甲氧基氮杂环丁烷-1-基)-2,3-二氢苯并[b][1,4]二恶英-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(78)的合成
氮气保护下,将78-4(40mg,0.16mmol),中间体A(42mg,0.16mmol),硫酸镁(386mg,3.2mol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(18mg,0.48mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,滤液旋干,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到黄色油状液体78(12mg,产率15%),[M+H]
+:480.2。
1H NMR(400MHz,CDCl
3)δ8.45(d,J=3.6Hz,1H),7.61(dt,J1=2.0Hz,J2=8.0Hz,1H),7.29(d,J=8.0Hz,1H),7.13(dd,J1=4.8Hz,J2=7.2Hz,1H),6.83(d,J=8.8,Hz 1H),6.36(d,J=9.2Hz 1H),4.29-4.02(m,9H),3.72-3.70(m,2H),3.64-3.59(m,2H),3.33(s,3H),2.77-2.70(m,1H),2.37-2.30(m,2H),2.25-2.21(m,1H),2.20-1.12(m,1H),2.06-1.99(m,1H),1.85-1.74(m,2H),1.68-1.62(m,2H),1.50-1.42(m,4H),1.12-1.08(m,1H),0.73-0.60(m,1H)。
实施例63
氮-(2-(3-甲氧基噻吩-2-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物79)的合成
步骤1:3-甲氧基-[2,3'-苯噻吩]-2'-甲醛(79-1)的合成
室温下,依次将26-1(0.3g,2.62mmol),34-1(484.47mg,2.62mmol),乙酸钾(770.57mg,7.85mmol),醋酸钯(117.52mg,0.523mmol),四丁基溴化胺(843.5mg,2.62mmol)加入到N,N’二甲基甲酰胺(50mL)中,氮气置换三次,在氮气氛围下,加热至80℃反应3h。反应完成后,将反应液冷至室温,加入水(100mL)稀释,用乙酸乙酯(100mL×3) 萃取,有机相用盐水洗涤(100mL×3),无水硫酸钠干燥后,过滤,滤液浓缩后,粗产物经硅胶柱层析纯化(V
PE:V
EA=10:1)得淡黄色油79-1(370mg,产率64.78%)。
步骤2:氮-(2-(3-甲氧基噻吩-2-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(79)的合成
氮气保护下,将79-1(100mg,458.14μmol),中间体A(119.29mg,458.14μmol),硫酸钠(100mg,0.714mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(52mg,1.37mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油79(15mg,产率7.07%,纯度90%),[M+H]
+:463.29。
1H NMR(400MHz,CD
3OD)δ8.52-8.47(m,1H),7.73(td,J=7.7,1.9Hz,1H),7.45-7.37(m,2H),7.34-7.20(m,5H),6.99(d,J=5.5Hz,1H),3.76-3.62(m,7H),2.39(m,3H),1.97-1.88(m,2H),1.83(d,J=13.9Hz,1H),1.67-1.39(m,8H),1.10-1.04(m,1H),0.73-0.66(m,1H)。
实施例64
氮-(2-氟-4-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物80)的合成
步骤1:2-氟-4-(3-甲氧基氮杂环丁烷-1-基)苯甲醛的合成(80-2)的合成
将80-1(200mg,1.41mmol),41-1(173.93mg,1.41mmol)和碳酸钾(583.54mg,4.22mmol)依次加入单口瓶中,加入氮,氮二甲基甲酰胺(10mL)溶解并加热到100℃搅拌16h。反应完后,冷却至室温,反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油80-2(75mg,产率25.5%)。
1H NMR(400MHz,CDCl
3)δ10.09(s,1H),7.73(t,J=8.2Hz,1H),6.21(dd,J=8.6,2.1Hz,1H),6.02(dd,J=12.9,2.2Hz,1H),4.45-4.35(m,1H),4.28-4.17(m,2H),3.95-3.84(m,2H),3.38(s,3H)。
步骤2:氮-(2-氟-4-(3-甲氧基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(80)的合成
氮气保护下,将80-2(75mg,358.48μmol),中间体A(93.34mg,358.48μmol),硫酸钠(75mg,0.53mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(40.69mg,1.08mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(2mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油80(20mg,产率12.3%,纯度95%),[M+H]
+:454.35。
1H NMR(400MHz,CD
3OD)δ8.59-8.49(m,1H),7.78(td,J=7.7,1.9Hz,1H),7.49(dt,J=8.1,1.0Hz,1H),7.31-7.22(m,1H),7.05(t,J=8.4Hz,1H),6.25-6.13(m,2H),4.41-4.32(m,1H),4.09(m,2H),3.82-3.55(m,6H),3.34(d,J=5.1Hz,3H),2.66-2.57(m,1H),2.52-2.40(m,2H),2.14-1.99(m,2H),1.96-1.91(m,1H),1.77-1.47(m,7H),1.32-1.30(m,1H),1.14-1.07(m,1H),0.75-0.68(m,1H)。
实施例65
氮-(2-(3-(甲硫基)氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物81)的合成
步骤1:2-(3-(甲硫基)氮杂环丁-1-基)苯甲醛(81-3)的合成
室温下,将34-1(100mg,0.465mmol)用甲苯(10mL)溶解,然后依次加入BINAP(68mg,0.093mmol)和81-2(99mg,0.558mmol)和碳酸铯(529mg,1.396mmol),最后加入醋酸钯(13mg,0.049mmol)。反应在氮气保护下室温过夜。反应16h后,将甲苯旋干。加入20mL水,加入乙酸乙酯(20×2mL)进行萃取然后用饱和碳酸钠溶液洗涤(10mL×2),有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色油状液体81-3(40mg,产率35.75%)。
步骤2:氮-(2-(3-(甲硫基)氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5] 癸-9-基)乙胺(81)的合成
室温下,将81-3(40mg,0.193mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(39mg,0.150mmol)和硫酸钠(106mg,0.746mmol)。反应在氮气保护下室温过夜。反应16h后,加入硼氢化钠(12mg,0.317mmol)反应半小时,再加入无水甲醇(2mL)再搅拌半小时。反应完全后,加入15mL水进行淬灭处理,加入乙酸乙酯(20×2mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
无水甲醇:V
二氯甲烷=10:1)得到淡黄色稠状固体81(19mg,产率28.08%,纯度98.00%),[M+H]
+:452.27。
1H NMR(400MHz,CDCl
3)δ8.49(d,J=5.3,1.8Hz,1H),7.60(td,J=7.7,1.9Hz,1H),7.25–7.17(m,2H),7.12–7.07(m,1H),7.02(dd,J=7.3,1.6Hz,1H),6.82(t,J=7.4Hz,1H),6.60(d,J=8.0Hz,1H),4.24–4.14(m,2H),3.79–3.69(m,6H),2.57(d,J=5.4Hz,1H),2.36–2.23(m,2H),2.18–2.03(m,5H),1.86(d,J=13.6Hz,2H),1.79–1.57(m,4H),1.51–1.36(m,4H),1.10(d,J=13.7Hz,1H),0.70–0.62(m,1H)。
实施例66
氮-(2-氟-4-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物86)的合成
步骤1:2-氟-4-(3-氟氮杂环丁烷-1-基)苯甲醛(86-1)的合成
将80-1(300mg,2.115mmol),45-2(235.48mg,2.115mmol)和碳酸钾(875.31mg,6.345mmol)依次加入单口瓶中,加入氮,氮二甲基甲酰胺(20mL)溶解并加热到100℃搅拌16h。反应完后,冷却至室温,反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油86-1(210mg,产率50.4%)。
1H NMR(400MHz,CDCl
3)δ10.11(d,J=0.8Hz,1H),7.75(dd,J=8.6,7.8Hz, 1H),6.24(dt,J=8.6,1.4Hz,1H),6.06(dd,J=12.6,2.2Hz,1H),5.59-5.39(m,1H),4.38-4.27(m,2H),4.21-4.09(m,2H)。
步骤2:氮-(2-氟-4-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(86)的合成
氮气保护下,将86-1(100mg,507.15μmol),中间体A(132.05mg,507.15μmol),硫酸钠(100mg,0.704mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(57.56mg,1.52mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油86(10mg,产率4.46%,纯度95%),[M+H]
+:442.35。
1H NMR(400MHz,CD
3OD)δ8.64-8.53(m,1H),7.83(td,J=7.8,1.9Hz,1H),7.53(dt,J=8.1,1.0Hz,1H),7.36-7.26(m,1H),7.23-7.13(m,1H),6.38-6.20(m,2H),5.55-5.35(m,1H),4.34-4.14(m,2H),4.03-3.90(m,3H),3.83-3.67(m,2H),3.01-2.90(m,1H),2.57-2.34(m,3H),2.18-2.07(m,1H),1.98-1.82(m,2H),1.80-1.17(m,8H),1.14-1.06(m,1H),0.76-0.67(m,1H)。
实施例67
氮-(2-((3-环丙基丙炔基-1-基)氧)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物87)的合成
步骤1:2-((3-环丙基丙炔基-1-基)氧基)苯甲醛(87-2)的合成
将87-1(200mg,1.64mmol),4-1(781.31mg,4.91mmol),K
2CO
3(452.68mg,3.28mmol)依次加入单口瓶中,加入丙酮(15mL)溶解并用氮气置换气体三次,在氮气氛围下加热到60℃搅拌16h。反应完后,降至室温,反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1)纯化得到淡黄色油87-2(210mg,产率61.0%)。
1H NMR(400MHz,CDCl
3)δ10.51(s,1H),7.87(dd,J=7.7,1.8Hz,1H),7.60-7.54(m,1H),7.15-7.05(m,2H),4.80(d,J=2.0Hz,2H),1.28(m,1H),0.84-0.78(m, 2H),0.74-0.69(m,2H)。
步骤2:氮-(2-((3-环丙基丙炔基-1-基)氧)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(87)的合成
氮气保护下,将87-2(50mg,249.71μmol),中间体A(65.02mg,249.71μmol),硫酸钠(50mg,0.35mmol),二氯甲烷(3mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(28.34mg,749.13μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油产物87(10mg,产率9.0%,纯度96%),[M+H]
+:445.34。
1H NMR(400MHz,CDCl
3)δ8.55(d,J=4.9Hz,1H),7.63(td,J=7.8,1.9Hz,1H),7.31(d,J=8.0Hz,1H),7.23(t,J=7.1Hz,1H),7.16-7.10(m,2H),6.96-6.89(m,2H),4.65(d,J=2.0Hz,2H),3.81-3.67(m,4H),2.62-2.53(m,1H),2.46-2.40(m,1H),2.37-2.32(m,1H),2.22-2.15(m,1H),2.02-1.70(m,9H),1.54-1.49(m,2H),1.33-1.29(m,1H),1.17-1.11(m,1H),0.94-0.85(m,1H),0.83-0.76(m,2H),0.72-0.67(m,2H)。
实施例68
氮-((5-(3-氟氮杂环丁烷-1-基)噻吩-2-基)甲基)2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物88)的合成
将88-1(60mg,323.94μmol),88-2(84.35mg,323.94μmol),MgSO
4(38mg,323.94μmol)依次加入单口瓶中,加入二氯甲烷(2mL)溶解并用氮气置换气体三次,反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
二氯甲烷:V
乙酸乙酯=7:1到20:1)纯化得到淡黄色油状物产物88(10mg,产率7.2%),[M+H]
+:430.32。
1H NMR(400MHz,CDCl
3)δ8.59-8.54(m,1H),7.65(td,J=7.7,1.9Hz,1H),7.32(d,J=8.0Hz,1H),7.16-7.12(m,1H),6.31(s,1H),5.87(s,1H),5.44-5.29(m,1H),4.20-4.10(m,2H),4.01-3.89(m,2H),3.80-3.69(m,3H),3.55(s,1H),2.63-2.55(m,1H),2.47-2.41(m,1H),2.39-2.34(m,1H),2.21-2.15(m,1H),2.07-2.00 (m,2H),1.95-1.91(m,1H),1.83-1.67(m,5H),1.46-1.39(m,2H),1.15-1.11(m,1H),0.74-0.69(m,1H)。
实施例69
氮-((2-(3-甲氧基氮杂环丁烷-1-基)萘-1-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物89)的合成
步骤1:2-(3-甲氧基氮杂环丁烷-1-基)-1-萘醛(89-2)的合成
室温下,将89-1(100mg,0.425mmol)用甲苯(10mL)溶解,然后依次加入BINAP(53mg,0.085mmol)和41-1(69mg,0.558mmol)和碳酸铯(416mg,1.277mmol),最后加入醋酸钯(10mg,0.045mmol)。反应在氮气保护下100℃过夜。反应16h后,将甲苯旋干。加入20mL水,加入乙酸乙酯(20×2mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色油状液体89-2(100mg,产率97.09%)。
步骤2:氮-((2-(3-甲氧基氮杂环丁烷-1-基)萘-1-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(89)的合成
室温下,将89-2(100mg,0.413mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(84mg,0.323mmol)和硫酸钠(226mg,1.592mmol)。反应在氮气保护下室温过夜。反应16h后,加入硼氢化钠(24mg,0.635mmol)反应半小时,再加入无水甲醇(2mL)再搅拌半小时。反应完全后,加入15mL水进行淬灭处理,加入乙酸乙酯(20×2mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
甲醇:V
二氯甲烷=10:1)得到淡黄色稠状固体89(33mg,产率16.44%,纯度99.00%),[M+H]
+:486.30。
1H NMR(400MHz,CDCl
3)δ8.52(s,1H),7.82(d,J=8.8Hz,1H),7.70(d,J=16.9,8.2Hz,2H),7.64–7.57(m,1H),7.44(d,J=7.7Hz,1H),7.30(d, J=7.7Hz,1H),7.25(d,J=7.7Hz,1H),7.14–7.07(m,1H),6.89(d,J=8.6Hz,1H),4.35–4.18(m,3H),4.01(s,2H),3.92(s,2H),3.75(d,J=4.3Hz,2H),3.38(s,3H),2.63(t,J=8.3Hz,1H),2.42(d,J=14.1Hz,1H),2.26(s,2H),2.04(d,J=5.0Hz,2H),1.81(d,J=43.0Hz,4H),1.55(d,J=5.0Hz,4H),1.12(s,1H),0.70(s,1H)。
实施例70
氮-(2-(氧杂-3-氧基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物90)的合成
步骤1:2-(氧杂-3-氧基)苯甲醛(90-1)的合成
室温下,将87-1(500mg,4.094mmol)用甲苯(30mL)溶解,然后依次加入BINAP(337mg,0.541mmol)和77-2(300mg,4.049mmol)和碳酸铯(2642mg,8.108mmol),最后加入醋酸钯(61mg,0.272mmol)。反应在氮气保护下100℃过夜。反应16h后,将甲苯旋干。加入50mL水,加入乙酸乙酯(50×3mL)进行萃取然后用饱和碳酸钠溶液(30mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色油状液体90-1(100mg,产率13.70%)。
步骤2:氮-(2-(氧杂-3-氧基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基乙胺(90)的合成
室温下,将90-1(100mg,0.561mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(146mg,0.561mmol)和硫酸钠(229mg,1.684mmol)。反应在氮气保护下室温过夜。反应16h后,加入硼氢化钠(43mg,1.122mmol)反应半小时,再加入无水甲醇(2mL)再搅拌半小时。反应完全后,加入20mL水进行淬灭处理,加入乙酸乙酯(20×3mL)进行萃取然后用饱和碳酸钠溶液(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
甲醇:V
二氯甲烷=10:1)得到淡黄色稠状固体90(19mg,产率 8.01%,纯度95.00%),[M+H]
+:423.26。
1H NMR(400MHz,Chloroform-d)δ8.54(d,J=3.6Hz,1H),7.64(td,J=7.7,1.8Hz,1H),7.31(d,J=8.1Hz,1H),7.19(t,J=7.6Hz,2H),7.13(dd,J=7.3,4.9Hz,1H),6.92(t,J=7.4Hz,1H),6.35(d,J=8.0Hz,1H),5.19(d,J=5.6Hz,1H),4.98(t,J=6.8Hz,2H),4.71(dd,J=7.3,5.2Hz,2H),3.86–3.68(m,4H),2.62(td,J=11.4,5.4Hz,1H),2.41(d,J=13.6Hz,2H),2.23–2.17(m,1H),2.11–2.04(m,2H),1.95–1.63(m,5H),1.57–1.39(m,4H),1.13(s,1H),0.71(dt,J=13.4,9.0Hz,1H)。
实施例71
氮-(2-(2-氧杂-5-氮杂双环[2.2.2]辛烷-5-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物93)的合成
步骤1:2-(2-氧代-5-氮杂双环[2.2.2]辛烷-5-基)苯甲醛(93-3)的合成
室温下,将34-1(100mg,0.540mmol)用甲苯(10mL)溶解,然后依次加入BINAP(68mg,0.108mmol)和93-2(171mg,0.540mmol)和碳酸铯(529mg,1.624mmol),最后加入Pd(OAc)
2(13mg,0.054mmol)。反应在氮气保护下室温过夜。反应16h后,将甲苯旋干。加入20mL水,加入乙酸乙酯(20×3mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色油状液体93-3(100mg,产率72.40%)。
步骤2:氮-(2-(2-氧杂-5-氮杂双环[2.2.2]辛烷-5-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(93)的合成
室温下,将93-3(85mg,0.391mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(100mg,0.384mmol)和硫酸钠(161mg,1.134mmol)。反应在氮气保护下室温过夜。反应16h后,加入硼氢化钠(29mg,0.767mmol)反应半小时,再加入无水甲醇(2mL)再搅拌半小时。反应完全后,加入15mL水进行淬灭处理,加入乙酸乙酯(20×2mL) 进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
无水甲醇:V
二氯甲烷=10:1)得到淡黄色稠状固体93(6mg,产率3.34%,纯度98.00%),[M+H]
+:462.3。
1H NMR(400MHz,Chloroform-d)δ8.48(d,J=4.8Hz,1H),7.61(d,J=7.7Hz,1H),7.29(s,1H),7.24(s,1H),7.19(d,J=7.3Hz,2H),7.13–7.08(m,1H),7.00(t,J=7.4Hz,1H),4.28(d,J=9.2Hz,1H),3.96(s,1H),3.90–3.82(m,2H),3.81–3.68(m,4H),3.25(d,J=10.5Hz,1H),3.08(s,1H),2.61(s,1H),2.33(d,J=7.4Hz,2H),2.16(d,J=11.2Hz,3H),1.91–1.81(m,4H),1.77–1.59(m,4H),1.47(d,J=3.8Hz,4H),1.10(s,1H),0.66(d,J=12.2Hz,1H)。
实施例72
氮-(2-(3-氟氮杂环丁烷-1-基)噻吩-2-基)甲基))-3-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物94)的合成
步骤1:2-(3-氟氮杂环丁烷-1-基)噻吩-3-甲醛(94-1)的合成
室温下,将61-1(200mg,1.047mmol)用甲苯(20mL)溶解,然后依次加入Xphos(132mg,0.277mmol)和45-2(152mg,1.363mmol)和碳酸铯(1024mg,3.143mmol),最后加入Pd
2(dba)
3(96mg,0.105mmol)。反应在氮气保护下室温过夜。反应16h后,将甲苯旋干。加入20mL水,加入乙酸乙酯(20×3mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色油状液体94-1(100mg,产率51.60%)。
步骤2:氮-(2-(3-氟氮杂环丁烷-1-基)噻吩-2-基)甲基))-3-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(94)的合成
室温下,将94-1(100mg,0.540mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(140mg,0.540mmol)和硫酸钠(230mg,1.620mmol)。反应在氮气保护下室温 过夜。反应16h后,加入硼氢化钠(41mg,1.080mmol)反应半小时,再加入无水甲醇(2.5mL)再搅拌半小时。反应完全后,加入15mL水进行淬灭处理,加入乙酸乙酯(20×2mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
无水甲醇:V
二氯甲烷=10:1)得到淡黄色稠状固体94(8mg,产率3.45%,纯度98.00%),[M+H]
+:430.2。
1H NMR(400MHz,Chloroform-d)δ8.55(d,J=3.8Hz,1H),7.65(td,J=7.8,1.8Hz,1H),7.31(d,J=8.1Hz,1H),7.15–7.11(m,1H),6.81(d,J=5.5Hz,1H),6.68(d,J=5.5Hz,1H),5.42–5.36(m,1H),5.28–5.22(m,1H),4.12(dd,J=17.4,5.9Hz,2H),3.90(ddd,J=23.5,8.9,4.1Hz,2H),3.78–3.73(m,2H),3.60(d,J=2.1Hz,2H),2.65–2.57(m,1H),2.41(d,J=14.0Hz,3H),2.18(td,J=11.3,4.9Hz,2H),2.08(d,J=8.3Hz,1H),1.91(d,J=13.7Hz,1H),1.82–1.66(m,4H),1.52(dd,J=12.5,5.9Hz,3H),1.12(s,1H),0.69(dd,J=8.6,4.7Hz,1H)。
实施例73
氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-氟苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物95)和(R)-氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-氟苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物95-P1)的合成
步骤1:2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-5-氟苯甲醛(95-2)的合成
室温下,将95-1(463mg,3.258mmol)用DMSO(20mL)溶解,然后依次加入K
2CO
3(1349mg,9.761mmol)和21-1(730mg,4.879mmol)。反应在氮气保护下120℃过夜。 反应16h后,加入20mL水,加入乙酸乙酯(20×3mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色固状物95-2(225mg,产率29.37%)。
步骤2:氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-4-氟苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(95)的合成
室温下,将95-2(80mg,0.340mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(88mg,0.338mmol)和硫酸钠(145mg,1.021mmol)。反应在氮气保护下室温过夜。反应16h后,加入硼氢化钠(26mg,0.687mmol)反应半小时,再加入无水甲醇(2mL)再搅拌半小时。反应完全后,加入15mL水进行淬灭处理,加入乙酸乙酯(20×2mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
无水甲醇:V
二氯甲烷=10:1)得到淡黄色稠状固体95(6mg,产率3.68%,纯度98.00%),[M+H]
+:480.29。
1H NMR(400MHz,Chloroform-d)δ8.50(d,J=3.2Hz,1H),7.63(td,J=7.7,1.8Hz,1H),7.29(d,J=8.1Hz,1H),7.22–7.17(m,1H),7.12(dd,J=7.4,4.8Hz,1H),6.64(s,1H),6.53(dd,J=11.1,2.4Hz,1H),3.87–3.41(m,10H),2.61(s,1H),2.35(dd,J=23.5,13.8Hz,2H),2.18(d,J=11.0Hz,1H),2.02–1.87(m,6H),1.70(dd,J=14.2,8.4Hz,4H),1.51–1.37(m,4H),1.10(s,1H),0.69(dd,J=15.5,6.8Hz,1H)。
化合物95-P1的合成方法参考化合物95的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例74
氮-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-2-氟苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物96)的合成
步骤1:4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-2-氟苯甲醛(96-1)的合成
室温下,将95-1(463mg,3.258mmol)用DMSO(20mL)溶解,然后依次加入K
2CO
3(1349mg,9.761mmol)和21-1(730mg,4.879mmol)。反应在氮气保护下120℃过夜。反应16h后,加入20mL水,加入乙酸乙酯(20×3mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到淡黄色固状物96-1(180mg,产率23.47%)。
步骤2:氮-(4-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-2-氟苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(96)的合成
室温下,将96-1(80mg,0.340mmol)用二氯甲烷(10mL)溶解,然后依次加入中间体A(88mg,0.338mmol)和硫酸钠(145mg,1.021mmol)。反应在氮气保护下室温过夜。反应16h后,加入硼氢化钠(26mg,0.687mmol)反应半小时,再加入无水甲醇(2mL)再搅拌半小时。反应完全后,加入15mL水进行淬灭处理,加入乙酸乙酯(20×2mL)进行萃取然后用饱和碳酸钠溶液(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
无水甲醇:V
二氯甲烷=10:1)得到淡黄色稠状固体96(5mg,产率3.05%,纯度98.00%),[M+H]
+:480.29。
1H NMR(400MHz,Chloroform-d)δ8.48(d,J=4.8Hz,1H),7.61(d,J=7.7Hz,1H),7.29(s,1H),7.24(s,1H),7.19(d,J=7.3Hz,2H),7.13–7.08(m,1H),7.00(t,J=7.4Hz,1H),4.28(d,J=9.2Hz,1H),3.96(s,1H),3.90–3.82(m,2H),3.81–3.68(m,4H),3.25(d,J=10.5Hz,1H),3.08(s,1H),2.61(s,1H),2.33(d,J=7.4Hz,2H),2.16(d,J=11.2Hz,3H),1.91–1.81(m,4H),1.77–1.59(m,4H),1.47(d,J=3.8Hz,4H),1.10(s,1H),0.66(d,J=12.2Hz,1H)。
实施例75
氮-(3-氟-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物97)的合成
步骤1:3-氟-2-(3-氟氮杂丁-1-基)苯甲醛(97-1)的合成
将52-1(50mg,246.30μmol),45-2(27.47mg,246.30μmol),BINAP(15.34mg,24.63μmol),Pd(OAc)
2(5.53mg,24.63μmol),Cs
2CO
3(240.74mg,738.89μmol)依次加入单口瓶中,加入甲苯(3mL)溶解并用氮气置换气体三次,升温至110℃反应16小时。反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=20:1)纯化得到淡黄色油状物97-1(40mg,产率82.37%),[M+H]
+:198.03。
步骤2:氮-(3-氟-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(97)的合成
氮气保护下,将97-1(40mg,202.86μmol),中间体A(52.82mg,202.86μmol),硫酸钠(50mg,0.35mmol),二氯甲烷(2mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(23.02mg,608.58μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油产物97(20mg,产率22.32%,纯度96%),[M+H]
+:442.21。
1H NMR(400MHz,CDCl
3)δ8.56-8.50(m,1H),7.67-7.61(m,1H),7.31(d,J=8.1Hz,1H),7.15-7.10(m,1H),6.98-6.88(m,2H),6.85-6.78(m,1H),5.42-5.21(m,1H),4.37(dt,J=16.8,7.1Hz,2H),4.23(dd,J=24.3,9.3Hz,2H),3.80-3.68(m,4H),2.64-2.58(m,1H),2.40(d,J=12.0Hz,1H),2.35-2.31(m,1H),2.24-2.18(m,2H),2.10-2.05(m,1H),1.93-1.86(m,2H),1.81-1.61(m,4H),1.51-1.49(m,1H),1.42-1.36(m,1H),1.16-1.10(m,1H),0.73-0.66(m,1H)。
实施例76
氮-(2-(3-氟氮杂环丁烷-1-基)-5-甲氧基吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物98)的合成
步骤1:2-(3-氟氮杂丁-1-基)-5-甲氧基烟醛(98-2)的合成
将98-1(100mg,644.64μmol),45-2(143.81mg,1.29mmol),K
2CO
3(267.28mg,1.93mmol),依次加入单口瓶中,加入二甲基亚砜(4mL)溶解并用氮气置换气体三次。 反应完后,反应液降至室温,过滤,滤液用水稀释至10mL,水相用乙酸乙酯萃取(10mL×3),合并有机相,用饱和食盐水洗涤(10mL×3),有机相用无水硫酸钠干燥,旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油状物98-2(30mg,产率22.14%),[M+H]
+:211.22。
步骤2:氮-(2-(3-氟氮杂丁-1-基)-5-甲氧基吡啶-3-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(98)的合成
氮气保护下,将98-2(30mg,142.72μmol),中间体A(37.16mg,142.72μmol),硫酸钠(202.7mg,1.43mmol),二氯甲烷(2mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(16.2mg,608.58μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油产物98(15mg,产率23.12%,纯度97.2%),[M+H]
+:455.24。
1H NMR(400MHz,CDCl
3)δ8.58-8.52(m,1H),7.82(d,J=2.9Hz,1H),7.64(td,J=7.8,1.9Hz,1H),7.31(dt,J=8.1,1.0Hz,1H),7.18-7.05(m,2H),5.45-5.25(m,1H),4.27-4.15(m,2H),4.13-4.00(m,2H),3.82-3.67(m,5H),3.52-3.43(m,2H),2.57-2.49(m,1H),2.47-2.41(m,1H),2.39-2.33(m,1H),2.18-2.10(m,1H),2.06-2.00(m,1H),1.95-1.91(m,1H),1.77-1.61(m,6H),1.51-1.47(m,1H),1.44-1.38(m,1H),1.17-1.12(m,1H),0.75-0.68(m,1H)。
实施例77
氮-(2-氟-6-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺的合成(化合物103)的合成
步骤1:2-氟-6-(3-氟氮杂环丁烷-1-基)苯甲醛的合成(103-1)的合成
将51-1(200mg,985.18μmol),45-2(109.89mg,985.18μmol),醋酸钯(22.12mg,98.52μmol),碳酸铯(962.97mg,2.95mmol)和1,1'-联萘-2,2'-双二苯膦(61.3mg,98.52μmol)依次加入到甲苯(20mL)溶解,用氮气置换气体三次,加热到110℃搅拌6h。反应 完后,冷却至室温,反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色固体103-1(140mg,产率72.1%),[M+H]
+:198.19。
步骤2:氮-(2-氟-6-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(103)的合成
氮气保护下,将103-1(100mg,507.15μmol),中间体A(92.43mg,355.0μmol)和硫酸钠(50.43mg,0.36mmol)依次加入到二氯甲烷(5mL)中溶解,室温搅拌12h,加入硼氢化钠(40.29mg,1.07mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油103(10mg,产率4.46%,纯度95%),[M+H]
+:442.40。
1H NMR(400MHz,CDCl
3)δ8.62-8.53(m,1H),7.68-7.59(m,1H),7.36-7.29(m,1H),7.17-7.04(m,2H),6.58-6.47(m,1H),6.25(d,J=8.2Hz,1H),4.31-4.11(m,2H),4.08-4.00(m,1H),3.99-3.92(m,1H),3.87-3.68(m,3H),3.57-3.52(m,2H),2.52-2.40(m,2H),2.38-2.31(m,1H),2.21-1.82(m,4H),1.78-1.63(m,4H),1.48-1.36(m,2H),1.30-1.25(m,1H),1.19-1.10(m,1H),0.77-0.67(m,1H)。
实施例78
氮-(5-氟-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物104)的合成
步骤1:5-氟-2-(3-氟氮杂环丁烷-1-基)苯甲醛的合成(104-2)的合成
将104-1(200mg,985.18μmol),45-2(109.89mg,985.18μmol),醋酸钯(22.12mg,98.52μmol),碳酸铯(962.97mg,2.95mmol)和1,1'-联萘-2,2'-双二苯膦(61.3mg,98.52μmol)依次加入到甲苯(20mL)溶解,用氮气置换气体三次,加热到110℃搅拌6h。反应完后,冷却至室温,反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色固体104-2(80mg,产率41.2%),[M+H]
+:198.19。
步骤2:氮-(5-氟-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5] 癸烷-9-基)乙胺(104)的合成
氮气保护下,将104-2(80mg,405.72μmol),中间体A(105.64mg,405.72μmol)和硫酸钠(80mg,0.56mmol)依次加入到二氯甲烷(5mL)中溶解,室温搅拌12h,加入硼氢化钠(46.05mg,1.22mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油104(10mg,产率5.58%,纯度95%),[M+H]
+:442.40。
1H NMR(400MHz,CDCl
3)δ8.60-8.55(m,1H),7.64(td,J=7.7,1.9Hz,1H),7.31(d,J=8.1Hz,1H),7.17-7.11(m,1H),6.88-6.81(m,2H),6.51-6.41(m,1H),5.43-5.23(m,1H),4.14-4.05(m,2H),3.91-3.85(m,1H),3.84-3.76(m,3H),3.49(s,2H),2.54-2.41(m,2H),2.39-2.33(m,1H),2.13-2.01(m,2H),1.94(d,J=13.7Hz,1H),1.81-1.72(m,3H),1.54-1.48(m,3H),1.28(s,2H),1.14(s,1H),0.75-0.68(m,1H)。
实施例79
2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基-氮-(2-(四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)苄基)乙胺(化合物124)和(R)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基-氮-(2-(四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)苄基)乙胺(化合物124-P1)的合成
步骤1:2-(四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)苯甲醛(124-2)的合成
将34-1(100mg,540.49μmol),124-1(80.87mg,540.49μmol),醋酸钯(12.13mg,54.05μmol),碳酸铯(528.31mg,1.62mmol)和1,1'-联萘-2,2'-双二苯膦(33.7mg,54.05 μmol)依次加入到甲苯(5mL)溶解,用氮气置换气体三次,加热到110℃搅拌3h。反应完后,冷却至室温,反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色油124-2(50mg,产率42.6%),[M+H]
+:218.04。
步骤2:2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基-氮-(2-(四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)苄基)乙胺(124)的合成
氮气保护下,将124-2(50mg,230.14μmol),中间体A(59.92mg,230.14μmol)和硫酸钠(50mg,0.35mmol)依次加入到二氯甲烷(5mL)中溶解,25℃搅拌12h,加入硼氢化钠(26.12mg,690.41μmol),25℃搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,加入水(1mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油124(20mg,产率18.8%,纯度90%),[M+H]
+:462.38。
1H NMR(400MHz,CDCl
3)δ8.53-8.46(m,1H),7.67-7.59(m,1H),7.37-7.29(m,2H),7.16-7.04(m,4H),4.20-4.12(m,2H),3.95-3.85(m,2H),3.77-3.67(m,4H),3.02(t,J=8.2Hz,4H),2.93(s,2H),2.71(d,J=4.6Hz,1H),2.32(t,J=13.7Hz,2H),2.22-2.12(m,2H),1.98-1.88(m,2H),1.80-1.61(m,6H),1.41-1.35(m,1H),1.12-1.06(m,1H),0.70-0.62(m,1H)。
化合物124-P1的合成方法参考化合物124的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例80
氮-((3-甲氧基噻吩-2-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(TRV130(消旋))的合成
在室温下,向25mL的单口瓶中加入中间体A(100mg,324.06μmol),1-1(81.9mg,576.09μmol),无水硫酸钠(272.77mg,1.92mmol),二氯甲烷(5mL)。室温下搅拌反应12小时。加入硼氢化钠(22mg,576.09mmol),反应0.5小时。反应完全后,减压浓缩除去溶剂。加入水(5mL),乙酸乙酯(3mL×2),合并有机相,饱和食盐水(5mL×1)洗 涤一次,无水硫酸钠干燥,过滤,滤液旋干,粗品柱层析(V
二氯甲烷:V
甲醇=10:1)纯化。得到淡黄色稠状固体1(15mg,产率10.10%),[M+H]
+:387.5。
1H NMR(400MHz,CDCl
3)δ8.54(d,J=4.8Hz,1H),7.63-7.58(m,1H),7.31-7.26(m,1H),7.11-7.08(m,1H),7.04(d,J=5.6Hz,1H),6.76(d,J=5.6Hz,1H),3.77(s,3H),3.75-3.73(m,2H),3.71-3.70(m,2H),2.53-2.52(m,1H),2.44-2.40(m,1H),2.34-2.33(m,1H),2.13-2.10(m,1H),2.04-1.95(m,1H),1.92-1.76(m,4H),1.75-1.73(m,2H),1.71-1.70(m,1H),1.69-1.54(m,1H),1.44-1.39(m,1H),1.27-1.23(m,1H),1.12-1.09(m,1H),0.70-0.67(m,1H)。
实施例81
氮-((2,3-二氢噻吩[3,4-b][1,4]二恶英-5-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物2)的合成
在室温下,向25mL的单口瓶中加入中间体A(50mg,192.03μmol),2-1(39.22mg,230.44μmol),无水硫酸钠(54.5mg,384.06μmol),二氯甲烷(2mL)。室温下搅拌反应12小时。加入硼氢化钠(10.09mg,288.05mmol),反应0.5小时。反应完全后,减压浓缩除去溶剂。加入水(5mL),乙酸乙酯(3mL×2),合并有机相,饱和食盐水(5mL×1)洗涤一次,无水硫酸钠干燥,过滤,滤液旋干,粗品柱层析(V
二氯甲烷:V
甲醇=10:1)纯化。得到淡黄色稠状固物2(20mg,产率25.12%),[M+H]
+:415.2。
1H NMR(400MHz,CDCl
3)δ8.56-8.55(m,1H),7.61-7.60(m,1H),7.29-7.26(m,1H),7.11-7.10(m,1H),6.15(s,1H),4.14(s,4H),3.76-3.74(m,2H),3.63-3.62(m,2H),2.50-2.42(m,2H),2.35-2.31(m,1H),2.08-2.07(m,1H),1.95-1.89(m,2H),1.76-1.62(m,5H),1.55-1.51(m,2H),1.42-1.39(m,1H),1.27-1.11(m,1H),1.09-1.08(m,1H),0.70-0.67(m,1H)。
实施例82
氮-(2-(3-氰基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物121)和(R)-氮-(2-(3-氰基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物121-P1)的合成
步骤1:2-(3-氰基氮杂环丁烷-1-基)苯甲醛(121-1)的合成
室温下,将34-1(400mg,2.16mmol),121-2(289.38mg,2.44mmol),醋酸钯(197.98mg,216.19mmol),BINAP(269.24mg,0.43mmol)碳酸铯(2.11g,6.49mmol)溶于甲苯(10mL),100℃反应12小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体121-1(150mg,产率38.2%)。
步骤2:氮-(2-(3-氰基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(121)的合成
氮气保护下,将121-1(50mg,0.19mmol),中间体A(41.29mg,0.23mmol),硫酸钠(81.82mg,0.57mol),二氯乙烷(5mL)依次加入单口瓶中,室温下搅拌12h,加入硼氢化钠(14.53mg,0.38mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:H
2O;B:MeCN)得到黄色油状液体121(20mg,产率:24.3%),[M+H]
+:431.2。
1H NMR(400MHz,CDCl
3)δ8.57(d,J=5.2Hz,1H),7.68-7.63(m,1H),7.33-7.30(m,1H),7.29-7.28(m,2H),7.23-7.21(m,1H),6.88(t,J=8.0Hz,1H),6.52(d,J=8.0Hz,1H),4.18-4.16(m,2H),4.06-3.89(m,2H),3.79-3.7.6(m,2H),3.53-3.50(m,2H),2.55-2.52(m,1H),2.45-2.42(m,1H),2.37-2.33(m,1H),2.14-2.11(m,1H),2.09-2.05(m,2H),1.99-1.91(m,1H),1.82-1.56(m,7H),1.48-1.42(m,1H),1.49-1.43(m,1H),1.27-1.12(m,1H),0.71-0.67(m,1H)。
化合物121-P1的合成方法参考化合物121的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例83
氮-((7-(3-甲氧基氮杂环丁烷-1-基)-2,3-二氢苯并[b][1,4]二恶英-6-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂吡啶[4.5]癸-9-基)乙胺(化合物68)的合成
步骤1:7-溴-2,3-二氢苯并[b][1,4]二恶英-6-碳醛(68-2)的合成
室温下,将68-1(164mg,1mmol)溶于甲醇(5mL),加入溴素(216mg,1.2mmol)并室温反应3小时。反应完全后,加入乙酸乙酯(50mL),然后用碳酸氢钠(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩得到黄色液体68-2(240mg粗品,产率100%)。
步骤2:7-(3-甲氧基氮杂环丁烷-1-基)-2,3-二氢苯并[b][1,4]二恶英-6-碳醛(68-4)的合成
室温下,将68-2(240mg,1mmol),41-1(185mg,1.5mmol),醋酸钯(23mg,0.1mmol),BINAP(63mg,0.1mmol)碳酸铯(813.5mg,2.5mmol)溶于甲苯(10mL),100℃反应16小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=3:1)得到黄色液体68-4(100mg,产率40%),[M+H]
+:250.2。
步骤3:氮-((7-(3-甲氧基氮杂环丁烷-1-基)-2,3-二氢苯并[b][1,4]二恶英-6-基)甲基)-2-(9-(吡啶-2-基)-6-氧杂吡啶[4.5]癸-9-基)乙胺(68)的合成
氮气保护下,将68-4(100mg,0.40mmol),中间体A(104mg,0.40mmol),硫酸镁(1.0mg,8μmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(45mg,1.2mmol),搅拌10分钟,加入甲醇(2mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到黄色稠状物68(20mg,产率10%),[M+H]
+:498.2。
1H NMR(400MHz,CDCl
3)δ8.54(d,J=3.6Hz,1H),7.61(dt,J1=1.6Hz,J2=7.6Hz,1H),7.28(d,J=8.0Hz,1H),7.10(dd,J1=5.6Hz,J2=7.2Hz,1H),6.59(s,1H),6.12(s,1H),4.22-4.16(m,5H),3.94(t,J=7.2Hz,2H),3.76-3.73(m,2H),3.55-3.47(m,4H),3.30(s,3H),2.51-2.29(m,3H),2.12-1.88(m,3H),1.81-1.62(m,4H),1.53-1.37(m,4H),1.14-1.08(m,1H),0.73-0.65(m,1H)。
实施例84
氮-(4-氯-6-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物102)的合成
步骤1:3-氟-2-(3-氟氮杂环丁烷-1-基)苯甲醛(102-2)的合成
将102-1(200mg,911.32μmol),45-2(109.89mg,985.18μmol),醋酸钯(22.12mg,98.52μmol),碳酸铯(962.97mg,2.95mmol)和1,1'-联萘-2,2'-双二苯膦(61.3mg,98.52μmol)依次加入到甲苯(20mL)溶解,用氮气置换气体三次,加热到110℃搅拌6h。反应完后,冷却至室温,反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(:V
正己烷:V
乙酸乙酯=10:1到5:1)纯化得到淡黄色固体102-2(140mg,产率72.1%),[M+H]
+:214.04。
步骤2:氮-(4-氯-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(102)的合成
氮气保护下,将102-2(100mg,468.07μmol),中间体A(92.43mg,355.0μmol)和硫酸钠(50.43mg,0.36mmol)依次加入到二氯甲烷(5mL)中溶解,室温搅拌12h,加入硼氢化钠(40.29mg,1.07mmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5 小时。反应完后,加入水(5mL),过滤旋干,粗品用反相中压制备得到淡黄色稠状油102(10mg,产率4.3%,纯度95%),[M+H]
+:458.23。
1H NMR(400MHz,CDCl
3)δ8.56-8.55(m,1H),7.65-7.63(m,1H),7.29-7.27(m,1H),7.14-7.12(m,1H),6.97-6.95(m,1H),6.48-6.43(m,1H),6.22(m,1H),5.48-5.25(m,1H),4.31-4.11(m,2H),4.08-4.00(m,1H),3.98-3.91(m,2H),3.88-3.69(m,2H),3.56-3.53(m,2H),2.56-2.32(m,7H),2.10-1.82(m,3H),1.78-1.63(m,3H),1.48-1.36(m,1H),1.30-1.25(m,1H),0.77-0.67(m,1H)。
实施例85
氮-(3-氰基-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂[4.5]癸-9-基)乙胺(化合物105)的合成
步骤1:3-氰基-2-(3-氟氮杂丁-1-基)苯甲醛(105-2)的合成
将105-1(50mg,238.306μmol),45-2(27.47mg,246.30μmol),BINAP(15.34mg,24.63μmol),Pd(OAc)
2(5.53mg,24.63μmol),Cs
2CO
3(240.74mg,738.89μmol)依次加入单口瓶中,加入甲苯(3mL)溶解并用氮气置换气体三次,升温至110℃反应16小时。反应完后,用硅藻土过滤,滤液减压旋干,粗品用柱层析(V
正己烷:V
乙酸乙酯=20:1)纯化得到淡黄色油状物105-2(40mg,产率82.30%),[M+H]
+:205.20。
步骤2:氮-(3-氰基-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂[4.5]癸-9-基)乙胺(105)的合成
氮气保护下,将105-2(40mg,195.88μmol),中间体A(52.82mg,202.86μmol),硫酸钠(50mg,0.35mmol),二氯甲烷(2mL)依次加入单口瓶中,室温搅拌12h,加入硼氢化钠(23.02mg,608.58μmol),搅拌30分钟,加入甲醇(1mL),搅拌反应3.5小时。反应完后,过滤旋干,粗品用反相中压制备得到淡黄色稠状油产物105(20mg,产率22.76%,纯度96%),[M+H]
+:449.26。
1H NMR(400MHz,CDCl
3)δ8.55-8.50(m,1H),7.68-7.62(m,1H),7.33-7.29(m,2H),7.14-7.11(m,2H),6.69-6.65(m,1H),5.42-5.21(m,1H),4.71(dt,J=16.8,7.1Hz,2H),4.65(dd,J=24.3,9.3Hz,2H),3.79-3.76(m,2H),3.47-3.43(m,2H),2.48-2.36(m,3H),2.10-2.05(m,1H),1.93-1.86(m,2H),1.81-1.61(m,4H),1.59-1.53(m,2H),1.51-1.49(m,1H),1.42-1.36(m,1H),1.16-1.10(m,1H),0.73-0.66(m,1H)。
实施例86
氮-(2-(氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(化合物107)的合成
步骤1:2-(氮杂丁-1-基)苯甲醛(107-2)的合成
将34-1(370mg,2mmol),107-1(279mg,3.0mmol),Pd
2(dba)
3(180mg,0.2mmol),Xantphos(231mg,0.4mmol),叔丁醇钠(480mg,5mmol)溶于甲苯(10mL),80℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=15:1)得到107-2(20mg,产率6%),[M+H]
+:162.2。
步骤2:氮-(2-(氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(107)的合成
氮气保护下,将107-2(20mg,0.12mmol),中间体A(32mg,0.12mmol),硫酸镁(300mg,2.5mmol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(14mg,0.37mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物107(10mg,产率20%),[M+H]
+:406.2。
1H NMR(400MHz,CDCl
3)δ8.54(d,J=4.0Hz,1H),7.60(dt,J1=2.0Hz,J2=8.0Hz, 1H),7.28-7.26(m,1H),7.14-7.09(m,2H),7.02-7.00(m,1H),6.74(t,J=7.2Hz,1H),6.50(d,J=7.6Hz,1H),3.85-3.73(m,6H),3.63-3.56(m,2H),2.51-2.41(m,1H),2.41-2.22(m,4H),2.14-2.07(m,1H),2.04-1.97(m,1H),1.91-1.88(m,1H),1.82-1.64(m,4H),1.53-1.37(m,3H),1.14-1.09(m,1H),0.73-0.65(m,1H)。
实施例87
氮-(4-氟-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(化合物108)的合成
步骤1:4-氟-2-(3-氟氮杂丁-1-基)苯甲醛(108-2)的合成
将108-1(203mg,1mmol),45-2(111mg,1.0mmol),Pd
2(dba)
3(90mg,0.1mmol),Xantphos(116mg,0.2mmol),碳酸铯(975mg,3mmol)溶于甲苯(10mL),80℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=15:1)得到108-2(100mg,产率51%),[M+H]
+:198.2。
步骤2:氮-(4-氟-2-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(108)的合成
氮气保护下,将108-2(100mg,0.51mmol),中间体A(132mg,0.51mmol),硫酸镁(600mg,5mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(58mg,1.53mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物108(50mg,产率22%),[M+H]
+:442.2。
1H NMR(400MHz,CDCl
3)δ8.56-8.54(m,1H),7.61(dt,J1=2.0Hz,J2=8.0Hz,1H),7.28(d,J=8.4Hz,1H),7.13-7.10(m,1H),6.97-6.94(m,1H),6.43(dt,J1=2.4Hz,J2=8.4Hz,1H),6.16(dd,J1=2.4Hz,J2=11.2Hz,1H),5.42-5.37(m,0.5H),5.27-5.22 (m,0.5H),4.19-4.11(m,2H),3.96-3.88(m,2H),3.77-3.74(m,2H),3.45(s,2H),2.50-2.31(m,3H),2.08-1.89(m,3H),1.78-1.59(m,4H),1.54-1.37(m,4H),1.14-1.09(m,1H),0.73-0.65(m,1H)。
实施例88
氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-3-氟苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(化合物109)的合成
步骤1:2-(3-氧代-8-氮杂双环[3.2.1]辛烷-8-基)-3-氟苯甲醛(109-1)的合成
将52-1(203mg,1mmol),21-1(145mg,1.0mmol),Pd
2(dba)
3(90mg,0.1mmol),Xantphos(116mg,0.2mmol),碳酸铯(975mg,3mmol)溶于甲苯(10mL),,80℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=15:1)得到产物109-1(100mg,产率42%),[M+H]
+:236.2。
步骤2:氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-3-氟苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(109)的合成
氮气保护下,将109-1(100mg,0.42mmol),中间体A(100mg,0.42mmol),硫酸镁(504mg,4.2mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(48mg,1.26mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物109(50mg,产率25%),[M+H]
+:480.2。
1H NMR(400MHz,CDCl
3)δ8.56-8.54(m,1H),7.62(dt,J1=1.6Hz,J2=7.6Hz,1H),7.29(d,J=8.4Hz,1H),7.12-7.10(m,1H),6.96-6.95(m,1H),6.86-6.82(m,2H),3.80-3.69(m,6H),3.61-3.56(m,4H),2.55-2.32(m,3H),2.13-1.90(m,7H),1.78-1.60(m,4H),1.55-1.37(m,4H),1.14-1.09(m,1H),0.74-0.66(m,1H)。
实施例89
氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-氟苄基)-2-(9-(吡啶-2-基)-2-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(化合物110)的合成
步骤1:2-(3-氧代-8-氮杂双环[3.2.1]辛烷-8-基)-6-氟苯甲醛(110-1)的合成
将51-1(203mg,1mmol),21-1(145mg,1.0mmol),Pd
2(dba)
3(90mg,0.1mmol),Xantphos(116mg,0.2mmol),碳酸铯(975mg,3mmol)溶于甲苯(10mL),,80℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=15:1)得到产物110-1(100mg,产率42%),[M+H]
+:236.2。
步骤2:氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-氟苄基)-2-(9-(吡啶-2-基)-2-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(110)的合成
氮气保护下,将110-1(100mg,0.42mmol),中间体A(100mg,0.42mmol),硫酸镁(504mg,4.2mol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(48mg,1.26mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物110(55mg,产率27%),[M+H]
+:480.2。
1H NMR(400MHz,CDCl
3)δ8.55(d,J=8.8Hz,1H),7.62(t,J2=7.6Hz,1H),7.28(d,J=8.4Hz,1H),7.12-7.03(m,2H),6.64(d,J=8.8Hz,1H),6.58(d,J=8.4Hz,1H),3.79-3.74(m,8H),3.61-3.56(m,2H),2.54-2.30(m,3H),2.09-1.88(m,7H),1.78-1.66(m,4H),1.54-1.39(m,4H),1.14-1.09(m,1H),0.74-0.66(m,1H)。
实施例90
氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-氯苄基)-2-(9-(吡啶-2-基)-2-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(化合物111)的合成
步骤1:2-(3-氧代-8-氮杂双环[3.2.1]辛烷-8-基)-6-氯苯甲醛(111-2)的合成
室温下,将111-1(158mg,1.0mmol),21-1(145mg,1.0mmol),碳酸钾(414mg,3mmol)溶于二甲基亚砜(6mL),120℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=10:1)得到产品111-2(50mg,产率20%),[M+H]
+:252.2。
步骤2:氮-(2-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-基)-6-氯苄基)-2-(9-(吡啶-2-基)-2-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(111)的合成
氮气保护下,将111-2(50mg,0.20mmol),中间体A(52mg,0.20mmol),硫酸镁(240mg,2.0mol),二氯甲烷(5mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(23mg,0.60mmol),搅拌10分钟,加入甲醇(0.5mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物111(20mg,产率20%),[M+H]
+:497.1。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=4.0Hz,1H),7.63(dt,J1=2.0Hz,J2=7.6Hz,1H),7.28(d,J=8.0Hz,1H),7.13-7.10(m,1H),7.04-6.95(m,2H),6.71(d,J=8.0Hz,1H),3.83-3.55(m,10H),2.52-2.32(m,3H),2.01-1.89(m,5H),1.75-1.69(m,4H),1.67-1.49(m,6H),1.14-1.09(m,1H),0.74-0.66(m,1H)。
实施例91
氮-(2-(3-氯氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物115)的合成
步骤1:2-(3-氯氮杂环丁烷-1-基)苯甲醛(115-1)的合成
室温下,将34-1(400mg,2.16mmol),115-2(289.38mg,2.26mmol),醋酸钯(197.98mg,216.19mmol),BINAP(269.24mg,0.43mmol)碳酸铯(2.11g,6.49mmol)溶于甲苯(10mL),,100℃反应12小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体115-1(150mg。产率35.5%)。
步骤2:氮-(2-(3-氯氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(115)的合成
氮气保护下,将115-1(50mg,0.25mmol),中间体A(41.29mg,0.23mmol),硫酸钠(81.82mg,0.57mol),二氯乙烷(5mL)依次加入单口瓶中,室温下搅拌12h,加入硼氢化钠(14.53mg,0.38mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:H
2O;B:MeCN)得到黄色油状液体115(20mg,产率:17.8%),[M+H]
+:440.2。
1H NMR(400MHz,CDCl
3)δ8.56(d,J=5.2Hz,1H),7.67-7.63(m,1H),7.32-7.28(m,1H),7.23-7.21(m,1H),7.20-7.18(m,1H),7.15-7.12(m,1H),6.88(t,J=8.0Hz,1H),6.52(d,J=8.0Hz,1H),4.67-4.62(m,1H),4.36-4.32(m,2H),3.95-3.89(m,2H),3.78-3.76(m,2H),3.61-3.60(m,2H),2.55-2.52(m,1H),2.45-2.42(m,1H),2.37-2.33(m,1H),2.14-2.05(m,3H),1.99-1.91(m,1H),1.82-1.56(m,4H),1.48-1.42(m,1H),1.49-1.43(m,2H),1.27-1.12(m,1H),0.71-0.67(m,1H)。
实施例92
氮-(2-(3-甲基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物116)的合成
步骤1:2-(3-甲基氮杂环丁烷-1-基)苯甲醛(116-1)的合成
室温下,将34-1(400mg,2.16mmol),116-2(289.38mg,2.26mmol),醋酸钯(197.98mg,216.19mmol),BINAP(269.24mg,0.43mmol)碳酸铯(2.11g,6.49mmol)溶于甲苯(10mL),100℃反应12小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体116-1(150mg。产率35.5%)。
步骤2:氮-(2-(3-甲基氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(116)的合成
氮气保护下,将116-1(50mg,0.28mmol),中间体A(41.29mg,0.23mmol),硫酸钠(81.82mg,0.57mmol),二氯乙烷(5mL)依次加入单口瓶中,室温下搅拌12h,加入硼氢化钠(14.53mg,0.38mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:H
2O;B:MeCN)得到黄色油状液体116(20mg,产率:17%),[M+H]
+:420.29。
1H NMR(400MHz,CDCl
3)δ8.55-8.53(m,1H),7.63-7.59(m,1H),7.28-7.26(m,1H),7.15-7.13(m,2H),7.12-7.10(m,1H),6.99-6.75(m,1H),6.49-6.47(m,1H),3.99-3.95(m,2H),3.76-3.73(m,2H),3.41-3.40(m,2H),3.38-3.35(m,2H),2.75-2.72(m,1H),2.50-2.49(m,1H),2.47-2.46(m,1H),2.41-2.38(m,1H),1.99-1.91(m,3H),1.82-1.76(m,2H),1.69-1.64(m,3H),1.54-1.51(m,2H),1.49-1.43(m,2H),1.43-1.40(m,1H),1.37-1.30(m,1H),1.27-1.12(m,1H),0.71-0.67(m,1H)。
实施例93
氮-(3-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(化合物123)和(R)-氮-(3-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(化合物123-P1)的合成
步骤1:3-(3-氟氮杂丁-1-基)苯甲醛(123-1)的合成
室温下,将69-1(370mg,2.0mmol),45-2(222mg,2.0mmol),Pd
2(dba)
3(183mg,0.2mmol),xantphos(115mg,0.2mmol),碳酸铯(1.63g,5mmol)溶于甲苯(6mL),120℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=10:1)得到123-1(200mg,产率56%),[M+H]
+:180.2。
步骤2:(3-(3-氟氮杂环丁烷-1-基)苯基)甲酰胺(123-2)的合成
室温下,将123-1(200mg,1.1mmol),Raney-Ni(100mg),溶于7N的氨甲醇(10mL),氢气氛围下室温反应16小时。反应完全后,过滤,浓缩,粗品用柱层析纯化(V
二氯甲烷:V
甲
醇=10:1)得到123-2(100mg,产率50%),[M+H]
+:179.2。
步骤3:(R)-氮-(3-(3-氟氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂吡咯[4.5]癸-9-基)乙烷-1-胺(123)的合成
氮气保护下,将123-2(100mg,0.56mmol),中间体A(145mg,0.56mmol),硫酸镁(670mg,5.6mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(64mg,1.68mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物123(50mg,产率21%),[M+H]
+:424.1。
1H NMR(400MHz,CDCl
3)δ8.53(d,J=4.0Hz,1H),7.62(dt,J1=1.6Hz,J2=8.0Hz,1H),7.29(d,J=8.0Hz,1H),7.14-7.10(m,2H),6.61(d,J=7.6Hz,1H),6.39(s, 1H),6.34(d,J=7.6Hz,1H),5.48-5.30(m,1H),4.19-4.13(m,2H),3.95-3.86(m,2H),3.76-3.74(m,2H),3.64-3.55(m,2H),2.59-2.32(m,3H),2.18-2.12(m,1H),2.05-1.89(m,2H),1.84-1.69(m,4H),1.59-1.37(m,4H),1.13-1.08(m,1H),0.71-0.63(m,1H)。
化合物123-P1的合成方法参考化合物123的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例94
氮-(2-(3-甲基砜氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物129)和(R)-氮-(2-(3-甲基砜氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙胺(化合物129-P1)的合成
步骤1:2-(3-甲基砜氮杂环丁烷-1-基)苯甲醛(129-1)的合成
室温下,将化合物34-1(400mg,2.16mmol),129-2(369.36mg,2.16mmol),醋酸钯(197.98mg,216.19mmol),BINAP(269.24mg,0.43mmol)碳酸铯(2.11g,6.49mmol)溶于甲苯(10mL),100℃反应12小时。反应完全后,加入水(20mL),然后用二氯甲烷(20mL×2)萃取,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=2:1)得到黄色液体129-1(150mg,产率29%)。
步骤2:氮-(2-(3-甲基砜氮杂环丁烷-1-基)苄基)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5] 癸-9-基)乙胺(129)的合成
氮气保护下,将129-1(50mg,0.21mmol),中间体A(41.29mg,0.23mmol),硫酸钠(81.82mg,0.57mmol),二氯乙烷(5mL)依次加入单口瓶中,室温下搅拌12h,加入硼氢化钠(14.53mg,0.38mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过反相(A:H
2O;B:MeCN)得到黄色油状液体129(20mg,产率:19.8%),[M+H]
+:484.26。
1H NMR(400MHz,CDCl
3)δ8.55-8.54(m,1H),7.67-7.54(m,1H),7.28-7.20(m,2H),7.15-7.13(m,1H),7.12-7.08(m,1H),6.89-6.85(m,1H),6.60-6.58(m,1H),4.23-4.11(m,3H),3.99-3.95(m,1H),3.78-3.73(m,1H),3.69-3.64(m,1H),3.51(s,3H),3.05(s,2H),2.58-2.56(m,1H),2.50-2.40(m,2H),2.35-2.32(m,1H),2.10-2.09(m,1H),1.94-1.90(m,1H),1.84-1.67(m,7H),1.49-1.43(m,2H),1.43-1.40(m,1H),1.27-1.12(m,1H),0.71-0.67(m,1H)。
化合物129-P1的合成方法参考化合物129的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例95
1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)氨基)甲基)苯基)氮杂丁-2-酮(化合物136)的合成和(R)-1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)氨基)甲基)苯基)氮杂丁-2-酮(化合物136-P1)的合成
步骤1:2-(2-氧代氮杂-1-基)苯甲醛(136-2)的合成
将34-1(370mg,2mmol),136-1(213mg,3mmol),Pd(AcO)
2(45mg,0.2mmol),Xantphos(116mg,0.2mmol),碳酸铯(1.6g,5mmol)溶于甲苯(20mL),100℃反应16小时。反应完全后,加入乙酸乙酯(30mL),然后用水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,滤液旋干,粗品用柱层析纯化(V
石油醚:V
乙酸乙酯=10:1)得到136-2(70mg,产率20%),[M+H]
+:176.2。
步骤2:1-(2-((2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸-9-基)乙基)氨基)甲基)苯基)氮杂丁-2-酮(136)的合成
氮气保护下,将136-2(70mg,0.40mmol),中间体A(104mg,0.40mmol),硫酸镁(480mg,4.0mmol),二氯甲烷(10mL)依次加入单口瓶中,室温搅拌16h,加入硼氢化钠(46mg,1.20mmol),搅拌10分钟,加入甲醇(1mL),搅拌反应2小时。反应完后,加入二氯甲烷(10mL),过滤,室温浓缩过柱(V
二氯甲烷:V
甲醇=10:1)得到淡黄色稠状物136(30mg,产率18%),[M+H]
+:420.2。
1H NMR(400MHz,CDCl
3)δ8.55(dd,J1=0.8Hz,J2=4.8Hz,1H),7.62(dt,J1=2.0Hz,J2=8.0Hz,1H),7.28(d,J=8.0Hz,1H),7.20-7.11(m,2H),7.02-6.90(m,1H),6.78(t,J=7.6Hz,1H),6.60(d,J=7.6Hz,1H),3.90-3.71(m,6H),3.15(t,J=4.4Hz,2H),2.53-2.30(m,3H),2.10-1.89(m,3H),1.79-1.66(m,4H),1.57-1.37(m,4H), 1.14-1.09(m,1H),0.74-0.66(m,1H)。
化合物136-P1的合成方法参考化合物136的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例96
氮-(7-苯并噻吩)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物131)和(R)氮-(7-苯并噻吩)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺(化合物131-P1)的合成
步骤1:氮-(7-苯并噻吩)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙胺的合成
将中间体A(100mg,384.40μmol),131-1(62.2mg,384.40μmol),无水硫酸钠(100mg,709.2μmol)和二氯甲烷(5mL)在室温下搅拌反应12小时,加入硼氢化钠(29.05mg,768μmol)搅拌反应0.5小时,然后加入1ml无水甲醇,并在常温下搅拌2小时。反应停止后,冷却到室温,并反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(洗脱液:V
DCM/V
MeOH=50/1到10/1)得到淡黄色稠状油化合物131(20mg),产率12.9%,纯度96%,[M+H]
+:407.2。
1H NMR(400MHz,Chloroform-d)δ8..54-8.52(m,1H),7.79-7.77(m,1H),7.63-7.61(m,1H),7.59-7.48(m,2H),7.46-7.42(m,2H),7.29–7.20(m,1H),7.11–7.09(m,1H),3.98-3.97(m,2H),3.76-3.75(m,2H),2.61-2.60(m,1H),2.45-2.42(m,1H),2.36-2.33(m,1H),2.23– 2.21(m,1H),2.06–2.03(m,1H),2.02–2.01(m,1H),1.94–1.68(m,7H),1.55-1.51(m,1H),1.49-1.46(m,1H),1.28-1.26(m,1H),0.78-0.75(m,1H)。
化合物131-P1的合成方法参考化合物131的合成路线,主要区别为将中间体A替换成中间体A-1。
实施例97
2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)-氮-(喹啉-5-甲基)乙胺(化合物134)的合成
步骤1:2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)-氮-(喹啉-5-基甲基)乙胺的合成
将化合物134-1(100mg,637μmol),中间体A(166mg,637μmol),硫酸钠(904mg,6.37mmol)依次加入到DCM(6mL)溶解,用氮气置换气体三次,搅拌过夜(12h)。反应完后,冷却至0℃,再将NaBH
4(47.1mg,1.27mmol)加入到反应瓶中还原,低温搅拌30min,然后加入2ml无水甲醇,并在常温下搅拌2小时。反应停止后,冷却到室温,并反应液用硅藻土过滤,滤液减压旋干,粗品用柱层析(洗脱液:V
DCM/V
MeOH=50/1到10/1)得到淡黄色稠状油化合物134(50mg),产率40%,纯度96%,[M+H]
+:402.6。
1H NMR(400MHz,Chloroform-d)δ8.78(d,J=4.4Hz,1H),8.55(ddd,J=4.8,1.9,0.9Hz,1H),8.09(dt,J=8.6,0.9Hz,1H),7.96–7.93(m,1H),7.69(ddd,J=8.4,6.9,1.4Hz,1H),7.60–7.52(m,2H),7.28(t,J=1.1Hz,1H),7.24(d,J=4.4Hz,1H),7.09(ddd,J=7.5,4.8,1.0Hz,1H),4.07(t,J=1.2Hz,2H),3.79–3.73(m,2H),2.58(dt,J=11.0,5.5Hz,1H),2.41(ddd,J=31.0,13.8,2.4Hz,2H),2.20(td,J=11.0,5.0Hz,1H),2.08–2.01(m,1H),1.93(d,J=13.7Hz,1H),1.83–1.61(m,6H),1.50(td,J=12.1,10.2,4.9Hz,3H),1.38(dd,J=9.1,5.0Hz,1H),1.11(dd,J=6.4,3.6Hz,1H)。
生物学评价
Op-Mu激动剂cAMP测试实验
本发明的化合物可以激活μ-阿片受体(MOR)。激活的MOR可以调节细胞内cAMP的水平,cAMP进入细胞核与报告基因荧光素酶(Luciferase)的CRE区结合,启动报告基因的表达。荧光素酶与其底物反应可发出荧光,通过测定荧光信号反映化合物的激动活性。
实验方法
实施例化合物激动MOR影响下游cAMP水平变化的活性通过以下的方法进行测试。
1.材料与试剂
产品名称 | 供应商 | 货号 | 批次号. |
MOR/HEK293细胞 | WuXi | NA | NA |
HBSS | Gibco | 14025-076 | 1929982 |
IBMX | Sigma | I5879 | STBF6061V |
DAMGO | Sigma | E7384 | NA |
Forskolin | CSN pharmaceuticals | 11051-10mg | CSN11051-001 |
384孔板 | PerkinElmer | 6007299 | NA |
2.实验操作步骤
检测缓冲液:1×stimulation buffer,500μM IBMX,ddH
2O。
化合物配制:化合物用DMSO溶解后配制为终浓度为10mM的母液,稀释成0.08mM的工作浓度,用Echo对化合物进行4倍梯度稀释,初始浓度为0.08mM,10个浓度梯度,并分别加50nL到384细胞板中,双复孔,终浓度为0.4μM,然后将细胞板1000rpm离心1min。用Echo转移50nL Forskolin(终浓度是1μM)至384细胞板中。
细胞铺板:将冻存的细胞融化,1000转离心5min,弃掉上清液,用HBSS缓冲液清洗两次细胞后,用检测缓冲液重悬细胞,将细胞密度调整到5.0×10
5个/mL,加入至384孔板中,每孔10μL,5000个细胞。震荡20s,1000rpm离心1min,将细胞板放入23℃孵箱中培养60min。
标准曲线的配制:用检测缓冲液对标准品cAMP进行4倍梯度稀释,共8个浓度点,最高浓度是800nM,按照微孔板布局图每孔加入10μL。
检测试剂配制:用裂解缓冲液将中间体Anti cAMP-Cryptate和AMP-d2稀释至1×,按照微孔板布局图,每孔加入10μL检测试剂,震荡20s,1000rpm离心1min,将细胞板放入23℃孵箱中培养60min;在Envision上读板。
3.结果分析
运用Microsoft Excel软件计算活性百分比,对于激动剂使用公式%Effect=100×(Sample Raw Value-Low Control Average)/(High Control Average-Low Control Average),运用GraphPad Prism 5数据分析软件,对于激动剂选用Dose-response-Stimulation—log[agonist]vs.response--Variable slope模式进行拟合分析,得出各检测样品的EC
50(半最大效应浓度)值。
本发明的化合物激动MOR影响下游cAMP水平的变化通过以上的试验进行测定,实验结果表明此系列化合物表现出较强的Op-Mu激动效应,其中测得的具有典型代表的化合物的EC
50值见表一。其中,设置两组对照组TRV130(消旋)和TRV130,分别具有以下结构式;E
max为化合物引起cAMP水平变化的最大效能。
表一:受试化合物对Mu阿片受体影响cAMP水平的EC
50和E
max
化合物编号 | EC 50(nM) | E max |
11 | 2.150 | 99.6 |
14 | 0.526 | 76.4 |
17 | 2.206 | 74.6 |
37 | 3.866 | 71.9 |
38 | 2.074 | 70.1 |
41 | 0.500 | 75.2 |
41-P1 | 1.204 | 68.7 |
42 | 4.480 | 77.7 |
45 | 2.469 | 76.2 |
48 | 4.939 | 82.3 |
48-P1 | 2.914 | 91.2 |
49 | 3.514 | 93.3 |
49-P1 | 3.501 | 90.3 |
50 | 9.553 | 86.9 |
51 | 1.215 | 76.6 |
52 | 46.540 | 71.8 |
53 | 5.228 | 60.7 |
54 | 12.840 | 60.2 |
56 | 0.048 | 78.2 |
57 | 18.800 | 60.0 |
58 | 0.699 | 85.5 |
58-P1 | 1.019 | 93.0 |
60 | 7.808 | 90.5 |
61 | 2.823 | 79.5 |
63 | 0.644 | 73.3 |
63-P1 | 2.694 | 79.6 |
64 | 1.224 | 96.0 |
64-P1 | 3.114 | 91.2 |
65 | 7.120 | 93.2 |
69 | 9.120 | 84.5 |
71 | 7.210 | 73.9 |
77 | 0.887 | 98.6 |
77-P1 | 0.982 | 88.6 |
90 | 5.114 | 83.0 |
93 | 4.327 | 70.6 |
94 | 2.736 | 78.6 |
95 | 4.423 | 71.4 |
95-P1 | 2.388 | 80.2 |
97 | 2.675 | 90.5 |
107 | 2.920 | 90.6 |
111 | 3.013 | 67.3 |
115 | 2.520 | 84.0 |
116 | 6.430 | 74.1 |
121 | 0.536 | 77.5 |
121-P1 | 1.021 | 83.2 |
123-P1 | 7.360 | 76.6 |
124 | 4.790 | 83.8 |
124-P1 | 4.010 | 93.0 |
129 | 0.980 | 81.3 |
129-P1 | 1.240 | 87.1 |
131-P1 | 0.171 | 92.5 |
134 | 6.306 | 85.4 |
136-P1 | 0.880 | 89.6 |
TRV130(消旋) | 5.749 | 81.8 |
TRV130 | 2.791 | 75.3 |
本发明实施例的优选化合物对Mu阿片受体具有明显的激动作用,部分化合物EC
50值和E
max远优于对照组。
Op-Kappa激动剂cAMP测试实验
ForsKolin(毛喉素)能够刺激人K阿片受体高表达细胞株-OPRKI细胞(DiscoveRx) cAMP的释放,而K阿片受体激动剂能够抑制forsKolin刺激的cAMP释放。通过检测受试化合物对forsKolin刺激的cAMP释放的抑制作用,能够测定化合物对人K片受体的激动活性。首先用一定浓度的forsKolin和不同浓度的受试化合物与人高表达K阿片受体细胞株一起孵育。使用基于时间分辨荧光共振能量转移(TR-FRET)的cAMP免疫测试法(LANCEPerKinElmer)来确定所激发的OPRK1细胞中的cAMP水平。具体方法如下:
检测缓冲液:1×stimulation buffer,500μM IBMX,ddH
2O。化合物配制:化合物用DMSO溶解后配制为终浓度为10mM的母液,稀释成2mM的工作浓度,用Echo对化合物进行4倍梯度稀释,初始浓度为2mM,10个浓度梯度,并分别加50nL到384细胞板中,双复孔,终浓度为10μM,然后将细胞板1000rpm离心1min;用Echo转移50nL ForsKolin(终浓度是3μM)至384细胞板。
细胞铺板:将冻存的细胞融化,1000转离心5min,弃掉上清液,用HBSS缓冲液清洗两次细胞后,用检测缓冲液重悬细胞,将细胞密度调整到3.0×10
5个/mL,加入至384孔板中,每孔10μL,3000个细胞。震荡20s,1000rpm离心1min,将细胞板放入23℃孵箱中培养60min。标准曲线的配制:用检测缓冲液对标准品cAMP进行4倍梯度稀释,共8个浓度点,最高浓度是800nM,按照微孔板布局图每孔加入10μL。检测试剂配制:用裂解缓冲液将中间体Anti cAMP-Cryptate和AMP-d2稀释至1×,每孔加入10uL检测试剂,震荡20s,1000rpm离心1min,将细胞板放入23℃孵箱中培养60min。最后在Envision上读板。
运用Microsoft Excel软件计算活性百分比,对于激动剂使用公式%Effect=100×(Sample Raw Value-Low Control Average)/(High Control Average-Low Control Average)。运用GraphPad Prism 5数据分析软件,对于激动剂选用Dose-response-Stimulation—log[agonist]vs.response--Variable slope模式进行拟合分析,得出各检测样品的EC
50值。实验数据见表二。
表二:受试化合物对K阿片受体影响
化合物编号 | EC 50(nM) | E max |
TRV130(消旋) | 189.6 | 56.2 |
6 | 365.5 | 55.2 |
11 | 232.2 | 46.5 |
38 | 19071 | 30.5 |
41 | >10000 | 1.4 |
58 | 14717 | 36.3 |
63 | 664.6 | 33.0 |
64 | 518.3 | 42.1 |
77 | 436.2 | 61.5 |
本发明实施例化合物对激动K阿片受体的活性相比对照组明显较弱;表现出本发明化合物对MOR受体有高的选择性,推测本发明实施例化合物具有更低的副作用。
Mμ阿片受体的β-arrestin信号通路的活性测试实验
本研究旨在通过CHO-K1/Arrestin/hMOR的EC
50和E
max测定来评估靶向μ-阿片受体MOR的激动剂的β-Arrestin招募效率。CHO-K1/Arrestin/hMOR细胞株表达与β-半乳糖苷酶供体片段融合的hMOR和与β-半乳糖苷酶受体片段融合的β-Arrestin。当β-arrestin与hMOR相互作用时,这些片段形成活性的β-半乳糖苷酶。准备384孔板,将60nL/孔系列稀释的化合物滴入384孔板,将20μLCHO-K1/Arrestin/hMOR细胞浮液注入测定板,细胞密度为7.5k细胞/孔。37℃,0.5%CO
2(体积分数,其余为空气)孵育分析板120分钟,用蜻蜓法将10μL/孔检测试剂加入分析板中,培养皿在室温孵育60分钟,通过Envision检测化学发光信号,使用XLfit进行数据分析。实验数据见表三。
表三:受试化合物对β-arrestin信号通路的影响
化合物编号 | EC 50(μM) | E max |
TRV130(消旋) | 0.30 | 6.20 |
38 | 2.79 | 3.10 |
41 | 2.12 | 4.10 |
58 | 0.39 | 2.52 |
63 | 0.45 | 3.37 |
77 | 0.47 | 7.36 |
本发明实施例化合物对β-arrestin信号通路几乎无激活作用,以及本发明化合物和对照组相比有更好的偏向性(cAMP与β-arrestin信号通路),推测本发明化合物相比对照组具有更低的副作用。
测试本发明化合物对hERG钾电流的阻断作用
试验系统
细胞:中国仓鼠卵巢(CHO)细胞系,CHO-hERG细胞用于本试验。
细胞培养液及培养条件:完全培养基为F12培养基,补充加入10vol%胎牛血清,1vol%
选择性抗生素(G418),89μg/mL潮霉素B(HB)。复苏培养基为F12培养基补充加入10vol%胎牛血清。CHO-hERG细胞生长在37℃(±2℃)、5%CO
2(4%至8%)的高湿度培养箱中。细胞用复苏培养基复苏,完全培养基传代,用于膜片钳试验的细胞在最后一次传代时换成复苏培养基。
细胞外液及内液成分:
试剂 | 外液(mM) | 内液(mM) |
CaCl 2 | 2 | 5.37 |
MgCl 2 | 1 | 1.75 |
KCl | 4 | 120 |
NaCl | 145 | - |
Glucose | 10 | - |
HEPES | 10 | 10 |
EGTA | - | 5 |
Na 2ATP | - | 4 |
pH | 7.3-7.4 | 7.2-7.3 |
试验方法
(1)将处于指数生长期的CHO-hERG细胞收集并重悬在ECS中备用。
(2)手动膜片钳试验
全细胞膜片钳技术下记录hERG电流,记录温度为室温。膜片钳放大器输出信号通过数模转换以及2.9KHz低通滤波。数据记录用Patchmaster Pro软件采集。
细胞种在细胞记录槽中放置在倒置显微镜载物台上,随机选择记录槽中的一个细胞进行试验。灌流系统固定在倒置显微镜载物台上用ECS持续灌流细胞。
用毛细玻璃管制备手动膜片钳试验记录微电极,其中充灌细胞內液。在膜片钳试验当天,使用硼硅酸盐玻璃管(BF150-117-10,SUTTER INSTRUMENT USA)制备电极。电极充灌ICS后电阻在2-5MΩ之间。
钳制电压为-80mV,第一步去极化至+60mV并维持850ms开放hERG通道。然后,电压设置为-50mV并维持1275ms,产生反弹电流或者称为尾电流,尾电流的峰值将被测量并用于分析。最后,电压恢复到钳制电压(-80mV)。试验过程中,这个指令电压程序每间隔15s重复一次。
在溶媒对照工作溶液灌流的记录开始阶段,监测尾电流峰值直至稳定3条以上扫描曲 线后则可以灌流待测试的供试品/阳性对照工作溶液,直到供试品/阳性对照工作溶液对hERG电流峰值的抑制作用达到稳定状态。一般以最近的连续3个电流曲线峰值基本重合作为判断是否稳定状态的标准。达到稳定态势以后继续灌流下一浓度供试品。一个细胞上可以测试一个或多个供试品/阳性对照,或者同一种药物的多个浓度,不同供试品/阳性对照之间需用溶媒对照工作液冲洗直到hERG电流回复到加药物之前80%以上的大小。同一浓度下各记录细胞抑制率的标准差不超过15%。
阳性对照西沙必利的测试浓度为0.1μM,重复测定两个细胞。根据科学文献报道,0.1μM的西沙必利抑制hERG电流超过50%。(Milnes,J.T.,et al.)。
(3)手动膜片钳数据接受标准
封接标准:全细胞模式形成后,施加钳制电压(-80mV),可以记录到细胞膜相关参数(Cm,Rm以及Ra)。一个好的的全细胞记录应该满足以下条件:路径电阻(Rs)小于10MΩ;膜电阻(Rm)大于500MΩ和膜电容(Cm)小于100pF。
电流大小:供试品/阳性对照品作用前峰电流幅度在400pA和5000pA之间。否则,放弃该细胞。
漏电流:在-80mV的钳制电压下,漏电流绝对值应该小于200pA。电流幅度将会用-80mV下的漏电流校正。漏电流绝对值大于200pA的扫描曲线不能用于分析。
数据分析
对于每个细胞,每一个浓度的供试品及阳性对照的抑制百分比由记录到的电流反应用以下公式算出:(1–供试品/阳性对照灌流后记录到的尾峰值电流/溶媒对照灌流记录到的尾峰值电流(起始电流))×100%。
对于每一个浓度记录到所有的细胞抑制百分比取均值,IC
50(半数抑制浓度)值由Hill拟合的方法由浓度效应曲线中得出。
试验结果
本发明部分化合物对hERG电流的抑制结果,具体见下表四;
表四:受试化合物对hERG电流的抑制结果
化合物编号 | IC 50 |
41-P1 | +++ |
48-P1 | + |
49-P1 | +++ |
58-P1 | ++ |
64-P1 | +++ |
77-P1 | +++ |
95-P1 | ++ |
121-P1 | ++ |
124-P1 | ++ |
129-P1 | ++ |
131-P1 | +++ |
136-P1 | ++ |
TRV130 | + |
注:IC
50>20μM为+++,20μM>IC
50>10μM为++,10μM>IC
50>1μM为+。
本发明实施例化合物相比对照组具有较高的hERG IC
50值,具有显著差异,表现出对hERG抑制作用更弱,说明本发明化合物的心脏毒性风险较低。
药代动力学实验
被研究化合物单次口服或者静脉给药(溶媒5vol%DMSO+10vol%聚乙二醇-15羟基硬脂酸酯(Solutol(HS-15))+85vol%生理盐水(saline))于动物(例如小鼠、大鼠、犬或者猴子),在固定的时间点取血。血样采集后,立即温和地颠倒试管至少5次,保证混合充分后放置于冰上。血液用肝素抗凝,然后8000rpm离心5分钟,将血清与红细胞分离。用移液器吸岀血清转移至2mL的聚丙烯管,标明化合物的名称和时间点,在进行LC-MS分析前保存在-40℃冰箱,待测。髙浓度样品用空白血浆稀释测定时。样品处理后,用LCMS/MS对血浆中的物质进行定量分析。通过进行了验证的药动学计算机程序,用以这种方式获得的血浆浓度/时曲线来计算药动学参数。实验发现本发明化合物均具有较好的药代动力学性质。
SD雄性大鼠以表五组别剂量静脉给药后(各组为等摩尔剂量给药,溶媒为5vol%DMSO+10vol%Solutol(HS-15)+85vol%saline,每组3只),在固定的时间点取血检测。本发明的部分化合物的在大鼠血浆中的原型化合物药代动力学参数如下表五;表五中,IV为静脉给药,AUC为血浆浓度-时间曲线下面积,C
max为最大血药浓度,T
1/2为消除半衰期,Variable为变量,Mean为平均数,SD为标准差。
表五:受试化合物药代动力学参数
本发明实施例化合物在大鼠体内展现出良好的药代动力学性质;与对照组相比,本发明化合物在血浆中游离碱的AUC(h*ng/mL)均有显著提高。
大鼠热板法镇痛药效实验
雌性SD大鼠,将大鼠开始训练日期记为D0。于D0,将测痛仪温度设定为52℃(52.0±0.5℃),大鼠置于热板同时计时,记录大鼠出现舔后足或跳跃时痛阈值所用的时间(s)。若大鼠于热板上超过30s没有出现热痛反应,立即取出大鼠,痛阈值记为30s。淘汰反应敏感和反应迟钝大鼠。于D1,取预筛后的大鼠,将测痛仪温度设定为52℃(52.0±0.5℃),大鼠置于热板并计时,记录大鼠出现舔后足或跳跃时痛阈值所用的时间(s),共测三次。以三次平均值作为大鼠baseline痛阈值。于D1,大鼠根据baseline痛阈值随机分组,每组8只动物。于D2,按照表中各剂量组,通过尾静脉注射方式(IV)给予溶媒或化合物(各组等摩尔剂量给药,溶媒为5vol%DMSO+10vol%Solutol(HS-15)+85vol%saline)。于D2,各组大鼠给药后0.5min、0.5h、1h、3h,将测痛仪温度设定为52℃(52.0±0.5℃),大鼠置于热板并计时,记录大鼠出现舔后足或跳跃时痛阈值所用的时间(s),每个时间点测1次。若大鼠于热板上超过30s没有出现热痛反应,立即取出大鼠,痛阈值记为30s。计算各组各个时间点痛阈%MPE,评价各受试样品体内镇痛药效。实验数据以Mean±SEM表示,各组间数据采用GraphPad Prism进行方差分析(ANOVA)检验(Two Way ANOVA或One-Way ANOVA),P<0.05认为是有显著性差异。最大镇痛效应百分率(即痛阈%MPE)=(给药后痛阈值-基础痛阈值)/(30-基础痛阈值)×100%,实验结 果下表六;表六中,Variable为变量,Average为平均数,SEM为标准误差。
表六:受试化合物体内镇痛药效
注:与对照组(溶媒,IV)相比,*p<0.05,**p<0.01,***p<0.001
本发明实施例的化合物相比对照组展现出更好的镇痛效果,在大鼠热板法镇痛药效研究中表现出痛阈更高,持续时间更长久的镇痛作用。
急性毒性实验
化合物单次静脉给药(溶媒5vol%DMSO+10vol%Solutol(HS-15)+85vol%saline)于SD大鼠(每个化合物设置4-6剂量组,每剂量组10只,雌性各半),给药后后进行临床观察。临床观察第一天两次,第二天开始一天一次,连续14天。包括行为学观察、自主活动和神经系统行为和死亡情况等,得到化合物的最大耐受量(MTD值)和半数致死量(LD
50值)。实验结果显示本发明化合物在大鼠单次静脉给药的MTD值和LD
50值相比对照组有显著提高,表明本发明化合物具有良好的安全性。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明保护的范围之内。
Claims (10)
- 式(Ⅰ)所示的化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,其中,环B为取代的或未取代的芳基、取代的或未取代的杂芳基;Z 1、Z 2、Z 3、Z 4、Z 5、Z 6中任一个为C,其它各自独立的选自CR 2、N;X 1选自-S(=O) m、O、NH或NR 4;R 4各自独立的选自-C 1-6烷基或-C 1-6烷基-O-C 1-6烷基;X 2、X 3、X 4、X 5中任一个为C,其它各自独立的选自CR 3、N;所述每个R 2、R 3各自独立的选自H、卤素、-OH、-CN、-C 1-6烷基、-NH 2、-NH-C 1-6烷基、-C 1-6烷基-NH-C 1-6烷基、-C 1-6烷基-O-C 1-6烷基、-O-3至12元杂环基、-O-C 1-6烷基、-(CH 2) g-3至12元环烷基、-(CH 2) g-3至12元杂环基、5至10元杂芳基、5至10元芳基、-S(=O) f-C 1-6烷基、-O-C 2-6炔基、-O-C 2-6烯基、-C 2-6烯基、-C 2-6炔基;其中,所述杂环基、环烷基、杂芳基、芳基、烷基、炔基、烯基可任选进一步被1至3个R b所取代;所述R b各自独立的选自H、卤素、-OH、-CN、-C 1-6烷基、氧代、-NH 2、-NH-C 1-6烷基、-S(=O) f-C 1-6烷基、-C 1-6烷基-O-C 1-6烷基、-O-C 1-6烷基、3至6元环烷基、-O-C 2-6炔基、-O-C 2-6烯基、-C 2-6炔基、-C 2-6烯基;或者相邻两个C原子上的两个R 2或两个R 3与其相连的C原子一起形成3至12元杂环基、3-12元环烷基、5至10元杂芳基、5至10元芳基;其中,所述杂环基、环烷基、杂芳基、芳基可任选进一步被1至4个R 1所取代;所述R 1各自独立的选自-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、卤素、-NH 2、-NH-C 1-6烷基、-OH、-O-C 1-6烷基、-O-C 2-6炔基、-O-C 2-6烯基、NR bR b、-S(=O) f-C 1-6烷基、3-6元环烷基、CN、5至10元芳基;所述g选自0、1、2、3、4;所述f选自0、1、2;所述m选自0、1、2。
- 根据权利要求1所述的化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,其特征在于,所述化合物选自式(Ⅱ)或(Ⅲ)所示结构;其中,所述R 2、R 3各自独立的选自3-6元单杂环基、7-10元并杂环基、7-11元螺杂环基、7-11元桥杂环基;所述R a选自H、卤素、-OH、-CN、-C 1-6烷基、-NH 2、-NH-C 1-6烷基、-C 1-6烷基-NH-C 1-6烷基、-C 1-6烷基-O-C 1-6烷基、-O-C 1-6烷基、-S(=O) f-C 1-6烷基、-O-C 2-6炔基、-O-C 2-6烯基、-C 2-6烯基、-C 2-6炔基;所述单杂环基可任选进一步被1至3个R b所取代。
- 根据权利要求1所述的化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,其特征在于,所述每个R 2、R 3各自独立的选自4元单杂环基,其中所述单杂环基任选进一步被1至3个R b所取代;所述每个R b各自独立选自卤素、-C 1-6烷基、-OH、氧代、-NH 2、-NH-C 1-6烷基、-S(=O) 2-C 1-6烷基、-O-C 1-6烷基、-O-C 2-6炔基、-O-C 2-6烯基、-C 2-6炔基、-C 2-6烯基。
- 一种药物组合物,所述药物组合物包括权利要求1至8中任一项所述的化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,以及药学上可接受的载体。
- 根据权利要求1至8中任一项所述的化合物、其溶剂化物、立体异构体、氘代化合物或其药学可接受的盐,或根据权利要求9所述的药物组合物在制备预防和/或治疗MOR受体激动剂介导的相关疾病的药物中的用途,所述的MOR受体激动剂介导的相关疾病选自疼痛、免疫功能障碍、炎症、食管回流、神经和精神疾病、泌尿和生殖疾病、心血管疾病和呼吸疾病,其中所述疼痛选自术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛。
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