WO2018224037A1 - 作为at2r受体拮抗剂的羧酸衍生物 - Google Patents

作为at2r受体拮抗剂的羧酸衍生物 Download PDF

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WO2018224037A1
WO2018224037A1 PCT/CN2018/090432 CN2018090432W WO2018224037A1 WO 2018224037 A1 WO2018224037 A1 WO 2018224037A1 CN 2018090432 W CN2018090432 W CN 2018090432W WO 2018224037 A1 WO2018224037 A1 WO 2018224037A1
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compound
group
pharmaceutically acceptable
compound according
acceptable salt
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PCT/CN2018/090432
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English (en)
French (fr)
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张杨
伍文韬
李志祥
滕明星
杨广文
李婕
黎健
陈曙辉
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南京明德新药研发股份有限公司
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Priority to CN201880029881.6A priority Critical patent/CN110914243B/zh
Priority to AU2018279669A priority patent/AU2018279669B8/en
Priority to ES18813230T priority patent/ES2878313T3/es
Priority to KR1020207000587A priority patent/KR102132761B1/ko
Priority to JP2019567596A priority patent/JP6873284B2/ja
Priority to EP18813230.2A priority patent/EP3620454B1/en
Publication of WO2018224037A1 publication Critical patent/WO2018224037A1/zh
Priority to US16/700,978 priority patent/US11021445B2/en

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    • 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
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound of the formula (II) or a pharmaceutically acceptable salt thereof, and to its use in the preparation of a medicament for treating an angiotensin II receptor 2 (AT 2 R)-related disease.
  • Angiotensin II is an octapeptide substance produced by the hydrolysis of angiotensin I under the action of angiotensin converting enzyme, which has the functions of regulating blood pressure, body fluid balance and pain perception.
  • Angiotensin receptors are G-protein coupled receptors that use angiotensin as a ligand and are an important component of the renin-angiotensin system.
  • AngII activates angiotensin II receptor 1 (AT 1 R) and angiotensin II receptor 2 (AT 2 R).
  • AT 1 R angiotensin II receptor 1
  • AT 2 R angiotensin II receptor 2
  • AT 2 R is related to the pain mechanism in the nervous system, mainly expressed in the dorsal root ganglia and the trigeminal ganglion.
  • AT 2 R antagonists have been demonstrated to be useful for mitigation in animal experiments (Pain. Medicine. 2013, 14, 1557-1568; Pain. Medicine. 2013, 14, 692-705) clinical trials (Lancet. 2014, 383, 1637-1647) pain.
  • a related review report can be found in Expert Opin. Investig. Drugs. 2014, 23, 1-12; Expert. Opin. Ther. Targets. 2015, 19, 25-35.
  • WO 2011088504 discloses compound EMA-401.
  • the present invention provides a compound of the formula (I) and a pharmaceutically acceptable salt thereof,
  • L 1 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -;
  • R 1 is selected from C 1 1-6 alkyl, C 1-6 heteroalkyl, C 3-7 cycloalkyl, 3 to 7-membered heterocycloalkyl, optionally substituted by 1, 2 or 3 R; ⁇ 10-membered aryl, 5- to 6-membered heteroaryl;
  • R 2 is selected from the group consisting of H, halogen, OH, NH 2 , CN, and is selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 3 is selected from the group consisting of 1, 2 or 3 R substituted: phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl;
  • R 4 is selected from H or is selected from C 1 - 3 alkyl optionally substituted by 1, 2 or 3 R;
  • R is selected from H, halogen, OH, NH 2 , CN, or selected from: C 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R';
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, CN, NH 2 ;
  • a carbon atom with a "*" is a chiral carbon atom, in the form of a single enantiomer of (R) or (S) or in the form of one enantiomer;
  • a carbon atom with a "#" is a chiral carbon atom, in the form of a single enantiomer of (R) or (S) or in the form of one enantiomer;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the carbon atom bearing a "*" or "#" is a chiral carbon atom, or is present as a single enantiomer (R) or (S) or enriched in one enantiomer.
  • An isomer refers to a content of one of the isomers ⁇ 100%, and ⁇ 60%, preferably ⁇ 70%, more preferably ⁇ 80%, more preferably ⁇ 90%, more preferably ⁇ 95%, more preferably ⁇ 96%, more preferably ⁇ 97%, more preferably ⁇ 98%, more preferably ⁇ 99%, more preferably ⁇ 99.5%, more preferably ⁇ 99.6%, more preferably ⁇ 99.7%, more preferably ⁇ 99.8%, more preferably ⁇ 99.9% .
  • the above R is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from: 1, 2 or 3 R' substituted: C 1-3 alkyl, C 1-3 Alkoxy.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, Et, CF 3 ,
  • R 1 is selected from C 1 1-4 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl, optionally substituted by 1, 2 or 3 R; ⁇ 10-membered aryl, 5- to 6-membered heteroaryl.
  • R 1 is selected from the group consisting of 1, 2 or 3 R substituted: C 1-4 alkyl, C 4-6 cycloalkyl, acetobutyl, tetrahydrofuranyl, tetrahydrogen Pyranyl, phenyl, naphthyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, morpholinyl, piperazinyl, piperidinyl, pyridyl, pyrazinyl, pyrimidinyl.
  • R 1 is selected from the group consisting of: 1, 2 or 3 R: Me, Et,
  • R 1 is selected from the group consisting of Me, Et,
  • the structural unit From:
  • R 2 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylthio, C 1-3 alkylamino.
  • R 2 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me,
  • R 3 is selected from the group consisting of: 1, 2 or 3 R substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazole Base, isoxazolyl, tetrahydropyranyl, piperidinyl, morpholinyl.
  • R 3 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • R 3 is selected from the group consisting of
  • the structural unit From:
  • R 4 is selected from the group consisting of: H, Me.
  • the above R is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from: 1, 2 or 3 R' substituted: C 1-3 alkyl, C 1-3 Alkoxy, other variables are as defined above.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, Et, CF 3 , Other variables are as defined above.
  • R 1 is selected from C 1 1-4 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl, optionally substituted by 1, 2 or 3 R; ⁇ 10-membered aryl, 5- to 6-membered heteroaryl, and other variables are as defined above.
  • R 1 is selected from the group consisting of 1, 2 or 3 R substituted: C 1-4 alkyl, C 4-6 cycloalkyl, acetobutyl, tetrahydrofuranyl, tetrahydrogen Pyranyl, phenyl, naphthyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, morpholinyl, piperazinyl, piperidinyl, pyridyl, pyrazinyl, pyrimidinyl, others
  • the variables are as defined above.
  • R 1 is selected from the group consisting of: 1, 2 or 3 R: Me, Et, Other variables are as defined above.
  • R 1 is selected from the group consisting of Me, Et, Other variables are as defined above.
  • R 2 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, other variables are as defined above.
  • R 2 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, Other variables are as defined above.
  • the above R 3 is selected from the group consisting of: 1, 2 or 3 R substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazole
  • phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazole The base, isoxazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and other variables are as defined above.
  • R 3 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R: Other variables are as defined above.
  • R 3 is selected from the group consisting of Other variables are as defined above.
  • R 4 is selected from the group consisting of: H, Me, and other variables are as defined above.
  • the above compounds, and pharmaceutically acceptable salts thereof are selected from the group consisting of:
  • R, R 2 , R 3 , R 4 , L 1 , L are as defined above;
  • T is selected from N or CH;
  • D is selected from CH 2 or O
  • n, p are each independently selected from 0, 1, 2 or 3, and m and p are not selected from 0 or 3 at the same time;
  • n is selected from 0, 1, 2 or 3;
  • n is not selected from 3.
  • the present invention provides a compound of the formula (II) and a pharmaceutically acceptable salt thereof,
  • L 1 is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -;
  • R 1 is selected from C 1 1-6 alkyl, C 1-6 heteroalkyl, C 3-7 cycloalkyl, 3 to 7-membered heterocycloalkyl, optionally substituted by 1, 2 or 3 R; ⁇ 10-membered aryl, 5- to 6-membered heteroaryl;
  • R 2 is selected from the group consisting of H, halogen, OH, NH 2 , CN, and is selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 3 is selected from the group consisting of 1, 2 or 3 R substituted: phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl;
  • R 4 is selected from H or is selected from C 1 - 3 alkyl optionally substituted by 1, 2 or 3 R;
  • R 5 is selected from the group consisting of: H, F, Cl, Br, I, OH;
  • R 6 is selected from the group consisting of: H, F, Cl, Br, I, OH;
  • R is selected from H, halogen, OH, NH 2 , CN, or selected from C 1 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R'; : F, Cl, Br, I, OH, CN, NH 2 ;
  • a carbon atom with a "*" is a chiral carbon atom, in the form of a single enantiomer of (R) or (S) or in the form of one enantiomer;
  • a carbon atom with a "#" is a chiral carbon atom, in the form of a single enantiomer of (R) or (S) or in the form of one enantiomer;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the carbon atom bearing a "*" or "#" is a chiral carbon atom, or is present as a single enantiomer (R) or (S) or enriched in one enantiomer.
  • An isomer refers to a content of one of the isomers ⁇ 100%, and ⁇ 60%, preferably ⁇ 70%, more preferably ⁇ 80%, more preferably ⁇ 90%, more preferably ⁇ 95%, more preferably ⁇ 96%, more preferably ⁇ 97%, more preferably ⁇ 98%, more preferably ⁇ 99%, more preferably ⁇ 99.5%, more preferably ⁇ 99.6%, more preferably ⁇ 99.7%, more preferably ⁇ 99.8%, more preferably ⁇ 99.9% .
  • the above R is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from: 1, 2 or 3 R' substituted: C 1-3 alkyl, C 1-3 Alkoxy, other variables are as defined herein.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, Et, CF 3 , Other variables are as defined by the present invention.
  • R 1 is selected from C 1 1-4 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl, optionally substituted by 1, 2 or 3 R; ⁇ 10-membered aryl, 5- to 6-membered heteroaryl, and other variables are as defined in the present invention.
  • R 1 is selected from C 1 1-4 alkyl, cyclobutylalkyl, cyclopentyl, cyclohexane, bicyclo [3.1] which is optionally substituted by 1, 2 or 3 R.
  • R 1 is selected from the group consisting of: 1, 2 or 3 R: Me, Et, Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of Me, Et, Other variables are as defined by the present invention.
  • R 2 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, other variables are as defined herein.
  • R 2 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, Other variables are as defined by the present invention.
  • R 3 is selected from the group consisting of: 1, 2 or 3 R substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, oxazole Other, isoxazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, other variables are as defined herein.
  • R 3 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R: Other variables are as defined by the present invention.
  • R 3 is selected from the group consisting of Other variables are as defined by the present invention.
  • R 4 is selected from the group consisting of: H, Me.
  • R 4 is selected from the group consisting of: H, Me, and other variables are as defined above.
  • the above compounds, and pharmaceutically acceptable salts thereof are selected from the group consisting of:
  • R, R 2 , R 3 , R 4 , R 5 , R 6 , L 1 , L are as defined above;
  • T is selected from N or CH;
  • D is selected from CH 2 or O
  • n, p are each independently selected from 0, 1, 2 or 3, and m and p are not selected from 0 or 3 at the same time;
  • n is selected from 0, 1, 2 or 3;
  • n is not selected from 3.
  • the present invention provides a compound of the formula selected from the group consisting of:
  • the above compound is selected from the group consisting of
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease associated with an AT 2 R receptor.
  • the invention also provides the use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of chronic pain.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of the appropriate base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • Wedge and dashed keys unless otherwise stated Represents the absolute configuration of a stereocenter, using wavy lines Indicates a wedge key or a dashed key ( or ),use Indicates the relative configuration of the stereocenter.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted at most by two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • a heteroatom or heteroatom can be located at any internal position of a heteroalkyl group, including where the alkyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkyl) Oxyl) is a conventional expression and refers to those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 .
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: Bn for benzyl; aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl Urea hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent weight, Equal; CDI stands for carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CB
  • a series of compounds of formula (I) are synthesized by a simple preparation method to obtain a novel class of selective inhibitors of angiotensin II type 2 receptor (AT 2 R) for the treatment of chronic pain.
  • the compounds of the present invention all exhibit better biological activity in vitro and exhibit excellent pharmacokinetic properties in a variety of genera.
  • the aqueous phase was adjusted to pH 4 to 5 with a 1N aqueous citric acid solution, and then extracted with ethyl acetate (200 mL ⁇ 3).
  • the combined organic phase was washed with saturated brine (200 mL), dried over sodium sulfate Crude product.
  • the compound S-A1-1 (340.0 mg, 1.2 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6.0 mL) and water (3.0 mL), and lithium hydroxide monohydrate (283.0 mg, 11.8 mmol) was added. Stir at 20-25 ° C for 48 hours.
  • Phenol (193.9 mg, 2.1 mmol) was dissolved in N,N-dimethylformamide (10.0 mL), and then compound A12-1 (500.0 mg, 2.1 mmol) and potassium carbonate (854.1 mg, 6.2 mmol). After the reaction mixture was warmed to 80 ° C, stirring was continued for 16 hours. After cooling to room temperature, 20 mL of water was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (10 mL x 3).
  • A12-2 (100.0 mg, 390.2 ⁇ mol) was dissolved in a mixed solvent of ethanol (2.0 mL) and water (0.5 mL). After adding lithium hydroxide monohydrate (14.0 mg, 585.3 ⁇ mol), the reaction solution was further stirred at 20 ° C for 16 hours. 2 mL of water was added to the reaction mixture, and the pH was adjusted to 3 to 4 with 1N hydrochloric acid, and then extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated This compound was used in the next step without further purification.
  • 1 H NMR 400MHz, CHLOROFORM- d
  • ⁇ 7.35-7.26 (m, 4H), 7.02-6.84 (m, 6H), 5.32 (s, 1H).
  • the compound S-A21-1 (831.0 mg, 5.0 mmol) was dissolved in dichloromethane (10.0 mL), then magnesium perchlorate (111.6 mg, 500.0 ⁇ mol) and di-tert-butyl dicarbonate (2.5 g, 11.5). Mm). After the reaction mixture was heated to 40 ° C, the reaction was further stirred for 40 hours. After cooling to room temperature, the reaction solution was poured into 25 mL of water and extracted with dichloromethane (10 mL ⁇ 3). The combined organic layers were washed with EtOAc EtOAc m.
  • MS m / z: 342.1 [M + 1] + . [ ⁇ ] +9.8.
  • Trifluoroacetic acid salt of compound C2-5 (1.0 g, 2.4 mmol) was added to aqueous formaldehyde (1.2 g, 14.4 mmol, 37%), 1M diluted hydrochloric acid (20 mL) was added, and the mixture was warmed to 60 ° C Stir for 1 hour. The organic solvent was removed under reduced pressure to give the crude compound C2-6.
  • the crude product is purified by silica gel column chromatography (eluent: 0-10% methanol / dichloromethane). Liquid chromatography (column: Phenomenex luna C18 250*50mm*10 ⁇ m; mobile phase: [water (0.1%TFA)-ACN]; B%: 15%-40%, 23min) separation and purification, removal of most acetonitrile under reduced pressure
  • the aqueous phase was adjusted to pH 8-9 with saturated sodium carbonate, and extracted with dichloromethane (150.0 mL).
  • the combined organic phase was washed with saturated brine (200.0 mL).
  • the compound (-)-C2-2 (21.0 g, 62.2 mmol) was dissolved in hydrochloric acid (1M, 187.3 mL), and aqueous aqueous formaldehyde (15.1 g, 186.5 mmol, 13.9 mL, 37%) was added, and the reaction mixture was continued at 25 ° C Stir for 16 hours. Filtration and drying of the filter cake in vacuo gave the crude compound (-)-C2-3 hydrochloride, which was used in the next step without further purification.
  • the compound (-)-C2-2 (1.0 g, 1.8 mmol) was dissolved in 1,4-dioxane (15.0 mL) under a nitrogen atmosphere, and then potassium chloride (275.0 mg, 3.7 mmol) was added. Potassium fluoride (54.0 mg, 929.5 ⁇ mol), Pd 2 (dba) 3 (26.0 mg, 28.4 ⁇ mol) and di-tert-butyl (2',4',6'-triisopropyl-3,6-dimethyl Oxybiphenyl-2-yl)phosphine (40.0 mg, 82.5 ⁇ mol), the reaction mixture was warmed to 130 ° C and stirring was continued for 16 hours.
  • the compound (-)-C2-1 (6.0 g, 14.9 mmol) was dissolved in tetrahydrofuran (120.0 mL) and water (40.0 mL), and lithium hydroxide monohydrate (1.9 g, 44.8 mmol) was slowly added. Stirring was continued for 5 hours at 25 °C. The reaction mixture was adjusted to pH 5-6 with 1M EtOAc (EtOAc) (EtOAc (EtOAc) The organic solvent was removed by pressure to give the compound (-)-C6-1, which was used in the next step without further purification.
  • EtOAc EtOAc
  • the compound (-)-C6-2 (5.0 g, 15.4 mmol) was dissolved in hydrochloric acid (1M, 83.0 mL), and aqueous solution of formaldehyde (7.5 g, 92.6 mmol, 37%) was added, and the reaction mixture was warmed to 60 ° C and stirring was continued. After an hour, the ice water bath was cooled, and a solution of sodium acetate (10.1 g, 123.5 mmol) in water (40.0 mL) was added to the reaction system, and stirring was continued at 0 °C for 2 hours. Filtration, the filter cake was washed with water (50 mL) and dried in vacuo to afford compound (-)-C6.
  • the compound (-)-C2-2 (4.0 g, 7.3 mmol) was dissolved in methanol (100 mL), then triethylamine (1.5 g, 14.7 mmol, 2.0 mL) and wet palladium carbon (0.3 g, 10% purity) The hydrogen was replaced three times, and the reaction solution was further stirred at 25 ° C under 15 ° C hydrogen for 16 hours.
  • the compound (-)-C7-2 (2.4 g, 6.0 mmol) was dissolved in dioxane (30 mL), hydrogen chloride in dioxane (4M, 8 mL) was added, and the mixture was stirred at 25 ° C for 16 hours. . The organic solvent was removed under reduced pressure to give the compound (-)-C7 hydrochloride, which was used for the next step without further purification.
  • Step 1 Preparation of Compounds (-)-C8-1 and (-)-C9-1
  • the compound (-)-C7-1 (0.7 g, 2.3 mmol) was dissolved in EtOAc (10 mL). 5 mL of methanol was added to the reaction solution, and the organic solvent was removed under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (eluent: 10-25% ethyl acetate / petroleum ether) and further purified by high-performance liquid chromatography (column: Xtimate C18150*25mm*5 ⁇ m; mobile phase: [water (10mM NH 4 HCO 3 )-ACN]; B%: 45%-70%, 9.5min) isolated and purified to give compound (-)-C8-1 and compound ( -)-C9-1.
  • the compound (-)-C10-1 (1.0 g, 2.3 mmol) was dissolved in methanol (20.0 mL), and wet Pd/C (100.0 mg, 226.5 ⁇ mol, 5% purity) was added, and the hydrogen was replaced three times, and the reaction solution was at 15 Psi. Stirring was continued for 1.5 hours under a hydrogen atmosphere at 15-20 °C. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc.
  • the compound (-)-C1 (150.0 mg, 439.4 ⁇ mol) was dissolved in anhydrous dichloromethane (6.0 mL), and then HATU (200.0 mg, 527.2 ⁇ mol), pyridine (104.0 mg, 1.32 mmol) and A2 (156.0). Mg, 659.1 ⁇ mol). After the reaction mixture was stirred at 25 ° C for 16 hours, the organic solvent was concentrated under vacuum. The crude product was isolated and purified by silica gel chromatography (eluent: 50-100% ethyl acetate / petroleum ether).
  • the hydrochloride salt of the compound C2 (60.0 mg, 172.5 ⁇ mol) was dissolved in dichloromethane (3.0 mL), and triethylamine (69.8 mg, 690.0 ⁇ mol) and the compound S-A1 (49.4 mg, 224.2) were sequentially added under a nitrogen atmosphere. ⁇ mol) and HATU (98.4 mg, 258.7 ⁇ mol), and the reaction solution was further stirred at 25 ° C for 16 hours.
  • Protease inhibitor mixture free of ethylenediaminetetraacetic acid-1 tablets (Roche #11873580001) (50mL plus one piece)
  • the reference ligand PD123319 and the test compound were prepared as 750 ⁇ M mother liquor in DMSO; each compound was configured into 8 concentration gradients (up to a concentration of 750 uM, 3 fold dilution) and added to a master of 10 ul/well to 384 well plates.
  • the SPA beads were buffered to a mother liquor of 25 mg/ml;
  • the isotope [ 125 I]-Sar1-Ile8-Angiotensin II plus pure water was placed in a mother liquor of 50 uCi/ml.
  • the cell membrane overexpressing hAT2 in HEK-293 cells was prepared to 2.5 mg/ml in buffer.
  • a 50 ml solution containing 10 ⁇ g/ ⁇ l of magnetic beads and 0.05 ⁇ g/ ⁇ l of AT2 membrane solution was placed and mixed on a shaker. (100 rpm, 30 min).
  • the test plate finally contained 1.25 ⁇ g/well of hAT2 membrane and 250 ⁇ g/well of magnetic beads.
  • a 3.2 ml membrane mix was added to the compound test plate using a Multidrop Combi pipette, and 25 ⁇ l was added to each well.
  • 0.2 nM solution was prepared with 50 uCi/ml isotope [ 125 I]-Sar1-Ile8-Angiotensin II mother liquor buffer, 0.2 nM 125I was added to the compound test plate with Multidrop Combi pipette, 25 ⁇ l per well was added. volume of. The final concentration of the 125 I isotope was 0.1 nM.
  • test plate was centrifuged with a centrifuge at 1200 rpm for 1 min.
  • the centrifuged test plates were read with Microbeta.
  • test compound was dissolved in DMSO to prepare a 10 mmol/L stock solution.
  • 980 ⁇ L of dissolution medium was pipetted into a 2 mL screw-capped glass vial using a pipette (Eppendorf Research).
  • 20 ⁇ L of the stock solution of each test compound and the QC sample were added to a buffer solution corresponding to a kinetic detection solution of pH 7.4.
  • the final concentrations of test compound and DMSO solution were 200 ⁇ M and 2%, respectively. Pill cover.
  • the theoretical maximum concentration is 200 ⁇ M.
  • the mixture was shaken at 880 rpm for 24 hours at room temperature.
  • the vial was centrifuged for 30 minutes at 13,000 rpm. 200 ⁇ L of the supernatant was added to a 96-well plate using a digital pipette.
  • the solubility of the test compound was determined by high performance liquid chromatography, and the experimental results are shown in Table 2.
  • the research project used a specific probe substrate for each isoenzyme to evaluate the inhibitory effect of the test compound on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4).
  • the diluted series of test compound working solutions are added to the incubation system containing cofactors of human liver microsomes, probe substrate and circulation system, and the methanol content is about 1% (v/v) of the final incubation system. .
  • a control containing no solvent and containing a solvent as a control for enzyme activity (100%).
  • the concentration of the analyte in the sample was determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). The calculation is performed using the average of the concentrations of the samples (blank solvent, positive control inhibitor, or test compound). Non-linear regression analysis was performed on the average percent activity of the compound to be tested using SigmaPlot (V.11).
  • the IC 50 value is calculated by a three-parameter or four-parameter recursive logarithmic equation. The experimental results are shown in Table 3.
  • the compounds of the present invention have no inhibitory effect on five CYP isoenzymes, or the inhibitory effects are weak, indicating that there is less possibility of drug-drug interaction in humans.
  • the bidirectional permeability of the test compound in Caco-2 cells was measured, and whether the test compound was transported by efflux was tested.
  • the compound is dissolved in dimethyl sulfoxide (DMSO) or other suitable solvent to prepare a stock solution of the appropriate concentration.
  • DMSO dimethyl sulfoxide
  • a suitable internal standard (IS) is dissolved in acetonitrile (ACN) or other organic solvent as a stop solution.
  • ACN acetonitrile
  • Nadolol, metoprolol, digoxin, estrone 3-sulfate potassium (E3S) and GF120918 were used as hypotonic control compounds in this study.
  • Hypertonic control compounds, P-glycoprotein (P-gp) substrates, breast cancer resistance protein (BCRP) substrates, and efflux transporter inhibitors are prepared in DMSO and stored at ⁇ -30 ° C for 6 months.
  • HBSS Hanks Balanced Salt Solution
  • HEPES 4-[4-(2-hydroxyethyl)-1-piperazine]ethanesulfonic acid
  • Caco-2 cells were cultured in MEM medium (Minimum Essential Media) under the conditions of 37 ⁇ 1 ° C, 5% CO 2 and saturated humidity. The cells were then seeded in a Corning Transwell-96 well plate at a seeding density of 1 x 105 cells/cm 2 and then placed in a carbon dioxide incubator for 21-28 days for transport experiments, every four to five days during the period. Replace the medium once.
  • MEM medium Minimum Essential Media
  • Compounds were administered at concentrations of 2, 10 and 100 [mu]M and were administered in both bidirectional (A-B and B-A directions) with or without 100 GF120918 containing three replicates for each dosing concentration.
  • Digoxin and E3S were tested at 10 and 5 ⁇ M, respectively, and administered bi-directionally with or without 10 ⁇ M GF120918.
  • the test concentrations of nadolol and metoprolol were 2 ⁇ M, and were unidirectional (AB direction) without 10 ⁇ M GF120918.
  • the drug, three control compounds were also made in three parallels.
  • the dosing solution, receiving solution and transport buffer were pre-incubated for 30 minutes at 37 °C.
  • the cell layer was rinsed twice with transport buffer.
  • the dosing solution and the receiving solution were separately added to the corresponding cell plate wells (75 and 250 ⁇ L, respectively, for each of the top and base end wells). After loading, the cell plates were incubated for 120 minutes in an incubator at 37 ⁇ 1 ° C, 5% CO 2 and saturated humidity.
  • the Lucifer Yellow Rejection Assay was used to test the integrity of Caco-2 cells. Six cell wells were randomly selected from each cell plate, and 100 ⁇ M fluorescent yellow was added respectively. The fluorescent yellow detection experiment and the transport experiment were performed simultaneously. After 120 minutes of incubation, a fluorescent yellow sample was taken and the relative fluorescence unit (RFU) of the fluorescent yellow in the sample was detected at a 425/528 nm (excitation/emission) spectrum.
  • REU relative fluorescence unit
  • the concentrations of the test compound and the control compounds nadolol, metoprolol, digoxin and E3S in the samples were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS).
  • the retention time of the analyte and internal standard, chromatogram acquisition and chromatogram integration were processed using the software Analyst (AB Sciex, Framingham, Massachusetts, USA). The experimental results are shown in Table 6.
  • the experiment will use a 96-well equilibrium dialysis plate (HTDialysis device) to determine the plasma protein binding rate of the test compound and the control compound.
  • HTDialysis device 96-well equilibrium dialysis plate
  • the dialysis membrane was pretreated according to the instructions for use and the dialysis unit was assembled as required.
  • %Unbound is the liberation rate of the compound
  • %Bound is the binding rate of the compound
  • [F] is the concentration of the compound at the buffer end of the dialysis plate
  • [T] is the concentration of the compound at the plasma end of the dialysis plate
  • results showed that the results showed that the plasma protein binding rate of the test compound was improved relative to EMA-401, which was beneficial to the drug reaching the target of drug action.

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Abstract

涉及式(Ⅱ)所示化合物或其药学上可接受的盐，并涉及其在制备治疗与血管紧张素II受体2(AT2R)相关疾病药物中的应用。(II)

Description

作为AT 2R受体拮抗剂的羧酸衍生物
相关申请的引用
本申请要求于2017年06月09日向中华人民共和国国家知识产权局提交的第201710434262.2号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本发明涉及式(Ⅱ)所示化合物或其药学上可接受的盐，并涉及其在制备治疗与血管紧张素II受体2(AT 2R)相关疾病药物中的应用。
背景技术
血管紧张素II(AngII)是由血管紧张素I在血管紧张素转化酶的作用下，水解产生的八肽物质,具有调节血压、体液平衡和痛觉感知等作用。血管紧张素受体是以血管紧张素作为配体的G蛋白偶联受体，是肾素-血管紧张素系统的重要组成部分。AngII可激活血管紧张素II受体1(AT 1R)和血管紧张素II受体2(AT 2R)。其中AT 2R在神经系统中与疼痛机制相关,主要表达在背根神经节和三叉神经节。与正常神经相比，受损神经和疼痛神经瘤具有更高的AT 2R表达。AT 2R激活后通过G蛋白偶联受体活化的第二信使通路，可致敏神经元中的离子通道。敏化作用导致离子通道活化从而使神经元兴奋。AT 2R拮抗剂已经通过动物实验(Pain.Medicine.2013,14,1557-1568；Pain.Medicine.2013,14,692–705))临床实验(Lancet.2014,383,1637-1647)证明可用于缓解疼痛。相关的综述性报道可见Expert Opin.Investig.Drugs.2014,23,1-12；Expert.Opin.Ther.Targets.2015,19,25-35.等。
WO 2011088504公开了化合物EMA-401。
Figure PCTCN2018090432-appb-000001
发明内容
本发明提供了式(Ⅰ)所示化合物及其药学上可接受的盐，
Figure PCTCN2018090432-appb-000002
其中，
L选自：-O-、-S-、-N(R)-、-N(R)C(＝O)-、-C(＝O)O-；
L 1选自：单键、-CH 2-、-CH 2CH 2-；
R 1选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 3-7环烷基、3～7元杂环烷基、6～10元芳基、5～6元杂芳基；
R 2选自H、卤素、OH、NH 2、CN，选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基；
R 3选自任选被1、2或3个R取代的：苯基、5～6元杂芳基、5～6元杂环烷基；
R 4选自H，或选自任选被1、2或3个R取代的：C 1-3烷基；
R选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3杂烷基；
R’选自：F、Cl、Br、I、OH、CN、NH 2；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
所述4～6元杂环烷基、5～6元杂芳基、C 1-6杂烷基、C 1-3杂烷基之“杂”分别独立地选自-C(＝O)NH-、-NH-、N、-O-、-S-、-C(＝O)O-、-C(＝O)-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，带“*”或“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在，“富含一种异构体”指其中一种异构体的含量＜100％，且≥60％，优选≥70％，更优选≥80％，更优选≥90％，更优选≥95％，更优选≥96％，更优选≥97％，更优选≥98％，更优选≥99％，更优选≥99.5％，更优选≥99.6％，更优选≥99.7％，更优选≥99.8％，更优选≥99.9％。
本发明的一些方案中，上述R选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基。
本发明的一些方案中，上述R选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、Et、CF 3、
Figure PCTCN2018090432-appb-000003
本发明的一些方案中，上述L选自：-O-、-S-、-NH-、-N(CH 3)-、-NHC(＝O)-、-N(CH 3)C(＝O)-、-C(＝O)O-。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：C 1-4烷基、C 3-7环烷基、3～7元杂环烷基、6～10元芳基、5～6元杂芳基。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：C 1-4烷基、C 4-6环烷基、恶丁环基、四氢呋喃基、四氢吡喃基、苯基、萘基、噻吩基、吡唑基、咪唑基、恶唑基、噻唑基、吗啉基、哌嗪基、哌啶基、吡啶基、吡嗪基、嘧啶基。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：Me、Et、
Figure PCTCN2018090432-appb-000004
Figure PCTCN2018090432-appb-000005
本发明的一些方案中，上述R 1选自：Me、Et、
Figure PCTCN2018090432-appb-000006
Figure PCTCN2018090432-appb-000007
本发明的一些方案中，上述结构单元
Figure PCTCN2018090432-appb-000008
选自：
Figure PCTCN2018090432-appb-000009
Figure PCTCN2018090432-appb-000010
本发明的一些方案中，上述R 2选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3烷氨基。
本发明的一些方案中，上述R 2选自：H、F、Cl、Br、I、OH、NH 2、CN，Me、
Figure PCTCN2018090432-appb-000011
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、噻吩基、噻唑基、异噻唑基、恶唑基、异恶唑基、四氢吡喃基、哌啶基、吗啉基。
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：
Figure PCTCN2018090432-appb-000012
Figure PCTCN2018090432-appb-000013
本发明的一些方案中，上述R 3选自：
Figure PCTCN2018090432-appb-000014
Figure PCTCN2018090432-appb-000015
本发明的一些方案中，上述结构单元
Figure PCTCN2018090432-appb-000016
选自：
Figure PCTCN2018090432-appb-000017
Figure PCTCN2018090432-appb-000018
本发明的一些方案中，上述R 4选自：H、Me。
本发明的一些方案中，上述R选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基，其他变量如上述所定义。
本发明的一些方案中，上述R选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、Et、CF 3、
Figure PCTCN2018090432-appb-000019
其他变量如上述所定义。
本发明的一些方案中，上述L选自：-O-、-S-、-NH-、-N(CH 3)-、-NHC(＝O)-、-N(CH 3)C(＝O)-、-C(＝O)O-，其他变量如上述所定义。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：C 1-4烷基、C 3-7环烷基、3～7元杂环烷基、6～10元芳基、5～6元杂芳基，其他变量如上述所定义。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：C 1-4烷基、C 4-6环烷基、恶丁环基、四氢呋喃基、四氢吡喃基、苯基、萘基、噻吩基、吡唑基、咪唑基、恶唑基、噻唑基、吗啉基、哌嗪基、哌啶基、吡啶基、吡嗪基、嘧啶基，其他变量如上述所定义。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：Me、Et、
Figure PCTCN2018090432-appb-000020
Figure PCTCN2018090432-appb-000021
Figure PCTCN2018090432-appb-000022
其他变量如上述所定义。
本发明的一些方案中，上述R 1选自：Me、Et、
Figure PCTCN2018090432-appb-000023
Figure PCTCN2018090432-appb-000024
Figure PCTCN2018090432-appb-000025
Figure PCTCN2018090432-appb-000026
其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018090432-appb-000027
选自：
Figure PCTCN2018090432-appb-000028
Figure PCTCN2018090432-appb-000029
Figure PCTCN2018090432-appb-000030
其他变量如上述所定义。
本发明的一些方案中，上述R 2选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3烷氨基，其他变量如上述所定义。
本发明的一些方案中，上述R 2选自：H、F、Cl、Br、I、OH、NH 2、CN，Me、
Figure PCTCN2018090432-appb-000031
其他变量如上述所定义。
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、噻吩基、噻唑基、异噻唑基、恶唑基、异恶唑基、四氢吡喃基、哌啶基、吗啉基，其他变量如上述所定义。
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：
Figure PCTCN2018090432-appb-000032
Figure PCTCN2018090432-appb-000033
其他变量如上述所定义。
本发明的一些方案中，上述R 3选自：
Figure PCTCN2018090432-appb-000034
Figure PCTCN2018090432-appb-000035
其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018090432-appb-000036
选自：
Figure PCTCN2018090432-appb-000037
Figure PCTCN2018090432-appb-000038
其他变量如上述所定义。
本发明的一些方案中，上述R 4选自：H、Me，其他变量如上述所定义。
本发明的一些方案中，上述化合物及其药学上可接受的盐，其选自：
Figure PCTCN2018090432-appb-000039
其中，
R、R 2、R 3、R 4、L 1、L如上述所定义；
T选自N或CH；
D选自CH 2或O；
m、p分别独立地选自0、1、2或3，且m和p不同时选自0或3；
n选自0、1、2或3；
且当m选自0，D选自O时，n不选自3。
本发明提供了式(Ⅱ)所示化合物及其药学上可接受的盐，
Figure PCTCN2018090432-appb-000040
其中，
L选自：-O-、-S-、-N(R)-、-N(R)C(＝O)-、-C(＝O)O-；
L 1选自：单键、-CH 2-、-CH 2CH 2-；
R 1选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 3-7环烷基、3～7元杂环烷基、6～10元芳基、5～6元杂芳基；
R 2选自H、卤素、OH、NH 2、CN，选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基；
R 3选自任选被1、2或3个R取代的：苯基、5～6元杂芳基、5～6元杂环烷基；
R 4选自H，或选自任选被1、2或3个R取代的：C 1-3烷基；
R 5选自：H、F、Cl、Br、I、OH；
R 6选自：H、F、Cl、Br、I、OH；
R选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3杂烷基；R’选自：F、Cl、Br、I、OH、CN、NH 2；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
所述3～7元杂环烷基、5～6元杂芳基、C 1-6杂烷基、C 1-3杂烷基、5～6元杂环烷基之“杂”分别独立地选自-C(＝O)NH-、-NH-、N、-O-、-S-、-C(＝O)O-、-C(＝O)-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，带“*”或“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在，“富含一种异构体”指其中一种异构体的含量＜100％，且≥60％，优选≥70％，更优选≥80％，更优选≥90％，更优选≥95％，更优选≥96％，更优选≥97％，更优选≥98％，更优选≥99％，更优选≥99.5％，更优选≥99.6％，更优选≥99.7％，更优选≥99.8％，更优选≥99.9％。
本发明的一些方案中，上述R选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基，其它变量如本发明所定义。
本发明的一些方案中，上述R选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、Et、CF 3、
Figure PCTCN2018090432-appb-000041
其它变量如本发明所定义。
本发明的一些方案中，上述L选自：-O-、-S-、-NH-、-N(CH 3)-、-NHC(＝O)-、-N(CH 3)C(＝O)-、-C(＝O)O-，其它变量如本发明所定义。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：C 1-4烷基、C 3-7环烷基、3～7元杂环烷基、6～10元芳基、5～6元杂芳基，其它变量如本发明所定义。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：C 1-4烷基、环丁烷基、环戊烷基、环己烷基、双环[3.1.0]己烷基、恶丁环基、四氢呋喃基、四氢吡喃基、苯基、萘基、噻吩基、吡唑基、咪唑基、恶唑基、噻唑基、吗啉基、哌嗪基、哌啶基、吡啶基、吡嗪基、嘧啶基，其它变量如本发明所定义。
本发明的一些方案中，上述R 1选自任选被1、2或3个R取代的：Me、Et、
Figure PCTCN2018090432-appb-000042
Figure PCTCN2018090432-appb-000043
Figure PCTCN2018090432-appb-000044
其它变量如本发明所定义。
本发明的一些方案中，上述R 1选自：Me、Et、
Figure PCTCN2018090432-appb-000045
Figure PCTCN2018090432-appb-000046
Figure PCTCN2018090432-appb-000047
其它变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018090432-appb-000048
选自：
Figure PCTCN2018090432-appb-000049
Figure PCTCN2018090432-appb-000050
Figure PCTCN2018090432-appb-000051
Figure PCTCN2018090432-appb-000052
其它变量如本发明所定义。
本发明的一些方案中，上述R 2选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3烷氨基，其它变量如本发明所定义。
本发明的一些方案中，上述R 2选自：H、F、Cl、Br、I、OH、NH 2、CN，Me、
Figure PCTCN2018090432-appb-000053
其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、噻吩基、噻唑基、异噻唑基、恶唑基、异恶唑基、四氢吡喃基、哌啶基、吗啉基，其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自任选被1、2或3个R取代的：
Figure PCTCN2018090432-appb-000054
Figure PCTCN2018090432-appb-000055
其它变量如本发明所定义。
本发明的一些方案中，上述R 3选自：
Figure PCTCN2018090432-appb-000056
Figure PCTCN2018090432-appb-000057
其它变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018090432-appb-000058
选自：
Figure PCTCN2018090432-appb-000059
Figure PCTCN2018090432-appb-000060
其它变量如本发明所定义。
本发明的一些方案中，上述R 4选自：H、Me。
本发明的一些方案中，上述R 4选自：H、Me，其他变量如上述所定义。
本发明的一些方案中，上述化合物及其药学上可接受的盐，其选自：
Figure PCTCN2018090432-appb-000061
其中，
R、R 2、R 3、R 4、R 5、R 6、L 1、L如上述所定义；
T选自N或CH；
D选自CH 2或O；
m、p分别独立地选自0、1、2或3，且m和p不同时选自0或3；
n选自0、1、2或3；
且当m选自0，D选自O时，n不选自3。
本发明还有一些方案是由上述变量任意组合而来。
本发明提供了下式所示化合物，其选自：
Figure PCTCN2018090432-appb-000062
Figure PCTCN2018090432-appb-000063
Figure PCTCN2018090432-appb-000064
本发明的一些方案中，上述化合物，其选自：
Figure PCTCN2018090432-appb-000065
Figure PCTCN2018090432-appb-000066
Figure PCTCN2018090432-appb-000067
Figure PCTCN2018090432-appb-000068
Figure PCTCN2018090432-appb-000069
Figure PCTCN2018090432-appb-000070
Figure PCTCN2018090432-appb-000071
Figure PCTCN2018090432-appb-000072
Figure PCTCN2018090432-appb-000073
Figure PCTCN2018090432-appb-000074
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗与AT 2R受体相关疾病的药物中的应用。
本发明还提供了化合物或其药学上可接受的盐在制备治疗慢性疼痛的药物中的应用。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与 化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，用楔形键和虚线键
Figure PCTCN2018090432-appb-000075
表示一个立体中心的绝对构型，用波浪线
Figure PCTCN2018090432-appb-000076
表示楔形键或虚线键(
Figure PCTCN2018090432-appb-000077
或
Figure PCTCN2018090432-appb-000078
)，用
Figure PCTCN2018090432-appb-000079
表示立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代， 并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018090432-appb-000080
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018090432-appb-000081
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018090432-appb-000082
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018090432-appb-000083
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被 季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代 烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方 式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：Bn代表苄基；aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；EDCI代表碳化二亚胺；HOBt代表1-羟基苯并三唑；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦)二茂铁]二氯化钯。
化合物经手工或者
Figure PCTCN2018090432-appb-000084
软件命名，市售化合物采用供应商目录名称。
技术效果
本专利中通过简单的制备方法合成了一系列式(I)化合物，获得了一类新的血管紧张素II 2型受体(AT 2R)的选择性抑制剂，用于治疗慢性疼痛。本发明化合物均在体外展现较好的生物活性，并在多种属中展现了优良的药代性质。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1:合成中间体A1
Figure PCTCN2018090432-appb-000085
步骤1：化合物A1的制备
在氮气保护下，将NaH(466.0mg,11.7mmol,纯度：60％)悬浮于无水四氢呋喃(2.5mL)中，缓慢滴加环戊醇(301.0mg,3.5mmol,316.9uL)的无水四氢呋喃(2.5mL)溶液。15℃下搅拌30分钟后，加入A1-1(500.0mg,2.3mmol)的无水四氢呋喃(2.5mL)溶液。加完后，反应液在15℃下继续搅拌1.5小时。将反应液缓慢倒入水中(15mL)淬灭反应后，用甲基叔丁基醚(20mL)洗涤。水相用2N的盐酸调节pH至3左右，再用甲基叔丁基醚(20mLx3)萃取。合并后的有机相用饱和食盐水(20 mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗品。粗品经硅胶层析柱(洗脱液：50-100％乙酸乙酯/石油醚)分离纯化得到产物A1。 1H NMR(400MHz,CHLOROFORM-d):δ7.46-7.43(m,2H),7.40-7.36(m,3H),4.94(s,1H),4.07-4.05(m,1H),1.83-1.67(m,6H),1.66-1.46(m,2H)。
以下化合物使用与化合物A1类似的方法合成得到：
Figure PCTCN2018090432-appb-000086
Figure PCTCN2018090432-appb-000087
Figure PCTCN2018090432-appb-000088
参考例12:中间体S-A12
Figure PCTCN2018090432-appb-000089
步骤1：化合物S-A12的制备
将化合物S-扁桃酸(4.6g,30.0mmol)溶于丁腈(62.0mL)中，依次加入碘苯(6.1g,30.0mmol,3.3mL)和碳酸铯(19.6g,60.0mmol)，然后在氮气保护下加入碘化亚铜(285.7mg,1.50mmol)，升温至75-80℃继续搅拌反应15小时后。冷却至室温后，反应液真空下浓缩除去有机溶剂。剩余物溶于200mL水中，用乙酸乙酯(150mLx2)洗涤。水相用1N的柠檬酸水溶液调节pH至4～5，再用乙酸乙酯(200mLx3)萃取，合并后的有机相用饱和食盐水(200mL)洗涤、水硫酸钠干燥、过滤、减压浓缩得到粗产物。粗产物经柱层析(洗脱液：乙酸乙酯/石油醚：0-50％)分离纯化得到的产物再用20ml的石油醚/乙酸乙酯(v:v＝6:1)重结晶得到产物S-A12(41.1％ee)。 1H NMR(400MHz,CHLOROFORM-d):δ7.60-7.58(m,2H),7.46-7.37(m,3H),7.33-7.27(m,2H),7.06-6.92(m,3H),5.68(s,1H).
以下化合物使用与化合物S-A12类似的方法合成得到：
Figure PCTCN2018090432-appb-000090
Figure PCTCN2018090432-appb-000091
参考例20:中间体S-A1
Figure PCTCN2018090432-appb-000092
步骤1：化合物S-A1-1的制备
将氧化银(1.5g,6.6mmol)加到化合物S-扁桃酸(500.0mg,3.3mmol)和溴代环戊烷(49.0g,328.6mmol)的混合液中，然后在20-25℃条件下搅拌反应16小时。将反应液过滤，滤液真空浓缩除去溶剂得到的粗产物。粗产物经硅胶层析柱(洗脱液：乙酸乙酯/石油醚0-10％)分离纯化得到产物S-A1-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.49-7.40(m,2H),7.38-7.28(m,3H),5.22-5.19(m,1H),4.88(s,1H),4.03-3.99(m,1H),1.89-1.64(m,10H),1.57-1.45(m,6H).MS m/z:311.1[M+Na] +.
以下化合物使用与化合物S-A1-1类似的方法合成得到：
Figure PCTCN2018090432-appb-000093
步骤2：化合物S-A1的制备
将化合物S-A1-1(340.0mg,1.2mmol)溶于四氢呋喃(6.0mL)和水(3.0mL)的混合溶剂中，加入氢氧化锂单水合物(283.0mg,11.8mmol)后反应液在20-25℃下搅拌48小时。反应液用1N盐酸调节pH<3后，用乙酸乙酯(20mL x 3)萃取。合并后的有机相用饱和食盐水(50mL)洗涤、无水硫酸钠干燥、真空下浓缩得到粗产物。粗产物经硅胶层析柱(洗脱液：0-37.5％石油醚/乙酸乙酯)分离纯化，得到产物S-A1(95.6％ee)。 1H NMR(400MHz,CHLOROFORM-d):δ7.45-7.34(m,5H),4.93(s,1H),4.07-4.03(m,1H),1.78-1.69(m,6H),1.62-1.48(m,2H).
以下化合物使用与化合物S-A1类似的方法合成得到：
Figure PCTCN2018090432-appb-000094
Figure PCTCN2018090432-appb-000095
参考例23:中间体A12
Figure PCTCN2018090432-appb-000096
步骤1：化合物A12-2的制备
将苯酚(193.9mg,2.1mmol)溶于N,N-二甲基甲酰胺(10.0mL)中，依次加入化合物A12-1(500.0mg,2.1mmol)和碳酸钾(854.1mg,6.2mmol)。反应液升温至80℃后，继续搅拌16小时。冷却至室温后，向反应液中加入20mL水，水相用乙酸乙酯(10mL x 3)萃取。合并后的有机相用无水硫酸钠干燥、过滤、真空下浓缩得粗产物。粗产物经硅胶层析柱(洗脱液：9％石油醚/乙酸乙酯)分离纯化，得到产物A12-2。 1H NMR(400MHz,CHLOROFORM-d):δ7.52-7.50(m,2H),7.32-7.30(m,3H),7.23-7.16(m,2H),6.93-6.84(m,3H),5.55(s,1H),4.19-4.04(m,2H),1.14-1.11(t,J＝7.2Hz,3H).MS m/z:257.1[M+1] +.
步骤2：化合物A12的制备
将A12-2(100.0mg,390.2μmol)溶于乙醇(2.0mL)和水(0.5mL)的混合溶剂中。加入氢氧化锂单水合物(14.0mg,585.3μmol)后，反应液在20℃条件下继续搅拌16小时。反应液中加入2mL水，用1N的盐酸调节pH至3～4后，再用乙酸乙酯(10mL)萃取。有机相用无水硫酸钠干燥、过滤、真空下浓缩得到粗产物A12。该化合物没有经过进一步纯化，直接用于下一步反应。 1H NMR(400MHz,CHLOROFORM-d):δ7.35-7.26(m,4H),7.02-6.84(m,6H),5.32(s,1H).
参考例24:中间体S-A21
Figure PCTCN2018090432-appb-000097
步骤1：化合物S-A21-2的制备
将化合物S-A21-1(831.0mg,5.0mmol)溶于二氯甲烷(10.0mL)中，依次加入高氯酸镁(111.6mg,500.0μmol)和二碳酸二叔丁酯(2.5g,11.5mmol)。反应液在加热至40℃后，继续搅拌反应40小时。冷却至室温后，反应液倒入25mL水中，用二氯甲烷(10mLx3)萃取。合并后的有机相用饱和食盐水(50mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得粗产物。粗产物硅胶层析柱(洗脱液： 0-20％石油醚/乙酸乙酯)分离纯化得到粗产物S-A21-2。 1H NMR(400MHz,CHLOROFORM-d):δ7.49-7.47(m,2H),7.35-7.31(m,3H),5.10(s,1H),3.71(s,3H),1.27(s,9H).
步骤2：化合物S-A21的制备
将S-A21-2(300.0mg,1.4mmol)溶于甲醇(11.0mL)中，然后加入氢氧化钾(1.5g,26.7mmol)，反应液在15℃条件下搅拌反应16小时。反应液用1N的盐酸调节pH至5～6，用二氯甲烷(50mL x 3)萃取。合并后的有机相用饱和食盐水(80mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗产物。粗产物经硅胶层析柱(洗脱液：0-33％石油醚/乙酸乙酯)分离纯化，得到产物S-A21(97.9％ee). 1H NMR(400MHz,CHLOROFORM-d):δ7.48-7.45(m,2H),7.41-7.29(m,3H),5.09(s,1H),1.30(s,9H).
参考例25:中间体S-A22
Figure PCTCN2018090432-appb-000098
步骤1：化合物S-A22-2的制备
在氮气保护下，将化合物S-A22-1(650.0mg,3.2mmol)的盐酸盐溶于二氯甲烷(10.0mL)。依次加入环戊甲酸(367.5mg,3.2mmol,350.03uL)、吡啶(1.0g,12.9mmol,1.0mL)和HATU(1.6g,4.2mmol)。反应液在10-15℃条件下继续搅拌12小时后，向反应液中加入30mL饱和碳酸氢钠萃灭反应，水相用二氯甲烷(20mL x 3)萃取。合并后的有机相用饱和食盐水(50mL)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗产物。粗产物经硅胶层析柱(洗脱液：0-33％石油醚/乙酸乙酯)分离纯化，得到产物S-A22-2。 1H NMR(400MHz,CHLOROFORM-d):δ7.40-7.31(m,5H),5.60-5.58(d,J＝7.2Hz,1H),3.74(s,3H),2.65-2.60(m,1H),2.25-2.11(m,1H),1.95-1.69(m,7H).MS m/z:261.9[M+1] +.
步骤2：化合物S-A22的制备
将S-A22-2(400.0mg,1.5mmol)溶于四氢呋喃(10.0mL)中。加入氢氧化锂单水合物(367.0mg,15.3mmol)的水(4.0mL)溶液，反应液在25℃条件下搅拌2小时。反应液用1N的盐酸调节pH至5～6，用乙酸乙酯(25mL x 3)萃取。合并后的有机相用无水硫酸钠干燥、过滤、真空下浓缩得到粗产物S-A22。该产物不经纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.45-7.22(m,5H),5.43(s,1H),2.86-2.60(m,1H),1.94-1.59(m,8H).MS m/z:247.9[M+1] +.
参考例26:中间体S-A23
Figure PCTCN2018090432-appb-000099
步骤1：化合物S-A23的制备
将化合物S-A23-1(500.0mg,3.3mmol)和环戊酮(835.0mg,9.9mmol)溶于甲醇(4.5mL)中，依次加入醋酸(150.0uL)和氰基硼氢化钠(624.0mg,9.93mmol)。反应液在10-15℃条件下搅拌12小时后，真空下浓缩得到粗产物。粗产物中加入5mL水，过滤，经高效液相色谱法制备分离得到产物S-A23。 1H NMR(400MHz,CHLOROFORM-d)δ:7.56-7.53(m,2H),7.44-7.41(m,3H),4.50(s,1H),3.45-3.35(m,1H),2.11-1.96(m,2H),1.88-1.43(m,6H).MS m/z:219.9[M+1] +.
以下化合物使用与化合物S-A23类似的方法合成得到：
Figure PCTCN2018090432-appb-000100
参考例28:合成中间体C1、(-)-C1和(+)-C1
Figure PCTCN2018090432-appb-000101
步骤1：化合物C1-2的制备
氮气保护下，将化合物C1-1(200.0g,1.31mol)溶于无水乙醇(1.50L)中。15℃搅拌下依次加入无水碳酸钾(181.1g,1.31mol)和苄溴(268.9g,1.57mol)，再将反应液加热至100℃继续搅拌15小时。反应液冷却到室温后，过滤，滤液在真空下浓缩后得到的油状物。用乙酸乙酯(3.0L)重新溶解后，依次用2N氢氧化钠水溶液(500mL x 2)和饱和食盐水(600mL x 2)洗涤、无水硫酸镁干燥、过滤、真空下浓缩得到粗产物。将粗产物分散在石油醚中搅拌1小时后，过滤得到247.0g化合物C1-2，。 1H NMR(400MHz,CHLOROFORM-d):δ10.25(s,1H),7.42-7.34(m,6H),7.21-7.12(m,2H),5.19(s,2H),3.96(s,3H).
步骤2：化合物C1-3的制备
氮气保护下，将化合物C1-2(220.0g,908.08mmol)、2-硝基乙酸乙酯(145.0g,1.09mol)和二 乙基胺盐酸盐(149.3g,1.36mol)在无水甲苯(2.1L)中的混合溶液加热至130℃回流15小时，反应生成的水使用Deane-Stark分水器分离。反应液冷却至室温后，真空下浓缩除去甲苯。剩余物重新溶解在二氯甲烷中(500mL)后，用饱和食盐水(1000mL x 2)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到化合物C1-3，该化合物未经纯化直接用于下一步反应。
步骤3：化合物C1-4的制备
氮气保护下，将上述步骤2中得到的粗品化合物C1-3(430.0g,1.2mol)和异丙醇(2.2g,36.0mmol)溶解在氯仿(4.5L)中，混合液冷却至0℃后，搅拌中加入100～200目的硅胶(1.8kg)，然后在1.5小时内分批加入硼氢化钠(201.1g,5.3mol)。反应液升温至15℃后继续搅拌反应12小时。缓慢加入乙酸(210mL)后继续搅拌15分钟，过滤反应液，滤饼用氯仿(500mL)洗涤。合并后的滤液在真空下浓缩后得到的剩余物经硅胶层析柱(洗脱液：6％～10％石油醚/乙酸乙酯)分离纯化，得到化合物C1-4。 1H NMR(400MHz,CHLOROFORM-d):δ7.48-7.33(m,5H),7.02-6.97(m,1H),6.94-6.90(m,1H),6.64-6.62(dd,J＝1.6,7.6Hz,1H),5.33-5.30(dd,J＝6.0,9.2Hz,1H),5.19-5.05(m,2H),4.15-4.10(q,J＝7.2Hz,2H),3.91(s,3H),3.44-3.31(m,2H),1.16-1.12(t,J＝7.2Hz,3H).
步骤4：化合物C1-5的制备
15℃下，将化合物C1-4(8.2g,22.82mmol)溶解在乙酸(100mL)中，缓慢加入锌粉(76.2g,212.04mmol)并保持反应温度在60-65℃之间，加完后，继续在60℃下搅拌反应2小时。反应液冷却至室温后，过滤，滤饼用乙酸(300mL)洗涤。合并后的滤液在真空下浓缩得到的剩余物重新溶解在二氯甲烷(500mL)中，用饱和碳酸氢钠水溶液(200mL x 3)和饱和食盐水(200mL x 2)洗涤、无水硫酸钠干燥、过滤、真空下浓缩得到粗产物C1-5，该化合物未经纯化直接用于下一步。MS m/z:330.1[M+1] +.
步骤5：化合物C1的制备
15℃氮气保护下，将化合物C1-5(48.9g,149.4mmol)溶解在2N盐酸溶液(500mL)中，随后加入37％甲醛水溶液(36.4g,448.1mmol)。搅拌25小时后，过滤，滤饼用水(100mL)洗涤、得到化合物C1的盐酸盐。MS m/z:342.1[M+1] +.
步骤6：化合物(-)-C1和(+)-C1的制备
化合物C1(40.0g,117.2mmol)经手性柱分离得到两个异构体(-)-C1和(+)-C1。
(-)-C1: 1H NMR(400MHz,CHLOROFORM-d):δ7.40-7.38(m,2H),7.33-7.22(m,3H),6.73-6.71(m,2H),4.93-4.92(m,2H),4.17-4.15(q,J＝7.2Hz,2H),4.10-3.93(m,2H),3.79(s,3H),3.62-3.58(m,1H),3.07-3.06(m,1H),2.77-2.65(m,1H),1.21(t,J＝7.2Hz,3H).MS m/z:342.1[M+1] +.[α]＝-23.4.
(+)-C1: 1H NMR(400MHz,CHLOROFORM-d):δ7.43-7.40(m,2H),7.33-7.22(m,3H),6.86(s,2H),5.06-4.95(q,J＝11.2Hz,2H),4.54-4.50(m,1H),4.33-4.21(m,3H),4.07-4.05(m,1H),3.88(s,3H),3.34 -3.25(m,1H),3.20-3.14(m,1H),1.30-1.26(t,J＝7.2Hz,3H).MS m/z:342.1[M+1] +.[α]＝+9.8.
参考例29:合成中间体C2
Figure PCTCN2018090432-appb-000102
步骤1：化合物C2-2的制备
在氮气保护下，将化合物C2-1(5.0g,36.2mmol)溶于N,N-二甲基甲酰胺(60mL)中，缓慢加入钠氢(1.5g,36.2mmol,60.0％purity)，0.5小时后降温至0℃，将溴化苄(6.2g,36.2mmol)滴加到反应液中，反应液缓慢升温至25℃继续搅拌19.5小时。将反应液倒入的冰水(50mL)中,加入乙酸乙酯(200mL)，分液，有机相用水(100mL x 3)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：9-25％乙酸乙酯/石油醚)分离纯化，得到化合物C2-2。 1H NMR(400MHz,CHLOROFORM-d):δ10.19(s,1H),7.45-7.36(m,6H),7.24-7.13(m,2H),5.77(s,1H),5.09(s,2H)
步骤2：化合物C2-3的制备
在0℃下将化合物C2-2(4.0g,17.5mmol)，Boc-α-膦酰基甘氨酸三甲酯(6.3g,21.0mmol)溶于四氢呋喃(60mL)中，加入四甲基胍(4.4g,38.5mmol)，反应液在25℃下搅拌20小时。反应液用1M的盐酸调pH约为6-7，乙酸乙酯(50mL x 3)萃取，合并后的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：9-25％乙酸乙酯/石油醚)分离纯化，得到化合物C2-3。 1H NMR(400MHz,CHLOROFORM-d):δ7.42-7.37(m,5H),7.16(brs,1H),7.05-6.98(m,2H),6.94-6.88(m,1H),6.74(brs,1H),5.58(s,1H),4.91(s,2H),3.88(s,3H),1.41(s,9H).
步骤3：化合物C2-4的制备
在0℃下将化合物C2-3(6.3g,15.8mmol)溶于甲醇(60mL)中，依次加入六水氯化镍(1.9g,7.9mmol)和硼氢化钠(1.8g,47.3mmol)，反应液缓慢升温至25℃继续搅拌20小时。向反应液中加入水(50mL)，减压除去甲醇，乙酸乙酯(50mL x 3)萃取，合并后的有机相用饱和食盐水(30mL)洗 涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：9-25％乙酸乙酯/石油醚)分离纯化，得到化合物C2-4。 1H NMR(400MHz,CHLOROFORM-d)：δ7.40-7.31(m,5H),6.93-6.86(m,1H),6.79-6.77(d,J＝7.2Hz,1H),6.62-6.60(d,J＝7.2Hz,1H),5.41(s,1H),4.89-4.81(m,2H),4.52-4.47(m,1H),3.57(s,3H),3.06-3.03(m,1H),2.99-2.94(m,1H),1.35(s,9H).MS m/z:423.9[M+Na] +.
步骤4：化合物C2-5的制备
将化合物C2-4(1.1g,2.7mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(6.2g,54.0mmol)，反应液在25℃反应1小时。减压除去有机溶剂，得到粗品化合物C2-5的三氟乙酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,CHLOROFORM-d):δ8.15(brs,2H),7.38-7.33(m,5H),6.94-6.89(m,2H),6.62-6.60(d,J＝7.6Hz,1H),4.96(s,2H),4.36-4.33(m,1H),3.71(s,3H),3.15-3.10(m,1H),2.93-2.87(m,1H).MS m/z:301.9[M+1] +.
步骤5：化合物C2-6的制备
将化合物C2-5的三氟乙酸盐(1.0g,2.4mmol)，加入到甲醛水溶液(1.2g,14.4mmol,37％)中，加入1M稀盐酸(20mL)，反应液升温至60℃继续搅拌1小时。减压除去有机溶剂，得到粗品化合物C2-6的盐酸盐，该化合物没有经过进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.47-7.44(m,2H),7.38-7.36(m,3H),6.90-6.85(m,2H),5.12(s,2H),4.37-4.25(m,3H),3.90(s,3H),3.33-3.30(m,1H),2.89-2.80(m,1H).MS m/z:314.0[M+1] +.
步骤6：化合物C2-7的制备
将化合物C2-6的盐酸盐(740.0mg,2.1mmol)溶于二氯甲烷(7mL)中，依次加入二碳酸二叔丁基酯(692.5mg,3.2mmol)和三乙胺(856.2mg,8.5mmol)，反应液在25℃继续搅拌3小时。减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：9-33％乙酸乙酯/石油醚)分离纯化，得到化合物C2-7。 1H NMR(400MHz,CHLOROFORM-d):δ7.44-7.39(m,5H),6.88-6.80(m,2H),5.34(s,1H),5.21-4.88(m,3H),4.76-4.63(m,1H),4.51-4.38(m,1H),3.67-3.65(d,J＝8.8Hz,3H),3.57-3.34(m,1H),3.07-2.99(m,1H),1.48-1.44(d,J＝13.6Hz,9H).MS m/z:436.1[M+Na] +.
步骤7：化合物C2-8的制备
将化合物C2-7(500.0mg,1.2mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入N,N-二异丙基乙胺(468.9mg,3.6mmol)和N-苯基双(三氟甲烷磺酰亚胺)(648.0mg,1.8mmol)，反应液在25℃继续搅拌16小时。反应液中加入乙酸乙酯(100mL)，用水(20mL x 3)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：9-25％乙酸乙酯/石油醚)分离纯化，得到化合物C2-8。 1H NMR(400MHz,CHLOROFORM-d):δ7.47-7.41(m,5H),7.17-6.96(m,2H),5.21-4.69(m,4H),4.56-4.41(m,1H),3.66-3.65(d,J＝6.0Hz,3H),3.54-3.28(m,1H),2.96-2.84(m,1H),1.55-1.48(d,J＝27.6Hz,9H).MS m/z:568.1[M+Na] +.
步骤8：化合物C2-9的制备
在氮气保护下，将化合物C2-8(200.0mg,366.6μmol)和甲基硼酸(109.7mg,1.8mmol)溶于二氧六环(3mL)中，依次加入Pd(dppf)Cl 2(26.8mg,36.6μmol)和碳酸钾(152.0mg,1.1mmol)，反应液升温至100℃反应2小时。减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：9-25％乙酸乙酯/石油醚)分离纯化，得到化合物C2-9。 1H NMR(400MHz,CHLOROFORM-d):δ7.50-7.39(m,5H),7.08-6.84(m,2H),5.18-4.67(m,4H),4.54-4.47(m,1H),3.66-3.64(d,J＝9.2Hz,3H),3.59-3.34(m,1H),3.07-2.94(m,1H),2.31(s,3H),1.55-1.48(d,J＝28.4Hz,9H).MS m/z:434.1[M+Na] +.
步骤9：化合物C2的制备
将化合物C2-9(140.0mg,340.2μmol)溶于甲醇(1mL)中，加入4M盐酸甲醇溶液(2mL)，反应液在25℃继续搅拌16小时。减压除去有机溶剂，得到粗品化合物C2的盐酸盐。 1H NMR(400MHz,METHANOL-d 4):δ7.49-7.40(m,5H),7.23-7.21(d,J＝8.0Hz,1H),7.00-6.98(d,J＝8.0Hz,1H),4.94(s,2H),4.49-4.39(m,3H),3.91(s,3H),3.47-3.42(m,1H),3.08-3.00(m,1H),2.33(s,3H).MS m/z:312.0[M+1] +.
参考例39:合成中间体C3
Figure PCTCN2018090432-appb-000103
步骤1：化合物C3-1的制备
氮气保护下，将化合物C2-8(190.0mg,348.3μmol)溶于二氧六环(3mL)中，依次加入氯化钾(51.9mg,696.9μmol)，Pd 2(dba) 3(4.8mg,5.2μmol)，二叔丁基(2',4',6'-三异丙基-3,6-二甲氧基联苯基-2-基)膦(7.6mg,15.7μmol)和氟化钾(10.1mg,174.1μmol)，反应液升温至130℃继续搅拌20小时。减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：5-16％乙酸乙酯/石油醚)分离纯化，得到化合物C3-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.56-7.37(m,5H),7.26-7.11(m,1H),6.94-6.72(m,1H),5.19-5.04(m,1H),5.03-4.85(m,2H),4.76-4.65(m,1H),4.54-4.39(m,1H),3.65-3.63(d,J＝8.0Hz,3H),3.58-3.30(m,1H),2.98-2.82(m,1H),1.54-1.44(m,9H)。MS m/z:331.9[M-100] +.
步骤2：化合物C3的制备
将化合物C3-1(110.0mg,254.7μmol)溶于甲醇(1mL)中，加入4M氯化氢甲醇溶液(1mL)，反应液在25℃继续搅拌16小时。减压除去有机溶剂，得到粗品化合物C3的盐酸盐。 1H NMR(400MHz,METHANOL-d 4):δ7.54-7.37(m,6H),7.13-6.91(m,1H),5.20-5.08(m,2H),4.55-4.33(m,3H),3.93-3.90(m,3H),3.54-3.38(m,1H),3.06-2.90(m,1H)。MS m/z:332.0[M+1] +.
参考例40:合成中间体C4
Figure PCTCN2018090432-appb-000104
步骤1：化合物C4-1的制备
在氮气保护下，将化合物C2-8(260.0mg,476.6μmol)溶于二氧六环(6mL)中，依次加入溴化钾(113.4mg,953.2μmol)，Pd 2(dba) 3(13.1mg,14.3μmol)，二叔丁基(2',4',6'-三异丙基-3,6-二甲氧基联苯基-2-基)膦(23.1mg,47.6μmol)和氟化钾(13.8mg,238.3μmol)，反应液升温至130℃继续搅拌20小时。减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：5-10％乙酸乙酯/石油醚)分离纯化，得到化合物C4-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.59-7.33(m,6H),6.90-6.77(m,1H),5.22-5.06(m,1H),5.03-4.84(m,2H),4.79-4.63(m,1H),4.54-4.37(m,1H),3.65-3.63(d,J＝8.0Hz,3H),3.59-3.32(m,1H),3.02-2.85(m,1H),1.54-1.45(m,9H).MS m/z:377.9[M-100] +.
步骤2：化合物C4-2的制备
氮气保护下,将浓硫酸(44.2mg,450.25μmol)加入到N,N-二甲基乙酰胺(10.0mL)中，反应液在25℃下搅拌0.5小时，加入醋酸钯(0.1g,668.12μmol)和XPhos(0.6g,1.30mmol)，升温至80℃继续搅拌0.5小时。取1mL上述溶液加入到化合物C4-1(50.0mg,104.9μmol)，氰化锌(18.5mg,157.4μmol)，锌粉(686.4ug,10.50μmol)和N,N-二甲基乙酰胺(2.0mL)的混合溶液中，反应液升温至90℃继续搅拌16小时。冷却，向反应液中加入乙酸乙酯(30.0mL)，用水(10.0mL)洗涤三次，饱和氯化钠水溶液(20.0mL)洗涤，无水硫酸钠干燥，过滤，滤液减压除去有机溶剂，所得粗产物经硅胶制备板(20％乙酸乙酯/石油醚)分离纯化，得到化合物C4-2。 1H NMR(400MHz,CHLOROFORM-d):δ7.55-7.37(m,6H),7.01-6.95(m,1H),5.23-5.12(m,2H),4.88-4.43(m,3H),3.65-3.63(d,J＝6.8Hz,3H),3.59-3.35(m,1H),2.93-2.77(m,1H),1.57-1.43(m,9H).MS m/z:323.0[M-100] +.
步骤3：化合物C4的制备
将化合物C4-2(76.0mg,179.9μmol)溶于甲醇(1mL)中，加入4M氯化氢甲醇溶液(1mL)，反应液在25℃继续搅拌2小时。减压除去有机溶剂，得到粗品化合物C4的盐酸盐。 1H NMR(400MHz,METHANOL-d 4):δ7.58-7.56(d,J＝8.0Hz,1H),7.42-7.28(m,5H),7.10-7.08(d,J＝8.0Hz,1H),5.25-5.16(m,2H),4.48-4.26(m,3H),3.80(s,3H),3.32-3.26(m,1H),2.92-2.75(m,1H).MS m/z:323.1[M+1] +.
参考例41:合成中间体C5
Figure PCTCN2018090432-appb-000105
步骤1：化合物C5-1的合成
将化合物C1-4(10.0g,27.8mmol)溶于N,N-二甲基甲酰胺(30.0mL)中，冰水浴条件下加入氢 化钠(13.4g,33.5mmol,60％purity),继续搅拌30分钟，加入碘甲烷(35.3g,248.7mmol)，反应液缓慢升温至15-20℃继续搅拌16小时。将反应液中倒入水(100.0mL)中，用乙酸乙酯(100.0mL)萃取三次，合并后的有机相用无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱液：0-17％乙酸乙酯/石油醚)分离纯化得到粗品化合物C5-1。 1H NMR:(400MHz,CHLOROFORM-d):δ7.45-7.35(m,5H),7.02-6.96(m,1H),6.92-6.86(m,1H),6.62-6.60(m,1H),5.09-5.07(d,J＝10.8Hz,1H),4.94-4.92(d,J＝10.8Hz,1H),4.28-4.18(m,2H),3.90(s,3H),3.62-3.43(m,2H),1.61(s,3H),1.27-1.23(t,J＝7.2Hz,3H).MS m/z:396.0[M+Na] +.
步骤2：化合物C5-2的合成
将化合物C5-1(3.7g,9.8mmol)溶于乙醇(50.0mL)中，依次加入还原铁粉(5.6g,99.6mmol)和氯化铵(7.9g,147.0mmol)，反应液升温至80℃继续搅拌16小时。冷却，用硅藻土过滤，滤饼用乙醇(50.0mL)洗涤，滤液减压除去有机溶剂得到粗品化合物C5-2，该化合物不经进一步纯化直接用于下一步反应。MS m/z:344.1[M+H] +.
步骤3：化合物C5的合成
将化合物C5-2(3.4g,9.8mmol)溶于二氯甲烷(50.0mL)和三氟乙酸(10.0mL)的混合溶液中，加入多聚甲醛(3.5g,39.3mmol)，反应液在20-25℃继续搅拌16小时。减压除去有机溶剂，所得粗品中加入二氯甲烷(50.0ml)和水(50.0ml)，用饱和碳酸钠调节pH至8-9，分液，水相用二氯甲烷萃取(80.0mL)三次，合并后的有机相用饱和食盐水(100.0mL)洗涤，减压除去有机溶剂，所得粗品通过硅胶柱层析(洗脱剂：0-10％甲醇/二氯甲烷)分离纯化，再通过高效液相色谱法(柱子:Phenomenex luna C18 250*50mm*10μm；流动相:[水(0.1％TFA)-ACN]；B％:15％-40％,23min)分离纯化，减压除去大部分乙腈，水相用饱和碳酸钠调节pH至8-9，用二氯甲烷萃取(150.0mL)三次，合并后的有机相用饱和食盐水(200.0mL)洗涤，减压除去有机溶剂得到化合物C5。 1H NMR:(400MHz,METHANOL-d 4):δ7.52-7.51(d,J＝7.2Hz,2H),7.44-7.31(m,3H),6.82-6.72(m,2H),5.08-4.88(m,2H),4.16-4.07(m,2H),4.06-3.93(m,2H),3.86(s,3H),3.39-3.35(d,J＝16.8Hz,1H),2.62-2.57(d,J＝16.8Hz,1H),1.40(s,3H),1.22-1.18(t,J＝7.2Hz,3H).MS m/z:356.1[M+H] +.
参考例42:合成中间体(-)-C2
Figure PCTCN2018090432-appb-000106
步骤1：化合物(-)-C2-1的制备
氩气保护下，将(S,S)-Et-DuPhos(202.9mg,559.8μmol)溶于甲醇(20mL)中，加入Rh(COD) +OTf -(231.9mg,495.2μmol)，继续搅拌15分钟，将此溶液在氩气气氛下，加入到化合物C2-3(86.0g,215.3mmol)的甲醇(1.0L)溶液中，氩气置换三次，氢气置换三次，反应液在25℃和15Psi氢气条件下继续搅拌16小时。减压除去有机溶剂得到粗产物(-)-C2-1，该化合物没有经过进一步纯化直接用于下一步反应。 1H NMR(400MHz,CHLOROFORM-d):δ7.41-7.28(m,5H),6.94-6.86(m,1H),6.80-6.78(d,J＝6.4Hz,1H),6.62-6.61(d,J＝7.2Hz,1H),5.32(brs,1H),5.16-5.14(m,1H),4.90-4.76(m,2H),4.60-4.42(m,1H),3.58(s,3H),3.15-2.87(m,2H),1.32(s,9H).MS m/z:424.1[M+Na] +.SFC:柱子：Chiralpak AY(150mm*4.6mm,3μm)；流动相：[0.05％DEA MeOH]；B％:5％-40％5min,40％2.5min,40％2.5min；Rt＝3.904min；98.9％ee.
步骤2：化合物(-)-C2-2的制备
将化合物(-)-C2-1(37.0g,92.2mmol)溶于乙酸乙酯(200mL)加入到中，然后将氯化氢乙酸乙酯溶液(4M,200mL)加入，反应液在25℃继续搅拌1.5小时。减压除去有机溶剂得到粗产物(-)-C2-2的盐酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.38-7.32(m,2H),7.30-7.19(m,3H),6.87-6.75(m,2H),6.55-6.50(m,1H),5.10-5.03(m,1H),5.00-4.93(m,1H),4.10-3.94(m,1H),3.60(s,3H),3.07-2.99(m,1H),2.79-2.69(m,1H).MS m/z:302.0[M+1] +.
步骤3：化合物(-)-C2-3的制备
将化合物(-)-C2-2(21.0g,62.2mmol)溶于盐酸(1M,187.3mL)中，加入甲醛水溶液(15.1g,186.5mmol,13.9mL，37％)，反应液在25℃继续搅拌16小时。过滤，滤饼真空干燥得到粗品化合物(-)-C2-3的盐酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.49-7.29(m,5H),6.92-6.82(m,2H),5.12(s,2H),4.40-4.22(m,3H),3.90(s,3H),3.32-3.28(m,1H),2.90-2.79(m,1H).MS m/z:314.0[M+1] +.
步骤4：化合物(-)-C2-4的制备
将化合物(-)-C2-3(16.0g,45.7mmol)溶于四氢呋喃(160.0mL)中，加入三乙胺(5.6g,54.9mmol,7.6mL)搅拌使其溶解，滴加Boc酸酐(10.0g,45.7mmol,10.5mL)的四氢呋喃(50mL)溶液，反应液在25℃继续搅拌16小时。将反应液倒入150mL水中，用乙酸乙酯(100mL)萃取三次。合并后的有机相用50mL饱和食盐水洗涤、无水硫酸钠干燥、过滤、减压除去有机溶剂得到粗品，经硅胶柱层析(洗脱剂：10-20％乙酸乙酯/石油醚)分离纯化化合物(-)-C2-4。MS m/z:436.1[M+Na] +.
步骤5：化合物(-)-C2-5的制备
将化合物(-)-C2-4(16.6g,40.2mmol)溶于DMF(200.0mL)中，加入二异丙基乙胺(15.6g,120.5mmol,20.98mL)和N-苯基双(三氟甲烷磺酰)亚胺(18.7g,52.2mmol)，反应液在25℃继续搅拌16小时。将反应液倒入200mL水中，用乙酸乙酯(180mL)萃取三次。合并后的有机相用150mL饱和食盐水各洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗产品经硅胶柱层析(洗脱剂：10-20％乙酸乙酯/石油醚)分离纯化得到化合物(-)-C2-5。 1H NMR(400MHz,CHLOROFORM-d):δ7.42-7.28(m,5H),7.10-7.04(m,1H),6.94-6.85(m,1H),5.10-5.01(m,0.5H),4.97-4.88(m,1H),4.86-4.78(m,1H),4.72-4.57(m,1.5H),4.51-4.29(m,1H),3.57-3.56(d,J＝6.0Hz,3H),3.48-3.15(m,1H),2.87-2.70(m,1H),1.48-1.32(m,9H).MS m/z:446.1[M-100] +.
步骤6：化合物(-)-C2-6的制备
在氮气保护下，将化合物(-)-C2-5(6.2g,11.4mmol)和甲基硼酸(3.4g,56.8mmol)溶于二氧六环(70mL)中，依次加入Pd(dppf)Cl 2(831.6mg,1.1mmol)和碳酸钾(4.7g,34.1mmol)，反应液升温至100℃反应10小时。降温，过滤，滤饼用50mL乙酸乙酯洗涤，合并有机相，减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：9-16％乙酸乙酯/石油醚)分离纯化，得到化合物(-)-C2-6。 1H NMR(400MHz,CHLOROFORM-d):δ7.52-7.34(m,5H),7.07-7.05(d,J＝7.6Hz,1H),6.91-6.81(m,1H),5.19-4.64(m,4H),4.55-4.41(m,1H),3.65-3.62(d,J＝9.2Hz,3H),3.58-3.30(m,1H),3.08-2.89(m,1H),2.30(s,3H),1.56-1.44(m,9H).MS m/z:434.1[M+Na] +.
步骤7：化合物(-)-C2的制备
将化合物(-)-C2-6(4.5g,10.9mmol)溶于二氧六环(20mL)中，加入4M氯化氢的二氧六环溶液(30mL)，反应液在25℃继续搅拌1.5小时。减压除去有机溶剂，得到粗品化合物(-)-C2的盐酸盐。 1H NMR(400MHz,METHANOL-d 4):δ7.51-7.36(m,5H),7.24-7.22(d,J＝7.6Hz,1H),7.00-6.98(d,J＝7.6Hz,1H),4.92(s,2H),4.51-4.35(m,3H),3.91(s,3H),3.49-3.41(m,1H),3.04-2.97(m,1H),2.33(s,3H).MS m/z:312.1[M+1] +.
参考例43:合成中间体(-)-C3
Figure PCTCN2018090432-appb-000107
步骤1：化合物(-)-C3-1的制备
在氮气气氛下，将化合物(-)-C2-2(1.0g,1.8mmol)溶于1,4-二氧六环(15.0mL)中，依次加入氯化钾(275.0mg,3.7mmol)、氟化钾(54.0mg,929.5μmol)、Pd 2(dba) 3(26.0mg,28.4μmol)和二叔丁基(2',4',6'-三异丙基-3,6-二甲氧基联苯基-2-基)膦(40.0mg,82.5μmol)，反应液升温至130℃继续搅拌16小时。减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱液：0-20％甲醇/乙酸乙酯)分离纯化得到化合 物(-)-C3-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.54-7.51(m,2H),7.48-7.35(m,3H),7.29-7.23(m,1H),6.92-6.85(m,1H),5.17-5.15(m,0.5H),5.05-4.87(m,2H),4.78-4.61(m,1.5H),4.53-4.34(m,1H),3.65-3.63(d,J＝8.0Hz,3H),3.57-3.53(m,0.5H),3.36-3.31(m,0.5H),3.01-2.77(m,1H),1.56-1.46(m,9H).MS m/z:454.1[M+Na] +.
步骤2：化合物(-)-C3的制备
将化合物(-)-C3-1(590.0mg,1.4mmol)溶于二氧六环(2.0mL)中，加入氯化氢的二氧六环溶液(4M,3mL)，反应液在20-25℃继续搅拌2.5小时。减压除去有机溶剂得到化合物(-)-C3的盐酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.50-7.36(m,6H),7.08-7.06(d,J＝8.0Hz,1H),5.08(s,2H),4.49-4.33(m,3H),3.89(s,3H),3.41-3.34(m,1H),2.96-2.88(m,1H).MS m/z:331.9[M+1] +.
参考例44:合成中间体(-)-C6
Figure PCTCN2018090432-appb-000108
步骤1：化合物(-)-C6-1的制备
将化合物(-)-C2-1(6.0g,14.9mmol)溶于四氢呋喃(120.0mL)和水(40.0mL)中，慢慢加入氢氧化锂单水化合物(1.9g,44.8mmol)，反应液在25℃继续搅拌5小时。反应液用1M的稀盐酸调pH至5-6，乙酸乙酯(40.0mL)萃取三次，合并后的有机相用饱和氯化钠水溶液(40.0mL)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂得到化合物(-)-C6-1，该化合物没有经过进一步纯化直接用于下一步反应。 1H NMR(400MHz,CHLOROFORM-d):δ7.48-7.30(m,5H),7.00-6.67(m,3H),5.38-5.37(m 1H),5.02-4.89(m,2H),4.58-4.41(m,1H),3.19-3.13(m,1H),3.02-2.96(m,1H),1.42-1.28(m,9H).MS m/z:410.1[M+Na] +.
步骤2：化合物(-)-C6-2的制备
将化合物(-)-C6-1(7.0g,18.1mmol)溶于乙酸乙酯(50.0mL)中，加入氯化氢的乙酸乙酯溶液(4M，50.0mL)，反应液在25℃继续搅拌2小时。减压除去有机溶剂得到化合物(-)-C6-2的盐酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.51-7.46(m,2H),7.39-7.31(m,3H),6.97-6.89(m,2H),6.69-6.67(m,1H),5.24-5.19(m,1H),5.14-5.09(m,1H),4.19-4.14(m,1H),3.31-3.26(m,1H),2.83-2.77(m,1H).MS m/z:287.9[M+1] +.
步骤3：化合物(-)-C6的制备
将化合物(-)-C6-2(5.0g,15.4mmol)溶于盐酸(1M,83.0mL)中，加入甲醛水溶液(7.5g,92.6 mmol,37％)，反应液升温至60℃继续搅拌1小时，冰水浴冷却，将乙酸钠(10.1g,123.5mmol)的水(40.0mL)溶液加入到反应体系中，在0℃继续搅拌2小时。过滤，滤饼用水(50mL)洗涤，真空干燥得到化合物(-)-C6。 1H NMR(400MHz,METHANOL-d 4):δ7.56-7.47(m,2H),7.42-7.30(m,3H),6.88-6.80(m,2H),5.11-5.03(m,2H),4.32-4.17(m,2H),3.74-3.70(m,1H),3.53-3.48(m,1H),2.92-2.85(m,1H).MS m/z:299.9[M+1] +.
参考例45:合成中间体(-)-C7
Figure PCTCN2018090432-appb-000109
步骤1：化合物(-)-C7-1的制备
将化合物(-)-C2-2(4.0g,7.3mmol)溶于甲醇(100mL)中，依次加入三乙胺(1.5g,14.7mmol,2.0mL)和湿钯碳(0.3g,10％纯度)，氢气置换三次，反应液在25℃和15Psi氢气条件下继续搅拌16小时。将反应液过滤，减压除去有机溶剂，所得粗产品经硅胶柱层析(洗脱液：10-30％乙酸乙酯/石油醚)分离纯化得到化合物(-)-C7-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.00-6.96(t,J＝7.6Hz,1H),6.80-6.54(m,2H),5.17-5.11(m,0.5H),4.86(s,1H),4.82-4.76(m,0.5H),4.71-4.60(m,1H),4.51-4.24(m,1H),3.62-3.55(m,3H),3.46-3.11(m,1H),3.08-2.74(m,1H),1.48-1.35(m,9H).MS m/z:207.9[M-100] +.
步骤2：化合物(-)-C7-2的制备
将化合物(-)-C7-1(2.0g,6.5mmol)溶于四氢呋喃(50mL)中，依次加入碳酸铯(4.2g,13.0mmol)和苄溴(1.7g,9.8mmol,1.2mL)，反应液加热至60℃继续搅拌3小时。减压除去有机溶剂，所得粗产品经硅胶柱层析(洗脱液：0-30％乙酸乙酯/石油醚)分离纯化得到化合物(-)-C7-2。 1H NMR(400MHz,CHLOROFORM-d):δ7.48-7.31(m,5H),7.19-7.12(m,1H),6.84-6.71(m,2H),5.23-5.19(m,0.5H),5.10(s,2H),4.90-4.69(m,1.5H),4.58-4.40(m,1H),3.68-3.63(m,3H),3.61-3.37(m,1H),3.14-2.93(m,1H),1.57-1.44(m,9H).MS m/z:420.0[M+Na] +.
步骤3：化合物(-)-C7的制备
将化合物(-)-C7-2(2.4g,6.0mmol)溶于二氧六环(30mL)中，加入氯化氢的二氧六环溶液(4M,8mL)，反应液在25℃继续搅拌16小时。减压除去有机溶剂得到化合物(-)-C7的盐酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d4):δ7.51-7.26(m,6H),7.06-7.04(d,J＝8.4Hz,1H),6.88-6.86(d,J＝7.8Hz,1H),5.18(s,2H),4.54-4.41(m,3H),3.93(s,3H),3.54-3.46(m,1H),3.05-2.96(m,1H).MS m/z:298.0[M+1] +.
参考例46:合成中间体(-)-C8
Figure PCTCN2018090432-appb-000110
步骤1：化合物(-)-C8-1和(-)-C9-1的制备
将化合物(-)-C7-1(0.7g,2.3mmol)溶于乙腈(10mL)中，加入Select F(968.2mg,2.7mmol)，反应液在25℃继续搅拌16小时。向反应液中加入5mL甲醇，减压除去有机溶剂，所得粗产品经硅胶柱层析(洗脱液：10-25％乙酸乙酯/石油醚)分离纯化，进一步经高效液相色谱(柱子:Xtimate C18150*25mm*5μm；流动相:[水(10mM NH 4HCO 3)-ACN]；B％:45％-70％,9.5min)分离纯化，得到化合物(-)-C8-1和化合物(-)-C9-1.
化合物(-)-C8-1： 1H NMR(400MHz,CHLOROFORM-d):δ6.96-6.91(t,J＝9.2Hz,1H),6.74-6.60(m,1H),5.76(br s,1H),5.31-4.96(m,0.5H),4.86-4.85(m,0.5H),4.74-4.66(m,1H),4.49-4.38(m,1H),3.69-3.66(m,3H),3.53-3.30(m,1H),3.10-2.94(m,1H),1.61-1.43(m,9H).MS m/z:225.9[M-100] +.
化合物(-)-C9-1： 1H NMR(400MHz,CHLOROFORM-d):δ6.80-6.75(t,J＝9.2Hz,1H),6.63-6.53(m,1H),5.94-5.75(m,1H),5.29-5.01(m,1H),4.85-4.75(m,1H),4.47-4.37(m,1H),3.69-3.66(m,3H),3.56-3.24(m,1H),2.98-2.85(m,1H),1.56-1.51(m,9H).MS m/z:226.0[M-100] +.
步骤2：化合物(-)-C8-2的制备
将化合物(-)-C8-1(30.0mg,92.2μmol)溶于四氢呋喃(5mL)中，加入碳酸铯(60.1mg,184.4μmol)和苄溴(23.7mg,138.3μmol,16.4uL)，反应液升温至60℃继续搅拌16小时。减压除去有机溶剂，所得粗产品经硅胶柱层析(洗脱液：0-30％乙酸乙酯/石油醚)分离纯化得到化合物(-)-C8-2。 1H NMR(400MHz,CHLOROFORM-d):δ7.43-7.24(m,5H),6.92-6.85(m,1H),6.81-6.67(m,1H),5.11-4.51(m,2.5H),4.64-4.54(m,1.5H),4.42-4.24(m,1H),3.58-3.51(m,3H),3.48-3.15(m,1H),2.93-2.67(m,1H),1.47-1.36(m,9H).MS m/z:438.2[M+Na] +.
步骤3：化合物(-)-C8的制备
将化合物(-)-C8-2(35.0mg,77.5μmol)溶于乙酸乙酯(2mL)中，加入氯化氢的乙酸乙酯溶液(4M,2.4mL)，反应液在25℃继续搅拌30分钟。减压除去有机溶剂得到化合物(-)-C8的盐酸盐。 1H NMR(400MHz,CHLOROFORM-d):δ7.57-7.32(m,5H),7.29-7.14(m,1H),7.12-6.94(m,1H),5.30-5.16(m,2H),4.56-4.30(m,3H),3.94(s,3H),3.73-3.43(m,1H),2.97-2.87(m,1H).MS m/z:316.0[M+1] +.
参考例47:合成中间体(-)-C9
Figure PCTCN2018090432-appb-000111
步骤1：化合物(-)-C9-2的制备
将化合物(-)-C9-1(80.0mg,245.9μmol)溶于四氢呋喃(5.0mL)中，加入碳酸铯(160.2mg,491.8μmol)和溴化苄(63.1mg,368.9μmol)，反应液升温至60℃继续搅拌16小时。冷却，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱液：0-20％乙酸乙酯/石油醚)分离纯化得到化合物(-)-C9-2。 1H NMR(400MHz,METHANOL-d 4):δ7.46-7.31(m,5H),6.90-6.82(m,1H),6.73-6.70(m,1H),5.35-5.22(m,0.5H),5.07(s,2H),5.01(s,0.5H),4.93-4.70(m,1H),4.53-4.30(m,1H),3.74-3.65(m,3H),3.65-3.45(m,1H),3.06-2.83(m,1H),1.58-1.48(m,9H).MS m/z:438.1[M+Na] +.
步骤2：化合物(-)-C9的制备
将化合物(-)-C9-2(82.0mg,197.4μmol)溶于乙酸乙酯(1.0mL)中，再加入氯化氢的乙酸乙酯(4.0M,1.0mL)，反应液在20-25℃继续搅拌3小时。减压除去有机溶剂，得到化合物(-)-C9的盐酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.45-7.29(m,5H),7.10-7.02(m,2H),5.15(s,2H),4.58-4.31(m,3H),3.92(s,3H),3.52-3.46(m,1H),3.03-2.95(m,1H).MS m/z:315.9[M+1] +.
参考例48:合成中间体(-)-C10
Figure PCTCN2018090432-appb-000112
步骤1：化合物(-)-C10-1的制备
将化合物(-)-C1(1.0g,2.9mmol)溶于二氯甲烷(12mL)中，依次加入三乙胺(600.0mg,5.9mmol)和二碳酸二叔丁酯(770.0mg,3.5mmol)，反应液在15-20℃继续搅拌5小时。减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱液：10-30％乙酸乙酯/石油醚)分离纯化得到化合物(-)-C10-1。 1H NMR (400MHz,CHLOROFORM-d):δ7.52-7.44(m,2H),7.43-7.31(m,3H),6.94-6.78(m,2H),5.10-4.99(m,1.5H),4.95-4.89(m,1H),4.67-4.53(m,1.5H),4.49-4.34(m,1H),4.15-4.00(m,2H),3.87(s,3H),3.53-3.49(m,0.5H),3.27-3.22(m,0.5H),2.99-2.75(m,1H),1.55-1.43(m,9H),1.19-1.13(m,3H).MS m/z:464.1[M+Na] +.
步骤2：化合物(-)-C10-2的制备
将化合物(-)-C10-1(1.0g,2.3mmol)溶于甲醇(20.0mL)中，加入湿Pd/C(100.0mg,226.5μmol,5％纯度)，氢气置换三次，反应液在15Psi氢气氛围和15-20℃继续搅拌1.5小时。反应液通过硅藻土过滤，减压除去有机溶剂，得到化合物(-)-C10-2，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,CHLOROFORM-d):δ6.79-6.58(m,2H),5.70(brs,1H),5.14-5.12(m,0.5H),4.79-4.59(m,1.5H),4.50-4.34(m,1H),4.16-4.02(m,2H),3.87(s,3H),3.50-3.44(m,0.5H),3.33-3.28(m,0.5H),3.14-2.90(m,1H),1.57-1.42(m,9H),1.20-1.17(m,3H).MS m/z:374.1[M+Na] +.
步骤3：化合物(-)-C10-3的制备
将化合物(-)-C10-2(100.0mg,284.6μmol)溶于四氢呋喃(8.0mL)中，再依次加入化合物4-氯苄溴(88.0mg,428.3μmol)和碳酸铯(185.0mg,567.8)，反应液升温至70℃继续搅拌16小时。冷却，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱液：0-30％乙酸乙酯/石油醚)分离纯化，得到化合物(-)-C10-3。 1H NMR(400MHz,CHLOROFORM-d):δ7.47-7.32(m,4H),6.93-6.77(m,2H),5.09-5.07(m,0.5H),5.02-4.82(m,2H),4.68-4.55(m,1.5H),4.48-4.34(m,1H),4.16-3.99(m,2H),3.86(s,3H),3.53-5.48(m,0.5H),3.26-3.21(m,0.5H),2.97-2.77(m,1H),1.54-1.41(m,9H),1.21-1.09(m,3H).MS m/z:498.2[M+Na] +.
以下化合物使用与化合物(-)-C10-3类似的方法合成得到：
Figure PCTCN2018090432-appb-000113
Figure PCTCN2018090432-appb-000114
Figure PCTCN2018090432-appb-000115
步骤4：化合物(-)-C10的制备
将化合物(-)-C10-3(120.0mg,252.1μmol)溶于乙酸乙酯(1.0mL)中，再加入氯化氢的乙酸乙酯(4.0M,1.0mL)，反应液在15-20℃继续搅拌16小时。减压除去有机溶剂，得到化合物(-)-C10的盐酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.46-7.33(m,4H),7.12-6.95(m,2H),5.12-5.02(m,2H),4.42-4.23(m,5H),3.91(s,3H),3.35-3.31(m,1H),2.88-2.80(m,1H),1.36-1.32(t,J＝7.2Hz,3H).MS m/z:376.0[M+1] +.
以下化合物使用与化合物(-)-C10类似的方法合成得到：
Figure PCTCN2018090432-appb-000116
Figure PCTCN2018090432-appb-000117
Figure PCTCN2018090432-appb-000118
参考例62:合成中间体(-)-C24
Figure PCTCN2018090432-appb-000119
步骤1：化合物(-)-C24-1的制备
将化合物(-)-C10-2(100.0mg,284.6μmol)和苯硼酸(70.1mg,574.9μmol)溶于二氯甲烷(10mL)中，加入醋酸铜(54.0mg,297.3μmol)，
Figure PCTCN2018090432-appb-000120
分子筛(321mg)，TEMPO(90.0mg,572.3μmol)和吡啶(226.0mg,2.9mmol)，反应液在15-20℃继续搅拌64小时。将反应液倒入水(30mL)中，分液，水相用二氯甲烷萃取(30mL)三次，合并后的有机相用饱和氯化钠水溶液(50mL)洗涤，减压除去有机溶剂，所得粗产物经硅胶柱层析(洗脱液：0-30％乙酸乙酯/石油醚)分离纯化，得到化合物(-)-C24-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.26-7.21(m,2H),7.06-6.96(m,2H),6.89-6.76(m,3H),5.06-5.05(m,0.5H),4.76-4.63(m,1.5H),4.58-4.46(m,1H),4.12-3.87(m,2H),3.75(s,3H),3.40-3.13(m,1H),2.96-2.75(m,1H),1.56-1.38(m,9H),1.16-1.02(m,3H).MS m/z:450.2[M+Na] +.
步骤2：化合物(-)-C24的制备
将化合物(-)-C23-1(125.0mg,292.4μmol)溶于乙酸乙酯(1.0mL)中，再加入氯化氢的乙酸乙酯(4.0M,1.0mL)，反应液在20-25℃继续搅拌16小时。减压除去有机溶剂，得到化合物(-)-C24的盐酸盐，该化合物不经进一步纯化直接用于下一步反应。 1H NMR(400MHz,METHANOL-d 4):δ7.28-7.24(m,2H),7.21-7.14(m,2H),7.04-6.95(m,1H),6.79-6.76(m,2H),4.53-4.37(m,3H),4.35-4.21(m,2H),3.74(s,3H),3.40-3.32(m,1H),2.97-2.90(m,1H),1.29-1.26(t,J＝7.2Hz,3H).MS m/z:325.1[M+1] +.
实施例1和2:化合物1和2的制备
Figure PCTCN2018090432-appb-000121
步骤1：化合物1-1的制备
将化合物(-)-C1(150.0mg,439.4μmol)溶于无水二氯甲烷(6.0mL)中，依次加入HATU(200.0mg,527.2μmol)，吡啶(104.0mg,1.32mmol)和A2(156.0mg,659.1μmol)。反应液在25℃搅拌16小时后，真空下浓缩除去有机溶剂。得到粗产物经硅胶层析柱(洗脱液：50-100％乙酸乙酯/石油醚)分离纯化得到化合物1-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.64-7.31(m,10H),6.93-6.32(m,2H),5.51-5.29(m,1H),5.13-4.81(m,3H),4.27-3.90(m,4H),3.90-3.79(m,2H),3.53-3.35(m,2H),1.87-1.49(m,5H),1.33-1.04(m,3H).MS m/z:560.2[M+1] +. 以下化合物使用与化合物1-1类似的方法合成得到：
Figure PCTCN2018090432-appb-000122
Figure PCTCN2018090432-appb-000123
Figure PCTCN2018090432-appb-000124
Figure PCTCN2018090432-appb-000125
步骤2：化合物1和2的制备
25℃下，将化合物1-1(200.0mg,357.4μmol)溶于四氢呋喃(3.0mL)和水(1.5mL)的混合溶液中，再加入氢氧化锂单水合物(85.0mg,2.0mmol)。搅拌72小时后，向反应液中加入1M的盐酸使pH<4。水相用乙酸乙酯(15.0mL x 3)萃取。合并后的有机相用饱和食盐水(30.0mL)洗涤，无水硫酸钠干燥，真空下浓缩得到粗产物。粗产物经层析柱分离纯化(洗脱液：50～100％乙酸乙酯/石油醚)得到白色固体(130.0mg)。再经SFC分离(AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O EtOH]；B％:30％-30％)得到两个非对映异构体化合物1(99.4％de)和化合物2(96.4％de).
化合物1： 1H NMR(400MHz,DMSO-d 6):δ7.54-7.21(m,10H),6.99-6.60(m,2H),5.55(s,1H),5.18-4.64(m,4H),4.43-4.24(m,1H),3.88-3.56(m,4H),3.27-3.14(m,2H),2.92-2.64(m,1H),2.37-2.24(m,1H),2.04-1.82(m,2H),1.63-1.41(m,2H).MS m/z:532.1[M+1] +.SFC:柱子：Chiralpak AD-3(150mm*4.6mm,3μm)；流动相：[0.05％DEA乙醇]；B％:5％-40％5min,40％2.5min,5％2.5min；Rt＝4.704min；99.4％de.
化合物2： 1H NMR(400MHz,DMSO-d 6):δ7.52-7.25(m,10H),6.97-6.72(m,2H),5.56-5.44(m,1H),5.08-4.66(m,4H),4.51-4.25(m,1H),3.88-3.60(m,6H),3.25-3.16(m,2H),2.83-2.63(m,1H),2.20-1.76(m,3H),1.62-1.36(m,2H).MS m/z:532.1[M+1] +.SFC:柱子：Chiralpak AD-3(150mm*4.6mm,3μm)；流动相：[0.05％DEA乙醇]；B％:5％-40％5min,40％2.5min,5％2.5min；Rt＝5.497min；96.4％de.
以下化合物使用与化合物1和2类似的方法合成得到：
Figure PCTCN2018090432-appb-000126
Figure PCTCN2018090432-appb-000127
Figure PCTCN2018090432-appb-000128
Figure PCTCN2018090432-appb-000129
Figure PCTCN2018090432-appb-000130
Figure PCTCN2018090432-appb-000131
Figure PCTCN2018090432-appb-000132
Figure PCTCN2018090432-appb-000133
Figure PCTCN2018090432-appb-000134
Figure PCTCN2018090432-appb-000135
Figure PCTCN2018090432-appb-000136
Figure PCTCN2018090432-appb-000137
实施例17和18:化合物17和18的制备
Figure PCTCN2018090432-appb-000138
步骤1：化合物17-1的制备
将化合物(-)-C1(150.0mg,439.4μmol)溶于二氯甲烷(5.0mL)中，依次加入HATU(251.0mg,660.1μmol)、吡啶(70.0mg,885.0μmol)和S-A18(120.0mg,487.4μmol)。反应液在25℃搅拌16小时后，真空下浓缩除去有机溶剂得到粗产物。粗产物通过硅胶层析柱(洗脱液：0-50％石油醚/乙酸乙酯)分离纯化得到产物17-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.68-7.57(m,2H),7.50-7.34(m,8H),7.21-6.94(m,4H),6.87-6.79(m,1H),6.73-6.50(m,1H),6.06-5.96(m,1H),5.43-5.11(m,1H),5.08- 4.70(m,4H),4.56-4.30(m,1H),4.08-3.92(m,1H),3.87-3.81(m,3H),3.68-3.41(m,1H),3.27-3.08(m,0.5H),2.98-2.74(m,0.5H),1.08-0.80(m,3H).MS m/z:570.1[M+1] +.
以下化合物使用与化合物17-1类似的方法合成得到：
Figure PCTCN2018090432-appb-000139
Figure PCTCN2018090432-appb-000140
Figure PCTCN2018090432-appb-000141
步骤2：化合物17和18的制备
25℃下，将化合物17-1(218.0mg,382.7μmol)溶于四氢呋喃(5.0mL)中，再加入氢氧化锂单水合物(93.0mg,2.2mmol)的水(2.0mL)溶液。15～20℃下搅拌反应40小时后，加入水(15.0mL)稀释，再用1M的盐酸调节pH<4。水相用乙酸乙酯(50.0mL x 3)萃取。合并后的有机相用饱和食盐水(50.0mL)洗涤，无水硫酸钠干燥，真空下浓缩得到粗产物。粗产物经层析柱分离纯化(洗脱液：0-80％石油醚/乙酸乙酯)得到产物，再经SFC分离(柱:AD(250mm*30mm,5μm)；流动相[0.1％NH 3H 2O EtOH]；B％:35％-35％)得到两个非对映异构体，主产物化合物17和少量化合物18.
化合物17： 1H NMR(400MHz,DMSO-d 6)δ7.69-7.30(m,11H),7.25-7.13(m,1H),7.06-6.77(m,4H),6.52-6.23(m,1H),5.11-4.75(m,4H),4.27(d,J＝16.0Hz,1H),3.84-3.74(m,3H),2.88-2.64(m,1H),2.43-2.29(m,1H).MS m/z:564.1[M+Na] +.SFC:柱子：Chiralpak AD-3(150mm*4.6mm,3μm)；流动相：B:[0.05％DEA Ethanol]；B％:5％-40％5.5min,40％3min,5％1.5min；Rt＝5.339min；97.5％de.
化合物18： 1H NMR(400MHz,DMSO-d 6)δ7.63-7.28(m,10H),7.25-6.99(m,3H),6.97-6.73(m,3H),6.47-6.28(m,1H),5.04-4.73(m,4H),4.56-4.27(m,1H),3.82-3.75(m,3H),2.83-2.59(m,1H),2.42-2.22(m,1H).MS m/z:564.1[M+Na] +.SFC:柱子：Chiralpak AD-3(150mm*4.6mm,3μm)；流动相：B: [0.05％DEA Ethanol]；B％:5％-40％5.5min,40％3min,5％1.5min；Rt＝5.745min；94.5％de.以下化合物使用与化合物17和18类似的方法合成得到：
Figure PCTCN2018090432-appb-000142
Figure PCTCN2018090432-appb-000143
Figure PCTCN2018090432-appb-000144
Figure PCTCN2018090432-appb-000145
Figure PCTCN2018090432-appb-000146
Figure PCTCN2018090432-appb-000147
实施例46:化合物46的制备
Figure PCTCN2018090432-appb-000148
步骤1：化合物46-1的制备
将化合物(-)-C1(280.0mg,820.2μmol)和A12(187.2mg,820.2μmol)溶于N,N-二甲基甲酰胺(8.0mL)中，依次加入二异丙基乙基胺(318.0mg,2.5mmol)和HATU(374.2mg,984.2μmol)。反应液在20℃搅拌5小时后，加入水(5.0mL)淬灭反应，水相用乙酸乙酯(2.0mL x 3)萃取。合并后的有机相用无水硫酸钠、过滤和真空下浓缩得到粗产物。粗产物通过硅胶层析柱(洗脱液：9％-11％石油醚/乙酸乙酯)分离纯化得到产物46-1。 1H NMR(400MHz,CHLOROFORM-d):δ1.27-1.29(m,3H)2.83(s,3H)3.84-3.86(m,2H)4.12-4.18(m,2H)4.84-5.12(m,2H)5.09-5.11(m,1H)5.97-6.05(m,1H)6.72-6.94(m,2H)6.94-7.15(m,3H)7.29-7.48(m,11H)7.48-7.65(m,2H).
以下化合物使用与化合物46-1类似的方法合成得到：
Figure PCTCN2018090432-appb-000149
Figure PCTCN2018090432-appb-000150
Figure PCTCN2018090432-appb-000151
Figure PCTCN2018090432-appb-000152
Figure PCTCN2018090432-appb-000153
步骤2：化合物46的制备
25℃下，将化合物46-1(123.0mg,223.0μmolμmol)溶于乙醇(2.0mL)中，再加入氢氧化锂单水合物(10.7mg,446.0μmol)。20℃下搅拌反应4小时后，加入5mL水稀释，再用1M的盐酸调节pH<4，水相用乙酸乙酯(5.0mL x 3)萃取。合并后的有机相用无水硫酸钠干燥、真空下浓缩得到粗产物。粗产物经层析柱分离纯化(洗脱液：0-80％石油醚/乙酸乙酯)得到产物46.
化合物46： 1H NMR(400MHz,DMSO-d 6)δ2.61-3.11(m,2H)3.71-3.91(m,3H)4.05-4.33(m,1H)4.78-5.06(m,4H)5.06-5.24(m,1H)6.30-6.42(m,1H)6.80-6.86(m,1H)6.88-6.98(m,4H)7.25(br t,J＝7.47Hz,2H)7.35-7.47(m,8H)7.44-7.48(m,1H)7.53-7.66(m,2H).MS m/z:524.2[M+1] +.
以下化合物使用与化合物46类似的方法合成得到：
Figure PCTCN2018090432-appb-000154
Figure PCTCN2018090432-appb-000155
实施例49和50:化合物49和50的制备
Figure PCTCN2018090432-appb-000156
步骤1：化合物49-1的制备
将化合物C2(60.0mg,172.5μmol)的盐酸盐分散于二氯甲烷(3.0mL)中，氮气保护下依次加入三乙胺(69.8mg,690.0μmol)、化合物S-A1(49.4mg,224.2μmol)和HATU(98.4mg,258.7μmol)，反应液在25℃下继续搅拌16小时。将反应液减压除去有机溶剂，所得粗产物经硅胶层析柱(洗脱液：9-25％乙酸乙酯/石油醚)分离纯化，得到化合物49-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.58-7.30(m,10H),7.10-6.45(m,2H),5.60-4.94(m,3H),4.85-4.47(m,3H),4.34-4.17(m,1H),3.69-3.51(m,3H),3.36-3.20(m,1H),3.08-2.79(m,1H),2.32-2.22(m,3H),1.95-1.61(m,8H).MS m/z:514.1[M+1] +.
以下化合物使用与化合物49-1类似的方法合成得到：
Figure PCTCN2018090432-appb-000157
Figure PCTCN2018090432-appb-000158
步骤2：化合物49和50的制备
将化合物49-1(80.0mg,155.7μmol)溶于四氢呋喃(3.0mL)和水(1.0mL)中，再加入一水合氢氧化锂(37.3mg,1.5mmol)，反应液在25℃下继续搅拌16小时。反应液用1.0M的盐酸调节pH至5-6，用乙酸乙酯(10mL x 3)萃取，合并后的有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，减压除去有机溶剂所得粗产物经硅胶层析柱(洗脱液：50～100％乙酸乙酯/石油醚)分离纯化，得到产物，再经SFC分离(柱:AD(250mm*30mm,10μm)；流动相[0.1％NH 3H 2O MeOH]；B％:20％-20％)得到两个非对映异构体，化合物49和化合物50。
化合物49： 1H NMR(400MHz,DMSO-d 6):δ7.58-7.21(m,10H),7.02-6.57(m,2H),5.49-5.09(m,1H),4.89-4.47(m,4H),4.41-4.37(d,J＝16.8Hz,1H),4.18-4.00(m,1H),3.22-3.18(m,1H),2.38-2.25(m,1H),2.18-2.17(d,J＝4.8Hz,3H),1.80-1.42(m,8H).MS m/z:500.2[M+1] +.SFC:柱子：Chiralpak AD-3(100mm*4.6mm,3μm)；流动相：B:[0.05％DEA Methanol]；B％:5％-40％4.5min,40％2.5min,5％1.0min；Rt＝3.207min；97.2％de.
化合物50： 1H NMR(400MHz,DMSO-d 6):δ7.54-7.23(m,10H),7.05-6.69(m,2H),5.35-5.30(d,J＝18.0Hz,1H),5.17-4.80(m,2H),4.79-4.29(m,3H),4.04(s,1H),3.22-3.18(m,1H),2.81-2.65(m,1H),2.19(s,3H),1.81-1.42(m,8H).MS m/z:500.1[M+1] +.SFC:柱子：Chiralpak AD-3(100mm*4.6mm,3μm)；流动相：B:[0.05％DEA Methanol]；B％:5％-40％4.5min,40％2.5min,5％1.0min；Rt＝3.813min；96.4％de.
以下化合物使用与化合物49和50类似的方法合成得到：
Figure PCTCN2018090432-appb-000159
Figure PCTCN2018090432-appb-000160
Figure PCTCN2018090432-appb-000161
实施例117:化合物117的制备
Figure PCTCN2018090432-appb-000162
步骤1：化合物117-1的制备
将化合物(-)-C23(110mg,437.76μmol)和S-A1(115.71mg,525.31μmol)溶于无水二氯甲烷(5mL)中，加入HATU(166.45mg,437.76μmol)和二异丙基乙胺(169.73mg,1.31mmol,228.75uL)，反应液在25℃继续搅拌16小时。向反应液中加入10mL水，分液，水相用二氯甲烷(10mL)萃取三次，合并有机相，减压除去有机溶剂，所得粗产物经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝2:1)得到化合物117-1。 1H NMR(400MHz,CHLOROFORM-d):δ7.48-7.22(m,5H),7.07-6.93(m,1H),6.75-6.58(m,1H),5.81-4.06(m,7H),3.85-3.83(d,J＝8.4Hz,3H),3.79-3.44(m,1H),3.27-2.83(m,1H),1.89-1.59(m,8H),1.27-0.85(m,3H).MS m/z:454.2[M+1] +.
步骤2：化合物117-2的制备
将化合物117-1(45mg,99.22μmol)溶于四氢呋喃(1mL)和水(2mL)的混合溶剂中，加入一水合氢氧化锂(83.27mg,1.98mmol)，反应液在25℃继续搅拌16小时。向反应液中加入10mL水，用乙酸乙酯(10mL)萃取三次，合并有机相，减压除去有机溶剂，所得粗产物经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝2:1)得到化合物117-2。 1H NMR(400MHz,CHLOROFORM-d):δ7.31-7.21(m,5H),7.05-6.98(m,1H),6.69-6.56(m,1H),5.61-5.51(m,1H),5.27-5.10(m,1H),4.93-4.56(m,1H),4.42-4.35(m,1H),4.08-4.03(m,1H),3.78-3.76(d,J＝8.8Hz,3H),3.40-3.17(m,1H),3.08-2.73(m,1H),1.74-1.71(m,8H).MS m/z:426.1[M+1] +.
步骤3：化合物117-3的制备
将化合物117-2(30mg,70.51μmol)溶于N,N-二甲基甲酰胺(1mL)中，加入碳酸钾(19.49mg,141.02μmol)，反应液在25℃搅拌30分钟，加入2-氯甲基噻吩(18.70mg,141.02μmol)，反应液升温至70℃继续搅拌1小时。向反应液中加入5mL水，用乙酸乙酯(5ml)萃取三次，合并有机相，减压除去有机溶剂，所得粗产物经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝10:1)得到化合物117-3。MS m/z:618.1[M+1] +.
步骤4：化合物117的制备
将化合物117-3(45mg,72.84μmol)溶于四氢呋喃(2mL)和水(1mL)的混合溶液中，加入一水合氢氧化锂(30.57mg,728.42μmol)，反应液在25℃下继续搅拌16小时。加入5mL水，用乙酸乙酯(10mL)萃取三次，合并有机相，减压除去有机溶剂，所得粗产物经制备硅胶板(石油醚：乙酸乙酯＝5:1)分离纯化得到化合物177。 1H NMR(400MHz,DMSO-d 6):δ8.41(br s,2H),7.55-7.51(m,1H),7.36-7.23(m,4H),7.07-7.06(m,1H),7.01-6.98(m,1H),6.85-6.80(m,1H),5.32-5.25(m,1H),5.08-4.90(m,3H),4.82-4.73(m,1H),4.40-4.31(m,1H),4.14-4.02(m,1H),3.78(s,3H),2.73-2.66(m,1H),2.33-2.24(m,1H),2.15-1.99(m,1H),1.73-1.85(m,6H),1.45-1.23(m,1H).MS m/z:522.1[M+1] +.SFC:柱子：Chiralcel OD-3(100mm*4.6mm,3μm)；流动相：B:[0.1％DEA EtOH]；B％:5％-40％4.5min,40％2.5min,5％1.0min；Rt＝3.370min；de＝87.16％.
实施例118:化合物118的制备
Figure PCTCN2018090432-appb-000163
步骤1：化合物118-1的制备
将化合物S-A1(25.3g,114.9mmol)溶于无水二氯甲烷(250.0mL)中，加入N,N-二甲基甲酰胺(0.5mL)，氮气气氛下滴加草酰氯(17.5g,137.8mmol,12.07mL)，反应液在20-25℃搅拌30分钟，减压除去有机溶剂，所得粗产物溶于二氯甲烷(200.0mL)配制成溶液。将吡唑(8.6g,126.3mmol)和N-甲基吗啡啉(15.1g,149.3mmol,16.4mL)溶于二无水氯甲烷(100.0mL)中，在氮气气氛下，缓慢滴加上述溶液，反应液在20-25℃继续搅拌16小时。用1.0M的硫酸溶液洗(300mL)两次，饱和碳酸氢钠(300mL)洗涤两次，水(300mL)洗涤，饱和氯化钠水溶液(500mL)洗涤，无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品中加入正己烷(150mL)，70℃搅拌30分钟，缓慢冷却至0℃，静置2小时。过滤，滤饼用正己烷(80mL)洗涤，真空干燥，得到化合物118-1。 1H NMR(400MHz,CHLOROFORM-d):δ8.24-8.23(d,J＝2.4Hz,1H),7.73(s,1H),7.60-7.58(d,J＝6.8Hz,2H),7.41-7.27(m,3H),6.44-6.43(m,1H),6.36(s,1H),4.21-3.98(m,1H),1.87-1.67(m,6H),1.56-1.42(m,2H).MS m/z:271.0[M+1] +.SFC：柱子:ChiralCel OJ-H(150mm*4.6mm,5μm)；流动相:B:[0.05％DEA EtOH]；B％:5％-40％-5％；Rt＝1.936min；99.4％de.
步骤2：化合物118的制备
将化合物(-)-C6(50.0mg,167.0μmol)溶于N,N-二甲基甲酰胺(2.0mL)中，加入1,1,3,3-四甲基胍(23.1mg,200.4μmol)，混合液在25℃搅拌1小时后，加入化合物118-1(54.2mg,200.4μmol)，反应液在25℃继续搅拌18小时。向反应液中加入乙酸乙酯(30mL)，用水(25mL)洗涤两次，饱和氯化钠的水溶液(20mL)洗涤一次，有机相用无水硫酸钠干燥，过滤，减压除去有机溶剂，所得粗品经 硅胶制备板(乙酸乙酯/石油醚＝1/1)分离纯化，得到化合物118。 1H NMR(400MHz,DMSO-d 6):δ7.54-7.23(m,10H),6.74-6.43(m,2H),5.39-5.26(m,1H),5.12-4.55(m,4H),4.51-4.25(m,1H),4.16-3.97(m,1H),3.46-3.42(m,1H),2.21-2.16(m,1H),1.80-1.40(m,8H).MS m/z:502.2[M+1] +.SFC:柱子：ChiralCel OJ-H(150mm*4.6mm,5μm)；流动相：B:[0.05％DEA EtOH]；B％:5％-40％5.5min,40％3.0min,5％1.5min；Rt＝4.009min；96.5％de.
实验例1：体外评价
hAT2受体结合实验
溶液与缓冲液
缓冲液
50mM Tris
100mM NaCl
5mM MgCl2
0.1％BSA
蛋白酶抑制剂混合物，不含乙二胺四乙酸-1片(Roche#11873580001)(50mL加一片)
pH 7.4
实验方法与步骤
化合物的配置
参考配体PD123319和测试化合物用DMSO制备成750μM的母液；把每个化合物配置成8个浓度梯度(最高浓度为750uM,3倍稀释)，并加入10ul/孔到384孔板的母版里。
SPA beads用缓冲液配置成25mg/ml的母液；
同位素[ 125I]-Sar1-Ile8-Angiotensin II加纯水配置50uCi/ml的母液。
膜的配置
HEK-293细胞过表达hAT2的细胞膜用缓冲液制备成2.5mg/ml。
实验步骤
用ECHO从母板中吸入200nl的化合物到测试384板的每个孔。ZPE加入等体积的DMSO。(测试化合物在反应中的浓度将稀释250倍)。
配置50ml含有10μg/μl的磁珠、0.05μg/μl的AT2膜溶液，置于摇床上混匀。(100rpm,30min)。测试板中最终含有1.25μg/孔的hAT2膜，250μg/孔的磁珠。
用Multidrop Combi移液器把3.2的膜混合液加入到化合物测试板，每孔加入25μl。
用50uCi/ml的同位素[ 125I]-Sar1-Ile8-Angiotensin II母液用缓冲液制备成0.2nM的溶液，用Multidrop Combi移液器把0.2nM的125I加入到化合物测试板中，每孔加入25μl的体积。 125I同位素的终浓度是0.1nM。
把配置好的测试板置于摇床上，200rpm，室温过夜。
测试板用离心机离心，1200rpm,1min
将离心后的测试板用Microbeta读数。
实验结果见表1。
表1
Figure PCTCN2018090432-appb-000164
Figure PCTCN2018090432-appb-000165
结论：结果显示本发明化合物的活性异构体与EMA-401相比具有良好的体外活性。
实验例2：动力学溶解度的测定
将待测化合物溶解在DMSO中，以制备10mmol/L的原液。用移液管(Eppendorf Research公司)将980μL溶出介质加入到2mL的螺旋盖的玻璃管形瓶中。将20μL各受试化合物的原液以及QC样品添加到相当于pH 7.4的动力学检测溶液的缓冲溶液中。受试化合物和DMSO溶液的终浓度分别是为200μM和2％。药瓶压盖。最大浓度的理论值为200μM。室温下以每分钟880转的速度旋转摇动该混合物24小时。将小瓶离心30分钟，每分钟13000转。用数字移液管将200μL上清液加入到96-孔板中。用高效液相色谱法光谱测定的受试化合物的溶解度，实验结果见表2。
表2
化合物 溶解度(μM)@pH＝7.4
EMA401 191.7
37 >200.0
49 >200.0
51 189.96
63 190.32
90 182.68
103 >200.0
107 181.07
111 >200.0
结论：结果显示本发明化合物具有良好的溶解度(在pH＝7.4)。
实例3：人肝微粒体CYP抑制实验
研究项目的是采用每个同工酶的特异性探针底物来评价待测化合物对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)的抑制性。
混合人肝微粒体(pooled HLM,n≥50)购自Corning Inc.(Steuben,New York,USA)或者其他有资质的供应商，使用前都储存在低于-60℃冰箱。
将稀释好的系列浓度的待测化合物工作液加入到含有人肝微粒体、探针底物和循环体系的辅助因子的孵育体系中，甲醇含量约为终孵育体系的1％(v/v)。不含待测化合物而含有溶剂的对照作为酶活性对照(100％)。分析物在样品中的浓度采用液相色谱-串联质谱(LC/MS/MS)方法进行测定。使用样品(空白溶剂、阳性对照抑制剂或者待测化合物)浓度的平均值进行计算。应用SigmaPlot(V.11)对待测化合物平均百分比活性对浓度作非线性回归分析。通过三参数或四参数反曲对数方程来计算IC 50值。实验结果见表3。
表3
Figure PCTCN2018090432-appb-000166
结论：本发明化合物对五个CYP同工酶没有抑制作用，或抑制作用均较弱，预示在人体内发生药物-药物相互作用的可能性较少。
实例4：化合物在CACO-2细胞的双向渗透性研究
测定待测化合物在Caco-2细胞的双向渗透性，并且测试待测化合物是否被外排转运。
实验方法
储备液的配制
将化合物溶解于二甲基亚砜(DMSO)或其他适宜的溶剂，配制成合适浓度的储备液。
合适的内标(internal standard,IS)溶解于乙腈(acetonitrile，ACN)或其它有机溶剂作为终止液，具体信息将在研究报告中描述。
纳多洛尔(nadolol)、美托洛尔(metoprolol)、地高辛(digoxin)、雌激素酮3-硫酸钾(estrone3-sulfate potassium，E3S)和GF120918在本研究中分别作为低渗对照化合物、高渗对照化合物、P-糖蛋白(P- gp)底物、乳腺癌耐药蛋白(BCRP)底物和外排转运体抑制剂。这些化合物的储备液用DMSO配制，储存于≤-30℃，6个月内使用有效。
给药液和接收液的配制
本研究使用HBSS(Hanks Balanced Salt Solution)含10mM HEPES(2-[4-(2-羟乙基)-1-哌嗪]乙磺酸)作为转运缓冲液(pH 7.40±0.05)。给药液以及接收液的配制方法见下表4。
表4
Figure PCTCN2018090432-appb-000167
细胞培养
Caco-2细胞用MEM培养基(Minimum Essential Media)培养，培养条件为37±1℃，5％CO 2和饱和湿度。之后将细胞接种于Corning Transwell-96孔板里，接种密度为1×105细胞/cm 2，然后将细胞置于二氧化碳培养箱中培养21-28天后用于转运实验，期间每隔四到五天更换一次培养基。
转运实验
化合物给药浓度为2、10和100μM，在含有或不含10 0含GF120918的条件下双向(A-B和B-A方向)给药，每个给药浓度做三个平行。Digoxin和E3S的测试浓度分别为10和5μM，在含有或不含10μM GF120918的条件下双向给药；nadolol和metoprolol测试浓度均为2μM，在不含10μM GF120918的条件下单向(A-B方向)给药，三个对照化合物也均做三个平行。
将给药液、接收液和转运缓冲液置于37℃预孵育30分钟。细胞层用转运缓冲液润洗两遍。将给药液和接收液分别加入到对应的细胞板孔位(每个顶端和基底端孔分别加样75和250μL)。加样后，将细胞板置于37±1℃，5％CO 2和饱和湿度的培养箱中孵育120分钟。
样品收集信息见下表5。
表5
Figure PCTCN2018090432-appb-000168
所有的化合物漩涡震荡后，于3220×g，20℃离心20分钟，转移适量体积的上清液到样品分析板，封板后化合物若不立即分析则储存于2-8℃。采用LC/MS/MS的方法进行分析，具体的化合物处理方法见研究报告。
细胞膜完整性测试
荧光黄检测实验(Lucifer Yellow Rejection Assay)用于测试Caco-2细胞的完整性。每块细胞板随机选取6个细胞孔，分别加入100μM荧光黄，荧光黄检测实验与转运实验同时进行。孵育120分钟后，取荧光黄样品，在425/528nm(激发/发射)波谱处检测样品中荧光黄的相对荧光强度(the relative fluorescence unit,RFU)。
样品分析
待测化合物和对照化合物nadolol、metoprolol、digoxin及E3S在样品中的浓度均采用液相色谱-串联质谱(LC/MS/MS)方法进行测定。分析物和内标的保留时间、色谱图采集和色谱图的积分采用软件Analyst(AB Sciex,Framingham,Massachusetts,USA)进行处理，实验结果见表6。
表6
化合物编号 Papp(AB)(10 -6cm/s) Papp(BA)(10 -6cm/s) 外排比
EMA-401 0.11 6.40 58.39
37 0.27 8.68 32.50
49 1.15 14.56 12.6
57 0.67 17.69 26.33
90 1.10 10.89 9.91
107 0.48 6.24 13.05
结论：测试结果显示相对于EMA-401，本发明化合物的渗透性有所改善，有利于化合物的吸收。
实例5：血浆蛋白结合率(PPB)测试
采用平衡透析法测定0.2、2、10μM的待测化合物与Sprague-Dawley大鼠、比格犬和人血浆的体外蛋白结合率。
实验方法
实验将采用96孔平衡透析板(HTDialysis装置)来测定待测化合物和对照化合物的血浆蛋白结合率。
实验开始前，将透析膜按照使用说明书进行预处理，然后按要求组装透析装置。
取CD-1小鼠、Sprague-Dawley大鼠、比格犬、食蟹猴和人的空白血浆(抗凝剂为EDTA-K2，为购买的商业化产品，或在上海药明康德新药开发有限公司药性评价部采集制备,在使用前均储存在低于-60℃的冰箱内)，加入一定体积的待测化合物或对照化合物工作溶液，配制成浓度为0.2、2、10μM待测化合物和浓度为2μM对照化合物的血浆样品(n＝1)。有机相含量≤1％。首先，取出一定体积的含待测化合物和对照化合物的血浆样品到样品接收板中，作为零时刻的样品(T0样品，n＝3)；其次，将含待测化合物和对照化合物的血浆样品加到透析膜的一侧(血浆端，n＝3)，在透析膜的另一侧加入一定体积的透析缓冲液(缓冲液端，n＝3)；然后将透析板置于湿润的含5％CO2的培养箱中，在37±1℃下孵育4小时。
孵育结束后，移取一定体积透析后的缓冲液样品(F样品)和透析后的血浆样品(T样品)到样品接收板中，所有样品经过蛋白沉淀后进行LC/MS/MS分析，化合物的游离率(％Unbound)并通过如下公式计算：％Unbound＝100*[F]/[T],％Bound＝100-％Unbound。其中其中％Unbound为化合物的游离率；％Bound为化合物的结合率；[F]是透析板缓冲液端化合物的浓度；[T]是透析板血浆端化合物的浓度；实验结果见表7。
表7
Figure PCTCN2018090432-appb-000169
Figure PCTCN2018090432-appb-000170
结果表明：结果显示相对于EMA-401，测试化合物的血浆蛋白结合率有改善，有利于化合物达到药物作用靶点。

Claims (21)

  1. 式(Ⅱ)所示化合物及其药学上可接受的盐，
    Figure PCTCN2018090432-appb-100001
    其中，
    L选自：-O-、-S-、-N(R)-、-N(R)C(＝O)-、-C(＝O)O-；
    L 1选自：单键、-CH 2-、-CH 2CH 2-；
    R 1选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基、C 3-7环烷基、3～7元杂环烷基、6～10元芳基、5～6元杂芳基；
    R 2选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基；
    R 3选自任选被1、2或3个R取代的：苯基、5～6元杂芳基、5～6元杂环烷基；
    R 4选自H，或选自任选被1、2或3个R取代的：C 1-3烷基；
    R 5选自：H、F、Cl、Br、I、OH；
    R 6选自：H、F、Cl、Br、I、OH；
    R选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3杂烷基；
    R’选自：F、Cl、Br、I、OH、CN、NH 2；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
    带“#”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
    所述3～7元杂环烷基、5～6元杂芳基、C 1-6杂烷基、C 1-3杂烷基、5～6元杂环烷基之“杂”分别独立地选自-C(＝O)NH-、-NH-、N、-O-、-S-、-C(＝O)O-、-C(＝O)-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物及其药学上可接受的盐，其中，R选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基。
  3. 根据权利要求2所述化合物及其药学上可接受的盐，其中，R选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、Et、CF 3、
    Figure PCTCN2018090432-appb-100002
  4. 根据权利要求1～3任意一项所述化合物及其药学上可接受的盐，其中，L选自：-O-、-S-、-NH-、- N(CH 3)-、-NHC(＝O)-、-N(CH 3)C(＝O)-、-C(＝O)O-。
  5. 根据权利要求1～3任意一项所述化合物及其药学上可接受的盐，其中，R 1选自任选被1、2或3个R取代的：C 1-4烷基、C 1-6杂烷基、C 3-7环烷基、3～7元杂环烷基、6～10元芳基、5～6元杂芳基。
  6. 根据权利要求5所述化合物及其药学上可接受的盐，其中，R 1选自任选被1、2或3个R取代的：C 1- 4烷基、环丁烷基、环戊烷基、环己烷基、双环[3.1.0]己烷基、恶丁环基、四氢呋喃基、四氢吡喃基、苯基、萘基、噻吩基、吡唑基、咪唑基、恶唑基、噻唑基、吗啉基、哌嗪基、哌啶基、吡啶基、吡嗪基、嘧啶基。
  7. 根据权利要求6所述化合物及其药学上可接受的盐，其中，R 1选自任选被1、2或3个R取代的：Me、Et、
    Figure PCTCN2018090432-appb-100003
    Figure PCTCN2018090432-appb-100004
  8. 根据权利要求7所述化合物及其药学上可接受的盐，其中，R 1选自：Me、Et、
    Figure PCTCN2018090432-appb-100005
    Figure PCTCN2018090432-appb-100006
  9. 根据权利要求1或8所述化合物及其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018090432-appb-100007
    选自：
    Figure PCTCN2018090432-appb-100008
    Figure PCTCN2018090432-appb-100009
  10. 根据权利要求1～3任意一项所述化合物及其药学上可接受的盐，其中，R 2选自H、卤素、OH、NH 2、CN，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基、C 1-3烷硫基、C 1-3烷氨基。
  11. 根据权利要求10所述化合物及其药学上可接受的盐，其中，R 2选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、
    Figure PCTCN2018090432-appb-100010
  12. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 3选自任选被1、2或3个R取代的：苯基、吡啶基、嘧啶基、吡嗪基、噻吩基、噻唑基、异噻唑基、恶唑基、异恶唑基、四氢吡喃基、哌啶基、吗啉基。
  13. 根据权利要求12所述化合物或其药学上可接受的盐，其中，R 3选自任选被1、2或3个R取代的：
    Figure PCTCN2018090432-appb-100011
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其中，R 3选自：
    Figure PCTCN2018090432-appb-100012
    Figure PCTCN2018090432-appb-100013
  15. 根据权利要求1或14所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018090432-appb-100014
    选自：
    Figure PCTCN2018090432-appb-100015
    Figure PCTCN2018090432-appb-100016
  16. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 4选自：H、Me。
  17. 根据权利要求1～5、9～16任意一项所述化合物及其药学上可接受的盐，其选自：
    Figure PCTCN2018090432-appb-100017
    其中，
    R、R 2、R 3、R 4、R 5、R 6、L 1、L如权利要求1～5、9～16所定义；
    T选自N或CH；
    D选自CH 2或O；
    m、p分别独立地选自0、1、2或3，且m和p不同时选自0或3；
    n选自0、1、2或3；
    且当m选自0，D选自O时，n不选自3。
  18. 下式所示化合物，其选自：
    Figure PCTCN2018090432-appb-100018
    Figure PCTCN2018090432-appb-100019
    Figure PCTCN2018090432-appb-100020
    Figure PCTCN2018090432-appb-100021
  19. 根据权利要求18所述化合物，其选自：
    Figure PCTCN2018090432-appb-100022
    Figure PCTCN2018090432-appb-100023
    Figure PCTCN2018090432-appb-100024
    Figure PCTCN2018090432-appb-100025
    Figure PCTCN2018090432-appb-100026
    Figure PCTCN2018090432-appb-100027
    Figure PCTCN2018090432-appb-100028
    Figure PCTCN2018090432-appb-100029
    Figure PCTCN2018090432-appb-100030
    Figure PCTCN2018090432-appb-100031
    Figure PCTCN2018090432-appb-100032
  20. 根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐在制备治疗与AT 2R受体相关疾病的药物中的应用。
  21. 根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐在制备治疗慢性疼痛的药物中的应用。
PCT/CN2018/090432 2017-06-09 2018-06-08 作为at2r受体拮抗剂的羧酸衍生物 WO2018224037A1 (zh)

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