WO2014198195A1 - Biaryl-substituted 4-amino-butyric acid derivative, preparation method therefor and uses thereof - Google Patents

Biaryl-substituted 4-amino-butyric acid derivative, preparation method therefor and uses thereof Download PDF

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WO2014198195A1
WO2014198195A1 PCT/CN2014/079278 CN2014079278W WO2014198195A1 WO 2014198195 A1 WO2014198195 A1 WO 2014198195A1 CN 2014079278 W CN2014079278 W CN 2014079278W WO 2014198195 A1 WO2014198195 A1 WO 2014198195A1
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group
substituted
alkyl
halogen
mmol
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PCT/CN2014/079278
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French (fr)
Chinese (zh)
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杨飞
王春娟
仝朝龙
喻红平
徐耀昌
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上海翰森生物医药科技有限公司
江苏豪森药业股份有限公司
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Priority to CN201480009596.XA priority Critical patent/CN105143183B/en
Publication of WO2014198195A1 publication Critical patent/WO2014198195A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and in particular relates to a biaryl substituted 4-aminobutyric acid derivative and a preparation method and use thereof. Background technique
  • Hypertension is one of the most common cardiovascular diseases and a major risk factor for morbidity and mortality in congestive heart failure, stroke, coronary heart disease, renal failure, and aortic aneurysm. According to a recent press release published by the International Society of Hypertension, there are 972 million people with high blood pressure or high blood pressure in the world, accounting for 26.4% of the world's adult population. With the increasing ageing population, the proportion of hypertensive patients has gradually increased. By 2025, the estimated number of patients will reach 1.56 billion. With the emergence and widespread application of a new generation of antihypertensive drugs, the mortality rate of various cardiovascular diseases has dropped significantly.
  • EP neutral endopeptidase, also known as Neprilysin
  • Neprilysin is a type II transmembrane glycoprotein of the Ml 3 zinc-dependent metalloproteinase family, also known as enkephalinase, which carries a zinc atom at the active site of the enzyme.
  • EP has a molecular weight of about 97 kDa and consists of 750 amino acids. It contains a signal peptide and two hydrophilic domains. The intracellular fragment has 26 amino acids and the extracellular fragment has 700 amino acids. EP can act on the amino terminus of the polypeptide to hydrolyze the polypeptide chain.
  • EP a neuropeptide degrading enzyme
  • endothelial cells vascular smooth muscle cells
  • cardiomyocytes vascular smooth muscle cells
  • renal epithelial cells vascular smooth muscle cells
  • fibroblasts which are also present in the lungs, intestines, Adrenal gland, brain, etc.
  • Natriuretic peptides are mainly degraded by EP, and EP also catalyzes the adrenal medulla and bradykinin.
  • EP-selective inhibitors inhibit EP activity, increase the concentration of natriuretic peptide and bradykinin, increase vasodilation, increase cardiac output, decrease aldosterone levels, and inhibit RAAS (renin-angiotensin-aldosterone system), reducing Pre- and post-loading of the heart delays myocardial remodeling and improves cardiac function in patients with heart failure.
  • RAAS renin-angiotensin-aldosterone system
  • EP/ACE dual inhibitors dual inhibitors of EP in the past decade, including EP/ACE dual inhibitors, dual inhibitors of EP/ARB (angiotensin receptor), and dual inhibition of EP/ECE (endothelin converting enzyme).
  • EP/APN aminopeptidase N
  • the antihypertensive effect of EP/ACE dual inhibitors is superior to that of single inhibitors, which increases the content of diastolic vasopeptides such as substance P, bradykinin and adrenomedullin, and reduces contractile blood vessels such as endothelin I and angiotensin II.
  • the peptide content and optimized to combine the dual effects of diuresis and blood pressure, to maintain organ blood supply.
  • Omapatrilat is a potent ACE/NEP double inhibitor developed by BMS, but due to side effects such as angioedema, the FDA declined to approve Omapatrilat for the treatment of hypertension in July 2002, even as a last resort for refractory patients.
  • Solvay has developed three EP/ECE (endothelin-converting enzyme) dual inhibitors, currently in the clinical phase II of daglutril (SLV-306, oral) and SLV-334 (intravenous) for the treatment of pulmonary hypertension and Brain injury, SLV-338 (intravenous administration) at the clinical stage is used to treat cardiovascular disease, metabolic disorders and neurological diseases.
  • the EP/APN (aminopeptidase N) double inhibitor PL-37 (Debio-0827, orally) developed by Pharmaleads is mainly used to treat pain, especially neuropathic pain.
  • LCZ-696 is an oral antihypertensive and cardioprotective drug developed by Novartis.
  • the object of the present invention is to solve the existing technical problems and provide a biaryl substituted 4-aminobutyric acid derivative which can be metabolized in vivo to produce compound LBQ657, which has EP inhibitory activity and can be used as an EP inhibitor. It can be used to treat related diseases such as high blood pressure, heart failure, pulmonary hypertension and kidney disease.
  • Z is selected from oxygen or sulfur;
  • R is selected from alkali metal, alkaline earth metal
  • Ri R 2 are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, D. 8 embankment group, C 2.
  • d. 8 fluorenyl, ⁇ . 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, 3 ⁇ 4 substituted d. 8 decyloxy, C 3.
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, d. 8 fluorenyl. 2. 8 alkenyl, . 2.8 alkynyl group,
  • d. 8 fluorenyl, ⁇ . 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, halo substituted d. 8 decyloxy, C 3.
  • R 5 and Re are selected from the group consisting of hydrogen and C M thiol. 3. 8 ring sulfhydryl;
  • r 0, 1, and 2.
  • R is selected from the group consisting of sodium, potassium, magnesium, calcium, and ammonium.
  • the biaryl substituted 4-aminobutyric acid derivative is selected from the group consisting of compounds of formula (II):
  • R 3 , , R 5 , Re, r are as defined in formula (I).
  • R 3 is selected from the group consisting of hydrogen, halogen, d. 8 fluorenyl, halogen substituted d. 8 fluorenyl, . 3. 8 ⁇ ⁇ , -d 0-C(0)R 4 , -0-C(0)OR 4 , -C 1-4 -0-C(0)OR4; , R 5 , , r as (I) is defined.
  • Another object of the present invention is to provide an intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative having a structure represented by the formula (III):
  • Z is selected from oxygen or sulfur
  • R is selected from the group consisting of alkali metals, alkaline earth metals, ammonium or '3 ⁇ 4 R -
  • Ri R 2 are each independently selected from hydrogen, halogen, a hydroxyl group 2, cyano, nitro, alkyl with CL 8, C 2 8 alkenyl group,. 8 alkynyl group. Cyclic alkyl with 8, D 8 embankment group, C 3. 8 cycloalkyl group embankment, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5. 1Q aryl group, C 5.
  • d. 8 fluorenyl, ⁇ . 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, 3 ⁇ 4 substituted d. 8 decyloxy, C 3.
  • R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, d. 8 fluorenyl. 2. 8 alkenyl, . 2.8 alkynyl group,
  • d. 8 fluorenyl, ⁇ . 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, halo substituted d. 8 decyloxy, C 3. 8 ring decyloxy, -
  • R 5 and Re are selected from the group consisting of hydrogen and C M thiol. 3. 8 ring sulfhydryl;
  • R 7 is selected from hydroxy, mercapto, d 8 embankment group, d 8 embankment thio group, C 3 8 cycloalkyl group embankment, C 3 8 cycloalkyl group embankment, -S (0) rR 12, - 0-C(0)Ri2 -NR 13 R 14 , -OM, the M is an alkali metal, an alkaline earth metal, an ammonium;
  • said d. 8 embankment group, c 3. 8 cycloalkyl are each independently alkyl with optionally further substituted with one or more substituents selected from halo, hydroxy, cyano, nitro, d. 8 alkyl with halogen substituent d.
  • r 0, 1, and 2.
  • R 7 is selected from the group consisting of sodium, potassium, magnesium, calcium, and ammonium.
  • the intermediate for preparing the biaryl substituted 4-aminobutyric acid derivative represented by the formula (I) is selected from the compound of the formula (IV):
  • Ri and R 2 are each independently selected from the group consisting of hydrogen, halogen, and d. 8 fluorenyl. 3. 8 fluorenyl, d. 8 decyloxy, C 3 .8 cyclodecyloxy; Z, R 3 , , R 5 , Re, r are as defined in formula (III).
  • R 3 is selected from hydrogen, halo, d. 8 alkyl with halogen substituent d. 8 embankment group, C 3. 8 cycloalkyl group embankment, -Ci -4 -0-C (0 ) R4 -0-C (0) OR4, -C 1-4 -0-C(0)OR4; Z, Ri R 2 , R 4 , R 5 , , r are as defined in the formula (III).
  • the intermediate is selected from the group consisting of:
  • the intermediate (III) has a similar pharmaceutical activity as the compound of the final product of the formula (I).
  • Another object of the present invention is to provide a process for preparing an intermediate of the biaryl substituted 4-aminobutyric acid derivative, which comprises the steps of:
  • R is the same as R of formula (III), but R is not hydrogen; and X is a halogen atom.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing and/or treating a disease associated with EP abnormalities, which comprises a therapeutically effective amount of said biaryl substituted 4-amino group.
  • Butyric acid derivative or an intermediate thereof, and at least one pharmaceutically acceptable carrier are examples of pharmaceutically acceptable carriers.
  • the diseases associated with EP abnormalities are hypertension, pulmonary hypertension, heart failure, and kidney disease.
  • the inventors have found through animal experiments that the compounds of the present invention have good pharmacokinetic activity. Detailed ways
  • d. 8 fluorenyl means a linear fluorenyl group having 1 to 8 carbon atoms and a branched fluorenyl group, and a fluorenyl group means a saturated aliphatic hydrocarbon group.
  • a fluorenyl group means a saturated aliphatic hydrocarbon group.
  • the fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano , nitro, CL 8 embankment group, a substituted 3 ⁇ 4 d. 8 embankment, hydroxy substituted d. 8 embankment group, d. 8 embankment group, a substituted 3 ⁇ 4 d. 8 embankment group, C 3.
  • Embankment ring group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent group, "C 3 8 cycloalkyl group embankment.” Refers to a ring alkyl with 3-8 carbon atoms, for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like.
  • Polycyclic fluorenyl groups include spiro, fused, and cyclic fluorenyl groups.
  • “Spirocyclic thiol” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the individual rings. These may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • the spirocyclic fluorenyl group is divided into a single spiro fluorenyl group, a bispirocyclic fluorenyl group or a polyspirocyclic fluorenyl group according to the number of shared snail atoms between the ring and the ring.
  • Non-limiting examples of the spiro fluorenyl group include: "Thick-ring thiol" means an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring fluorenyl groups, and non-limiting examples of fused ring fluorenyl groups include:
  • Bridge ring thiol refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded. These may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged fluorenyl groups. Non-limiting examples of bridged ring fluorenyl groups
  • the cyclononyl ring may be fused to an aryl, heteroaryl or heterocyclic indenyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. ....
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0)i ⁇ where r is an integer 0, 1, 2 a hetero atom, but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon.
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic fluorenyl groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0)r (where r is an integer) The heteroatoms of 0, 1, and 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocyclic thiol group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspiroheterocyclic group depending on the number of common snail atoms between the ring and the ring.
  • Non-limiting examples of spirocyclic thiol groups include: "Fused heterocyclic group” means that each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0)r (wherein r is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic fluorenyl groups, fused heterocyclic rings.
  • “Bridge heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or a hetero atom of S(0)r (wherein r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged fluorenyl groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cyclodecyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group,
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. ....
  • Aryl means an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated ⁇ -electron system (ie, a ring with adjacent pairs of carbon atoms) ;) group, "C 5 . 1Q aryl” refers to an all-carbon aryl group containing 5-10 carbons, such as phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cyclodecyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halogen substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -....
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(0)r (wherein r is an integer 0, 1, 2), 5-
  • a 10-membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, pyrrolyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring with the parent is a heteroaryl ring, non-limiting examples comprising:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. ....
  • Alkenyl refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of alkyl with, C 2 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched alkylene. base.
  • alkyl with, C 2 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched alkylene. base.
  • base for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -....
  • Alkynyl means at least two carbon atoms and at least one carbon - carbon triple bond group as embankment composition as defined,
  • C 2 8 alkynyl group means a straight chain comprising 2-8 carbon atoms or a branched alkynyl group.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -....
  • the methoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 ⁇ group, a halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment,
  • Cyclopentoxy refers to and -O- (unsubstituted cyclodecyl), wherein cyclodecyl is as defined above.
  • 3.8 embankment cycloalkyl group refers to a 3-8 carbon cyclic embankment group, non-limiting embodiment includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the methoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. ....
  • Halogen means fluoro, chloro, bromo or iodo.
  • -Ci -4 -S(0)rR4" refers to an R4 substituted d. 4 mercaptosulfide, d. 4 mercaptosulfinyl, d. 4 mercaptosulfonyl.
  • R4 refers to R4 ⁇ 4 alkyl with butoxycarbonyl.
  • heterocyclic group optionally substituted by a thiol group means that a fluorenyl group may be, but is not necessarily, present, including the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by a thiol group.
  • Substituted means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents.
  • substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort.
  • an amino or hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
  • Ethyl carbonate chloromethyl ester (3.1 g, 22.4 mmol) was dissolved in 25 mL of acetonitrile, then sodium iodide (6.7 g, 44.7 mmol) was added and allowed to react at room temperature for 20 hours. Filtration and concentrating. The obtained crude material was taken from ethyl ether.
  • (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid isopropoxycarboxymethyl ester dissolved in 20 In methanol, add palladium on charcoal (400 mg), exchange gas, and hydrogenate at atmospheric pressure for 2 hours. Filtration, concentration, reverse phase column chromatography to give a colorless oily liquid (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid Isopropoxy carboxymethyl ester (166 mg, 49%).
  • 2,3,4,6-Tetrabenzyl-glucose (5407 mg, 10.0 mmol) was dissolved in 20 mL of dichloromethane, and trichloroacetonitrile (1.5 mL, 15.0 mmol) and 1 drop of DBU were added in an ice water bath. The mixture was naturally warmed to room temperature and allowed to react for 4 hours. The reaction was stopped, concentrated directly, and the resulting product was used in the next step.
  • the compound 1-chloroethyl chloroformate (3 ml, 27.8 mmol) was diluted with DCM (25 ml), cooled to 0 ° C, isopropyl alcohol (2.1 ml, 27.8 mmol) diluted with DCM (25 ml) Slowly add with a constant pressure dropping funnel, react for about 15 min, and slowly add pyridine (2.4 ml, 30.6 mmol) diluted with DCM (5 ml) with a constant pressure dropping funnel. After completion, the reaction was carried out at room temperature overnight, then diluted with water, extracted with DCM, and then dried and evaporated.
  • Cyclohexanol (2.6 mL, 25.0 mmol) was added to 25 mL of dichloromethane and cooled in an ice water bath; 1-chloroethyl chloroformate (2.2 mL, 25.0 mmol) was dissolved in 25 mL of dichloromethane and slowly added dropwise to the reaction system. Middle; pyridine (2.2 mL, 27.5 mmol) was diluted in 5 mL of dichloromethane and slowly added dropwise to the reaction system. Room Warm reaction overnight. Diluted with dichloromethane, washed 3 times with water and dried over anhydrous sodium sulfate. Concentrated to give a colorless liquid of 5.05 g.
  • the following in vitro assays can be used to determine the inhibitory activity of the compounds of the invention against EP enzymes in rat plasma, the activity of which can be expressed as IC 5Q values.
  • the half-inhibitory concentration of the compound IC 5Q (the concentration of the compound required to inhibit a certain concentration of the enzyme activity to 50%) is determined by mixing a certain amount of the enzyme with a specific substrate and a different concentration of the test compound.
  • the NEP enzyme system used in this experiment is fresh blood taken from normal SD rats, placed in a tube containing heparin sodium anticoagulant, collected at 5000 rpm, centrifuged at 4 ° C for 10 min, and plasma is collected; different concentrations of EP inhibitors are prepared.
  • the EP inhibitor had a maximum final concentration of 100 ⁇ and was diluted 10 times in a 3-fold gradient; 60 ⁇ L of fresh rat plasma was added to each well in a 384-well plate; then, 10 ⁇ of a gradient dilution of ⁇ was added to each well.
  • Inhibitor 37 ° C, after incubation for 30 min, add 10 ⁇ ⁇ substrate per well (SenoLyte 520 Neprilysin Activity Assay Kit, AnaSpec, 72223); incubate at 37 ° C for 18 h ( ⁇ lh); at excitation light 490 nm and emission The fluorescence signal was measured at a wavelength of 520 nm; and the IC 50 was determined using Prism 5.0 software.
  • the EP enzyme inhibitory activity of the compound of the present invention was measured by the above test, and the measured IC 5Q value is shown in the following table.
  • 0.1 ml of blood was collected, placed in a heparinized test tube, and centrifuged at 3,500 rpm for 10 min to separate the plasma, and stored at 20 ° C; Eat 2 h after administration. Because the test object is unstable in plasma, the blood sample is quickly placed in the ice water bath after collection, and the whole process of blood sample collection, processing and analysis is kept at a low temperature.
  • Simultaneous detection of prodrugs and metabolites LBQ657 Take 25 ⁇ l of rat plasma at each time after administration, add internal standard SHR133162 (200 ng/ml, methanol) 50 ⁇ l, methanol 175 ⁇ l, vortex for 3 min, centrifuge 10 Min (13500 rpm), the supernatant was taken 10 ⁇ for LC/MS/MS analysis.
  • Simultaneous detection of prodrugs and metabolites LBQ657 Take 25 ⁇ l of rat blank plasma, add 25 ⁇ l of mixed standard series solution, and make blood concentration 1.00, 2.00, 5.00, 25.0, 100, 500, 2000, 5000, 20000 and 40000 ng /ml , add internal standard SHR133162 (200 ng/ml, prepared in methanol) 50 ⁇ l, methanol 150 ⁇ 1, press
  • Example 11 y 0.000942x + 0.00116 0.9989
  • Rats were intragastrically administered with 30.0 mg/kg of prodrug 2, and the blood concentration of the compound of Example 2 was lower than the lower limit of quantification in rats at all times. It is speculated that the prodrug was rapidly hydrolyzed by the enzyme; the blood of metabolite LBQ657
  • the drug concentration peak time 1 is (0.67 ⁇ 0.29) 11, peak concentration. (8145 ⁇ 2101 3 ⁇ 4/1 ⁇ , the area under the blood concentration-time curve AUC 0-t is (20301 ⁇ 3404) ng/ml-h, and the elimination half-life t 1/2 is (1.63 ⁇ 1.56)h.
  • the blood concentration of the prodrug at each time after administration is less than 10 ng/ml, and it is speculated that the prodrug is rapidly enzyme-enzymed in rats.
  • Hydrolysis; the peak concentration t max of the metabolite LBQ657 is (0.50 ⁇ 0.00) h, the peak concentration C max is (30041 ⁇ 13427) ng/ml, and the area under the plasma concentration-time curve is AUC Q. t ( 78570 ⁇ 31469) ng/ml-h, elimination half-life t 1/2 is (2.36 ⁇ 0.39)h.
  • the test results showed that after the rats were administered with 30.0 mg/kg of the prodrug of the compound of Example 4 by intragastric administration, the blood concentration of the compound of Example 4 was lower than the lower limit of quantification in the rats at all times, and it was speculated that the prodrug was rapidly hydrolyzed by the enzyme.
  • the blood product concentration peak time t x of the metabolite LBQ657 is (0.833 ⁇ 0.289) h
  • peak concentration. nie ⁇ is (13308 ⁇ 3949) ng/ml
  • the area under the blood concentration-time curve is AUCo- t (35276 ⁇ 16283) ng/ml-h
  • the elimination half-life t 1/2 is (4.54 ⁇ 1.77)h.
  • the blood concentration of the compound of Example 13 at each time in the rat is lower than the lower limit of quantification, and the prodrug is presumed to be rapidly hydrolyzed by the enzyme; metabolite LBQ657
  • the blood concentration peak time t max was (0.83 ⁇ 0.29) h
  • the peak concentration C ⁇ was (12466 ⁇ 5106) ng/ml
  • the area under the plasma concentration-time curve was AUCo- t (33505 ⁇ 14118) ng/ Ml-h
  • elimination half-life t 1/2 is (1.91 ⁇ 1.50) h.
  • the compounds of the examples of the present invention can be metabolized into the active pharmaceutical ingredient LBQ657 in rats.

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Abstract

The present invention relates to a biaryl-substituted 4-amino-butyric acid derivative, a preparation method therefor and uses thereof. In particular, it relates to a biaryl-substituted 4-amino-butyric acid derivative as represented by formula (I), a preparation method therefor and uses thereof, an intermediate of a biaryl-substituted 4-amino-butyric acid derivative prepared by cyclization and a pharmaceutical composition containing a biaryl-substituted 4-amino-butyric acid derivative. The present biaryl-substituted 4-amino-butyric acid derivatives have NEP inhibitory activity and can be used as NEP inhibitors.

Description

联芳基取代的 4-氨基丁酸衍生物及其制备方法和用途  Biaryl substituted 4-aminobutyric acid derivative, preparation method and use thereof
技术领域 Technical field
本发明属于药物合成领域， 具体涉及一种联芳基取代的 4-氨基丁酸衍生物及 其制备方法和用途。 背景技术  The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a biaryl substituted 4-aminobutyric acid derivative and a preparation method and use thereof. Background technique
高血压是最常见的心血管疾病之一， 也是导致充血性心力衰竭、 脑卒中、 冠 心病、 肾功能衰竭、 主动脉瘤的发病率和致死率升高的主要危险因素。 据国际高 血压学会最近发表的新闻公报报道， 全球高血压或血压偏高人群已有 9.72亿人， 约占世界成年人口的 26.4%。 随着不断加剧的人口老龄化趋势， 高血压病人的比 例逐步上升。 至 2025年， 估计患病人数将达到 15.6亿。 随着新一代抗高血压药 物的相继问世和广泛应用， 各类心血管疾病的死亡率有了较大幅度的下降。 但 是， 全球每年仍有 1700万人死于因高血压导致的心脑血管疾病， 其中一半以上 的病人死于急性心肌梗塞或脑血管栓塞症。 2009年， 中国治疗高血压药物的销售 额已达到 113.57亿元人民币， 同比增长 17.81%。 目前我国高血压患者约有两亿 人， 每年还要新增高血压患者 1000万。 2006美国心脏学会估计美国心力衰竭人 数接近 580万； World FS Society估计心力衰竭在西方的流行率为 2.5%。 我国成 年人心衰的患病率为 0.9%， 患病人口约有 400万。 尽管经过多年的努力， 我国高 血压 /心衰治疗率和控制率仍远远低于发达国家。 我国此类药物市场发展前景可 期。 Hypertension is one of the most common cardiovascular diseases and a major risk factor for morbidity and mortality in congestive heart failure, stroke, coronary heart disease, renal failure, and aortic aneurysm. According to a recent press release published by the International Society of Hypertension, there are 972 million people with high blood pressure or high blood pressure in the world, accounting for 26.4% of the world's adult population. With the increasing ageing population, the proportion of hypertensive patients has gradually increased. By 2025, the estimated number of patients will reach 1.56 billion. With the emergence and widespread application of a new generation of antihypertensive drugs, the mortality rate of various cardiovascular diseases has dropped significantly. However, 17 million people worldwide die every year from cardiovascular and cerebrovascular diseases, and more than half of them die from acute myocardial infarction or cerebrovascular embolism. In 2009, the sales of Chinese medicines for treating hypertension had reached 11.357 billion yuan, a year-on-year increase of 17.81%. At present, there are about 200 million people with hypertension in China, and 10 million new hypertensive patients are added each year. The American Heart Association estimates that the number of people with heart failure in the United States is close to 5.8 million; the World FS Society estimates that the prevalence of heart failure in the West is 2.5%. The prevalence of heart failure in adults in China is 0.9%, and the number of sick people is about 4 million. Despite years of efforts, the treatment rate and control rate of high blood pressure/heart failure in China is still far lower than that of developed countries. The development prospects of such drugs in China are promising.
EP (neutral endopeptidase, 又称 Neprilysin) 是 Ml 3锌依赖的金属蛋白酶 家族的一种 II型跨膜糖蛋白， 也称脑啡肽酶， 其上带有的锌原子处于酶的活性部 位。 EP分子量约为 97kDa， 由 750个氨基酸组成， 包含一个信号肽和两个亲水 结构域， 胞内片段有 26个氨基酸， 胞外片段有 700个氨基酸。 EP可作用于多 肽的氨基端， 使多肽链水解。 自从 1974年首次被定义以来， EP作为一种神经 肽的降解酶， 已被发现广泛分布于内皮细胞、 血管平滑肌细胞、 心肌细胞、 肾脏 上皮细胞、 纤维母细胞， 其还存在于肺、 肠、 肾上腺、 脑等， 并具有众多组织特 异性功能。 钠利尿肽主要被 EP 降解， 而且 EP还能催化肾上腺髓质和缓激 肽。 EP选择性抑制剂抑制 EP的活性， 可以提高钠利尿肽及缓激肽的浓度， 使血管扩张， 心排出量增加， 醛固酮水平下降并抑制 RAAS (肾素-血管紧张素-醛 固酮系统)， 降低心脏前、 后负荷， 延缓心肌重构， 改善心力衰竭患者的心功能。  EP (neutral endopeptidase, also known as Neprilysin) is a type II transmembrane glycoprotein of the Ml 3 zinc-dependent metalloproteinase family, also known as enkephalinase, which carries a zinc atom at the active site of the enzyme. EP has a molecular weight of about 97 kDa and consists of 750 amino acids. It contains a signal peptide and two hydrophilic domains. The intracellular fragment has 26 amino acids and the extracellular fragment has 700 amino acids. EP can act on the amino terminus of the polypeptide to hydrolyze the polypeptide chain. Since its first definition in 1974, EP, a neuropeptide degrading enzyme, has been found to be widely distributed in endothelial cells, vascular smooth muscle cells, cardiomyocytes, renal epithelial cells, and fibroblasts, which are also present in the lungs, intestines, Adrenal gland, brain, etc., and has many tissue-specific functions. Natriuretic peptides are mainly degraded by EP, and EP also catalyzes the adrenal medulla and bradykinin. EP-selective inhibitors inhibit EP activity, increase the concentration of natriuretic peptide and bradykinin, increase vasodilation, increase cardiac output, decrease aldosterone levels, and inhibit RAAS (renin-angiotensin-aldosterone system), reducing Pre- and post-loading of the heart delays myocardial remodeling and improves cardiac function in patients with heart failure.
近十年 EP 的双重抑制剂的研究非常多， 包括 EP/ACE 双抑制剂、 EP/ARB (血管紧张肽受体） 的双抑制剂、 EP/ECE (内皮素转化酶） 的双抑制 剂及 EP/APN (氨肽酶 N) 双抑制剂。There have been many studies on dual inhibitors of EP in the past decade, including EP/ACE dual inhibitors, dual inhibitors of EP/ARB (angiotensin receptor), and dual inhibition of EP/ECE (endothelin converting enzyme). And EP/APN (aminopeptidase N) dual inhibitors.
EP/ACE双抑制剂的抗高血压效应优于单一抑制剂， 在于增加了 P物质、 缓 激肽、 肾上腺髓质素等舒张血管肽含量， 减少了内皮素 I、 血管紧张素 II等收缩 血管肽含量， 并优化结合了利尿和降压的双重效应， 从而维持器官供血。 Omapatrilat是 BMS公司开发的强效 ACE/NEP双抑制， 但因为血管神经性水肿等 副作用， 2002年 7月 FDA拒绝批准 Omapatrilat用于治疗高血压， 甚至作为难治 患者的最后治疗手段。  The antihypertensive effect of EP/ACE dual inhibitors is superior to that of single inhibitors, which increases the content of diastolic vasopeptides such as substance P, bradykinin and adrenomedullin, and reduces contractile blood vessels such as endothelin I and angiotensin II. The peptide content, and optimized to combine the dual effects of diuresis and blood pressure, to maintain organ blood supply. Omapatrilat is a potent ACE/NEP double inhibitor developed by BMS, but due to side effects such as angioedema, the FDA declined to approve Omapatrilat for the treatment of hypertension in July 2002, even as a last resort for refractory patients.
Solvay公司研发有三个 EP/ECE (内皮素转化酶） 的双抑制剂， 目前处于临 床二期阶段的 daglutril ( SLV-306, 口服） 和 SLV-334 (静脉给药） 分别用于治疗 肺动脉高压和脑损伤， 处于临床一期阶段的 SLV-338 (静脉给药） 用于治疗心血 管疾病、 代谢失调和神经性疾病。 Pharmaleads公司研发的 EP/APN (氨肽酶 N) 双抑制剂 PL-37 (Debio-0827, 口服） 主要用于治疗疼痛， 尤其是神经性疼 痛。 LCZ-696是由 Novartis公司开发的口服降压药、 保心药， 是作用于 EP/ARB (血管紧张肽受体） 的双抑制剂， 目前处于临床三期阶段， 最新的临床结果表 明： 在射血分数正常的心脏衰竭患者中， 12周时 LCZ-696引起的 NT-proB P降 幅大于缬沙坦， 且 LCZ-696耐受性良好 （NCT00887588) 。 至于这些效应能否转 化为预后的改善， 还需要进行前瞻性测试。 Thomson-pharma预测其将于 2014年 上市， 2017年的销售额将达到 2.04亿美元。 发明内容  Solvay has developed three EP/ECE (endothelin-converting enzyme) dual inhibitors, currently in the clinical phase II of daglutril (SLV-306, oral) and SLV-334 (intravenous) for the treatment of pulmonary hypertension and Brain injury, SLV-338 (intravenous administration) at the clinical stage is used to treat cardiovascular disease, metabolic disorders and neurological diseases. The EP/APN (aminopeptidase N) double inhibitor PL-37 (Debio-0827, orally) developed by Pharmaleads is mainly used to treat pain, especially neuropathic pain. LCZ-696 is an oral antihypertensive and cardioprotective drug developed by Novartis. It is a dual inhibitor of EP/ARB (angiotensin receptor) and is currently in clinical phase III. The latest clinical results show that: In patients with heart failure with normal ejection fraction, LCZ-696 caused a decrease in NT-proB P greater than that of valsartan at 12 weeks, and LCZ-696 was well tolerated (NCT00887588). Prospective testing is needed to see if these effects can be translated into prognosis improvements. Thomson-pharma predicts that it will be available in 2014 and its sales in 2017 will reach $204 million. Summary of the invention
本发明的目的在于解决目前存在的技术问题， 提供一种联芳基取代的 4-氨基 丁酸衍生物， 这些化合物在体内都可以经代谢产生化合物 LBQ657, 具有 EP抑 制活性， 可以作为 EP抑制剂， 可以用来治疗相关疾病， 例如高血压、 心衰、 肺 动脉高压以及肾脏疾病。  The object of the present invention is to solve the existing technical problems and provide a biaryl substituted 4-aminobutyric acid derivative which can be metabolized in vivo to produce compound LBQ657, which has EP inhibitory activity and can be used as an EP inhibitor. It can be used to treat related diseases such as high blood pressure, heart failure, pulmonary hypertension and kidney disease.
本发明的目的在于提供一种如式 （I) 所示的联芳基取代的 4-氨基丁酸衍生 物，  It is an object of the present invention to provide a biaryl substituted 4-aminobutyric acid derivative as shown in formula (I).
Figure imgf000004_0001
Figure imgf000004_0001
( I )  (I)
其中： Z选自氧或硫； R选自碱金属、 碱土金属
Figure imgf000004_0002
Ri R2各自独立的选自氢、 卤素、 羟基、 氰基、 硝基、 d.8垸基、 C2.8链烯 基、 .8链炔基、 .8环垸基、 d.8垸氧基、 C3.8环垸氧基、 3-8元杂环基、 3-8元 杂环基氧基、 C5.1Q芳基、 C5.1Q芳基氧基、 5-10元杂芳基、 5-10元杂芳基氧基、 - S(0)rR4、 -Ci-4-S(0)rR4 -C(0)R4、 -C1-4-C(0)R4、 -C(0)OR4、 -C1-4-C(0)OR4、 -O- C(0)R4、 -Ci.4-0-C(0)R4、 -0-C(0)OR4、 -C1-4-0-C(0)OR4、 -NRjRe、 -C1-4- R5Re、 -C(0) R5R6 -C1-4C(0) R5R6、 -N(R4)-C(0)R4或- H- R5R6 ; Wherein: Z is selected from oxygen or sulfur; R is selected from alkali metal, alkaline earth metal
Figure imgf000004_0002
Ri R 2 are each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, D. 8 embankment group, C 2. 8 alkenyl group,. 8 alkynyl group. Cyclic alkyl with 8, D 8 embankment alkoxy, C 3. 8 cycloalkyl group embankment, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5. 1Q aryl group, C 5. 1Q aryloxy, 5-10 membered Heteroaryl, 5-10 membered heteroaryloxy, -S(0)rR4, -Ci -4 -S(0)rR4 -C(0)R 4 , -C 1-4 -C(0)R4 , -C(0)OR4, -C 1-4 -C(0)OR 4 , -O- C(0)R4, -Ci.4-0-C(0)R4, -0-C(0) OR 4 , -C 1-4 -0-C(0)OR 4 , -NRjRe, -C 1-4 - R 5 Re, -C(0) R 5 R6 -C 1-4 C(0) R 5 R6, -N(R4)-C(0)R4 or -H-R 5 R6 ;
其中所述的 d.8垸基、 ^.8环垸基、 3-8元杂环基、 C5.1Q芳基或 5-10元杂芳基各 自独立任选进一步被一个或多个选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取 代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 ¾取代 d.8垸氧基、 C3.8环垸氧基、 - S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4 、 撒 5R6、 -C1-4- R5R6 -C(0) R5R6 -CwC C NRsRe或 -N(R4)-C(0)R4取代基所取代； Wherein d. 8 fluorenyl, ^. 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, 3⁄4 substituted d. 8 decyloxy, C 3. 8垸 垸 垸, - S (0) rR4, -C (0) R4, -C (0) OR4, -0-C (0) R4, -0-C (0) OR 4 , 5 R 6 , -C 1-4 - R 5 R6 -C(0) R 5 R6 -CwC C NRsRe or -N(R4)-C(0)R4 substituent;
R3选自氢、 卤素、 羟基、 氰基、 硝基、 d.8垸基、 。2.8链烯基、 。2.8链炔基、R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, d. 8 fluorenyl. 2. 8 alkenyl, . 2.8 alkynyl group,
。3.8环垸基、 d.8垸氧基、 C3.8环垸氧基、 3-8元杂环基、 3-8元杂环基氧基、 C5.10 芳基、 C5.1Q芳基氧基、 5-10 元杂芳基、 5-10 元杂芳基氧基、 -S(0;)rR4、 -Ci-4- S(0)rR4、 -C(0)R4、 -C1-4-C(0)R4、 -C(0)OR4、 -C1-4-C(0)OR4、 -0-C(0)R4、 -C1-4- 0-C(0)R4 、 -0-C(0)OR4 、 -Ci.4-0-C(0)OR4 、 - RjRe 、 -Ci-4-NR5R6 、 - C(0) R5R6 -Ci-4C(0) R5R6 -N(R4)-C(0)R4或- H- R5R6 ; . 3.8 embankment cycloalkyl group, d. 8 embankment group, C 3.8 cycloalkyl group embankment, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5. 10 aryl, C 5 . 1Q aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -S(0;)rR4, -Ci -4 - S(0)rR4, -C(0)R4 , -C 1-4 -C(0)R4, -C(0)OR4, -C 1-4 -C(0)OR4, -0-C(0)R4, -C 1-4 - 0-C (0) R 4 , -0-C(0)OR4 , -Ci.4-0-C(0)OR4 , - RjRe , -Ci -4 -NR 5 R6 , - C(0) R 5 R6 -Ci -4 C(0) R 5 R6 -N(R 4 )-C(0)R4 or -H- R 5 R6 ;
其中所述的 d.8垸基、 ^.8环垸基、 3-8元杂环基、 C5.1Q芳基或 5-10元杂芳基各 自独立任选进一步被一个或多个选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取 代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 - S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4 、 撒 5R6、 -C1-4- R5R6 -C(0) R5R6 -^.^((^ ^Ι^或 -N(R4)-C(0)R4取代基所取代； Wherein d. 8 fluorenyl, ^. 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, halo substituted d. 8 decyloxy, C 3. 8垸 垸 垸, - S (0) rR4, -C (0) R4, -C (0) OR4, -0-C (0) R4, -0-C (0) OR 4 , 5 R 6 , -C 1-4 - R 5 R6 -C(0) R 5 R6 -^.^((^^Ι^ or -N(R4)-C(0)R4 substituent;
、 R5、 Re选自氢、 CM垸基、 。3.8环垸基； And R 5 and Re are selected from the group consisting of hydrogen and C M thiol. 3. 8 ring sulfhydryl;
r为 0、 1、 2。  r is 0, 1, and 2.
优选的， R选自钠、 钾、 镁、 钙、 铵。  Preferably, R is selected from the group consisting of sodium, potassium, magnesium, calcium, and ammonium.
优选的， 所述的联芳基取代 4-氨基丁酸衍生物选自式 （II) 化合物：  Preferably, the biaryl substituted 4-aminobutyric acid derivative is selected from the group consisting of compounds of formula (II):
Figure imgf000005_0001
其中 R3、 、 R5、 Re、 r如式 （I) 所定义。
Figure imgf000005_0001
Wherein R 3 , , R 5 , Re, r are as defined in formula (I).
优选的， R3选自氢、 卤素、 d.8垸基、 卤取代 d.8垸基、 。3.8环垸基、 -d 0-C(0)R4、 -0-C(0)OR4、 -C1-4-0-C(0)OR4; 、 R5、 、 r如式 （I) 所定义。 本发明的另一目的还在于提供一种制备所述联芳基取代的 4-氨基丁酸衍生物 的中间体， 其具有如通式 （III) 所示的结构： Preferably, R 3 is selected from the group consisting of hydrogen, halogen, d. 8 fluorenyl, halogen substituted d. 8 fluorenyl, . 3. 8垸 垸, -d 0-C(0)R 4 , -0-C(0)OR 4 , -C 1-4 -0-C(0)OR4; , R 5 , , r as (I) is defined. Another object of the present invention is to provide an intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative having a structure represented by the formula (III):
Figure imgf000006_0001
Figure imgf000006_0001
(III)  (III)
其中 Z选自氧或硫 R选自碱金属、 碱土金属、 铵或'¾ R - Wherein Z is selected from oxygen or sulfur R is selected from the group consisting of alkali metals, alkaline earth metals, ammonium or '3⁄4 R -
Ri R2各自独立的选自氢、 卤素、 羟 2基、 氰基、 硝基、 CL8垸基、 C2.8链烯 基、 .8链炔基、 .8环垸基、 d.8垸氧基、 C3.8环垸氧基、 3-8元杂环基、 3-8元 杂环基氧基、 C5.1Q芳基、 C5.1Q芳基氧基、 5-10元杂芳基、 5-10元杂芳基氧基、 - S(0)rR4、 -Ci-4-S(0)rR4 -C(0)R4、 -C1-4-C(0)R4、 -C(0)OR4、 -C1-4-C(0)OR4、 -O- C(0)R4、 -Ci-4-0-C(0)R4、 -0-C(0)OR4、 -C1-4-0-C(0)OR4、 -NRjRe、 -C1-4- R5R6 -C(0) R5R6 -C1-4C(0) R5R6、 -N(R4)-C(0)R4或-顺-服5 ； Ri R 2 are each independently selected from hydrogen, halogen, a hydroxyl group 2, cyano, nitro, alkyl with CL 8, C 2 8 alkenyl group,. 8 alkynyl group. Cyclic alkyl with 8, D 8 embankment group, C 3. 8 cycloalkyl group embankment, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5. 1Q aryl group, C 5. 1Q aryloxy, 5-10 Heteroaryl, 5-10 membered heteroaryloxy, -S(0)rR4, -Ci -4 -S(0)rR4 -C(0)R 4 , -C 1-4 -C(0) R4, -C(0)OR4, -C 1-4 -C(0)OR 4 , -O- C(0)R4, -Ci -4 -0-C(0)R4, -0-C(0 )OR 4 , -C 1-4 -0-C(0)OR 4 , -NRjRe, -C 1-4 - R 5 R6 -C(0) R 5 R6 -C 1-4 C(0) R 5 R6, -N(R4)-C(0)R4 or -cis-service 5 ;
其中所述的 d.8垸基、 ^.8环垸基、 3-8元杂环基、 C5.1Q芳基或 5-10元杂芳基各 自独立任选进一步被一个或多个选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取 代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 ¾取代 d.8垸氧基、 C3.8环垸氧基、 - S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 撒 5R6、 -C1-4- R5R6 -C(0) R5R6 -CwC C NRsRe或 -N(R4)-C(0)R4取代基所取代； Wherein d. 8 fluorenyl, ^. 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, 3⁄4 substituted d. 8 decyloxy, C 3. 8垸 垸 垸, - S (0) rR4, -C (0) R4, -C (0) OR4, -0-C (0) R4, -0-C (0) OR 4 , 5 R 6 , -C 1-4 - R 5 R6 -C(0) R 5 R6 -CwC C NRsRe or -N(R4)-C(0)R4 substituent;
R3选自氢、 卤素、 羟基、 氰基、 硝基、 d.8垸基、 。2.8链烯基、 。2.8链炔基、R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, d. 8 fluorenyl. 2. 8 alkenyl, . 2.8 alkynyl group,
。3.8环垸基、 d.8垸氧基、 C3.8环垸氧基、 3-8元杂环基、 3-8元杂环基氧基、 C5.10 芳基、 C5.1Q芳基氧基、 5-10 元杂芳基、 5-10 元杂芳基氧基、 -S(0;)rR4、 -Ci-4- S(0)rR4、 -C(0)R4、 -C1-4-C(0)R4、 -C(0)OR4、 -C1-4-C(0)OR4、 -0-C(0)R4、 -C1-4-. 3.8 embankment cycloalkyl group, d. 8 embankment group, C 3.8 cycloalkyl group embankment, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 5. 10 aryl, C 5 . 1Q aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -S(0;)rR4, -Ci -4 - S(0)rR4, -C(0)R4 , -C 1-4 -C(0)R4, -C(0)OR4, -C 1-4 -C(0)OR4, -0-C(0)R4, -C 1-4 -
0-C(0)R4 、 -0-C(0)OR4 、 -Ci.4-0-C(0)OR4 、 - RjRe 、 -Ci-4-NR5R6 、 -0-C(0)R 4 , -0-C(0)OR4 , -Ci.4-0-C(0)OR4 , - RjRe , -Ci -4 -NR 5 R6 , -
C(0) R5R6 -Ci-4C(0) R5R6 -N(R4)-C(0)R4或- H- R5R6 ; C(0) R 5 R6 -Ci -4 C(0) R 5 R6 -N(R 4 )-C(0)R4 or -H- R 5 R6 ;
其中所述的 d.8垸基、 ^.8环垸基、 3-8元杂环基、 C5.1Q芳基或 5-10元杂芳基各 自独立任选进一步被一个或多个选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取 代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 -Wherein d. 8 fluorenyl, ^. 8 cyclodecyl, 3-8 membered heterocyclic, C 5 .1Q aryl or 5-10 membered heteroaryl are each independently optionally further selected by one or more From halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted d. 8 fluorenyl, hydroxy substituted d. 8 fluorenyl, d. 8 decyloxy, halo substituted d. 8 decyloxy, C 3. 8 ring decyloxy, -
S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 撒 5R6、 -C1-4- R5R6 -C(0) R5R6 -CwC C NRsRe或 -N(R4)-C(0)R4取代基所取代； S(0)rR4, -C(0)R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR 4 , scatter 5 R 6 , -C 1-4 - Substituting R 5 R6 -C(0) R 5 R6 -CwC C NRsRe or -N(R4)-C(0)R4;
、 R5、 Re选自氢、 CM垸基、 。3.8环垸基； And R 5 and Re are selected from the group consisting of hydrogen and C M thiol. 3. 8 ring sulfhydryl;
R7选自羟基、 巯基、 d.8垸氧基、 d.8垸基硫基、 C3.8环垸氧基、 C3.8环垸硫 基、 -S(0)rR12、 -0-C(0)Ri2 -NR13R14、 -OM， 所述 M为碱金属、 碱土金属、 铵； 其中所述的 d.8垸基、 c3.8环垸基各自独立任选进一步被一个或多个选自卤 素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧 基、 卤取代 CL8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 -C(0)R4 -C(0)OR4 、 -O- C(0)R4、 -0-C(0)OR4、 撒 5Re、 -C1-4- R5R6、 -C(0) R5R6、 -C1-4C(0) R5R6或- N(R4)-C(0)R X代基所取代； .... R 7 is selected from hydroxy, mercapto, d 8 embankment group, d 8 embankment thio group, C 3 8 cycloalkyl group embankment, C 3 8 cycloalkyl group embankment, -S (0) rR 12, - 0-C(0)Ri2 -NR 13 R 14 , -OM, the M is an alkali metal, an alkaline earth metal, an ammonium; Wherein said d. 8 embankment group, c 3. 8 cycloalkyl are each independently alkyl with optionally further substituted with one or more substituents selected from halo, hydroxy, cyano, nitro, d. 8 alkyl with halogen substituent d. 8 embankment, hydroxy substituted d. 8 embankment group, d. 8 embankment group, a halogen-substituted alkoxy embankment CL 8, C 3. 8 cycloalkyl group embankment, -S (0) rR4, -C (0) R4 -C (0)OR 4 , -O- C(0)R4, -0-C(0)OR4, 5 5 Re, -C 1-4 - R 5 R6, -C(0) R 5 R 6 , -C 1-4 C(0) R 5 R6 or -N(R4)-C(0)RX is substituted;
r为 0、 1、 2。  r is 0, 1, and 2.
优选的， R7选自钠、 钾、 镁、 钙、 铵。 Preferably, R 7 is selected from the group consisting of sodium, potassium, magnesium, calcium, and ammonium.
优选的， 所述的制备如式 （I) 所示的联芳基取代的 4-氨基丁酸衍生物的中间 体选自式 （IV) 化合物：  Preferably, the intermediate for preparing the biaryl substituted 4-aminobutyric acid derivative represented by the formula (I) is selected from the compound of the formula (IV):
Figure imgf000007_0001
其中 Z、 Ri R2、 R3、 、 R5、 Re、 r如式 （III) 所定义。
Figure imgf000007_0001
Wherein Z, Ri R 2 , R 3 , , R 5 , Re, r are as defined in formula (III).
更优选的， Ri、 R2各自独立的选自氢、 卤素、 d.8垸基、 。3.8环垸基、 d.8垸 氧基、 C3.8环垸氧基; Z、 R3、 、 R5、 Re、 r如式 (III) 所定义。 More preferably, Ri and R 2 are each independently selected from the group consisting of hydrogen, halogen, and d. 8 fluorenyl. 3. 8 fluorenyl, d. 8 decyloxy, C 3 .8 cyclodecyloxy; Z, R 3 , , R 5 , Re, r are as defined in formula (III).
进一步优选的， R3选自氢、 卤素、 d.8垸基、 卤取代 d.8垸基、 C3.8环垸 基、 -Ci-4-0-C(0)R4 -0-C(0)OR4、 -C1-4-0-C(0)OR4 ; Z、 Ri R2、 R4、 R5、 、 r如式 （III) 所定义。 Further preferably, R 3 is selected from hydrogen, halo, d. 8 alkyl with halogen substituent d. 8 embankment group, C 3. 8 cycloalkyl group embankment, -Ci -4 -0-C (0 ) R4 -0-C (0) OR4, -C 1-4 -0-C(0)OR4; Z, Ri R 2 , R 4 , R 5 , , r are as defined in the formula (III).
优选的， 所述中间体选自：  Preferably, the intermediate is selected from the group consisting of:
Figure imgf000007_0002
Figure imgf000007_0002
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0001
Figure imgf000008_0002
所述中间体 （III) 具有与终产物式 （I) 的化合物类似的医药活性。  The intermediate (III) has a similar pharmaceutical activity as the compound of the final product of the formula (I).
本发明的另一目的还在于提供一种制备所述联芳基取代的 4-氨基丁酸衍生物 的中间体的方法， 其包括如下步骤：  Another object of the present invention is to provide a process for preparing an intermediate of the biaryl substituted 4-aminobutyric acid derivative, which comprises the steps of:
Figure imgf000008_0003
Figure imgf000008_0003
( V ) (VI) 步骤 2: 式 （VI) 的化合物脱保护基后得到式 （III) 的化合物；  (V) (VI) Step 2: Deprotecting a compound of formula (VI) to give a compound of formula (III);
其中 R与式 （III) 的 R定义相同， 但 R不为氢； X为卤原子。  Wherein R is the same as R of formula (III), but R is not hydrogen; and X is a halogen atom.
进一步地， 本发明的目的还在于提供一种使中间体式 （III) 的化合物经环合 反应得到式 （I) 的化合物的制备方法。  Further, it is an object of the present invention to provide a process for producing a compound of the formula (I) by subjecting a compound of the formula (III) to a cyclization reaction.
更进一步地， 关于本发明化合物的盐的制备， 可以通过本领域技术人员常用 的成盐方式制得。 本发明的另一目的还在于提供一种用于预防和 /或治疗与 EP异常有关的疾 病的药物组合物， 所述药物组合物中含有治疗有效量的所述联芳基取代的 4-氨基 丁酸衍生物或其中间体， 以及至少一种药学上可接受的载体。 Further, the preparation of the salt of the compound of the present invention can be carried out by a salt-forming method commonly used by those skilled in the art. Another object of the present invention is to provide a pharmaceutical composition for preventing and/or treating a disease associated with EP abnormalities, which comprises a therapeutically effective amount of said biaryl substituted 4-amino group. Butyric acid derivative or an intermediate thereof, and at least one pharmaceutically acceptable carrier.
优选的， 所述与 EP异常有关的疾病是高血压、 肺动脉高压、 心衰以及肾脏 疾病。  Preferably, the diseases associated with EP abnormalities are hypertension, pulmonary hypertension, heart failure, and kidney disease.
发明人经过动物实验发现， 本发明化合物具有良好的药代动力学活性。 具体实施方式  The inventors have found through animal experiments that the compounds of the present invention have good pharmacokinetic activity. Detailed ways
详细说明： 除非有相反陈述， 下列用在说明书和权利要求书中的术语具有下 述含义。  DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.
"d.8垸基"指包括 1至 8个碳原子的直链垸基和含支链垸基， 垸基指饱和的脂 族烃基团。 例如甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 仲丁 基、 正戊基、 1， 1-二甲基丙基、 1， 2-二甲基丙基、 2， 2-二甲基丙基、 1-乙基丙 基、 2-甲基丁基、 3-甲基丁基、 正己基、 1-乙基 -2-甲基丙基、 1， 1， 2-三甲基丙 基、 1， 1-二甲基丁基、 1， 2-二甲基丁基、 2， 2-二甲基丁基、 1， 3-二甲基丁基、 2-乙基丁基、 2-甲基戊基、 3-甲基戊基、 4-甲基戊基、 2， 3-二甲基丁基、 正庚 基、 2-甲基己基、 3-甲基己基、 4-甲基己基、 5-甲基己基、 2， 3-二甲基戊基、 2， 4-二甲基戊基、 2， 2-二甲基戊基、 3， 3-二甲基戊基、 2-乙基戊基、 3-乙基戊基、 正辛基、 2， 3-二甲基己基、 2， 4-二甲基己基、 2， 5-二甲基己基、 2， 2-二甲基己 基、 3， 3-二甲基己基、 4， 4-二甲基己基、 2-乙基己基、 3-乙基己基、 4-乙基己 基、 2-甲基 -2-乙基戊基、 2-甲基 -3-乙基戊基或其各种支链异构体等。 "d. 8 fluorenyl" means a linear fluorenyl group having 1 to 8 carbon atoms and a branched fluorenyl group, and a fluorenyl group means a saturated aliphatic hydrocarbon group. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-di Methylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl 1, 1, 1-trimethylpropyl, 1, 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethyl Butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl , 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3 , 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-di Methylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2 -methyl-2-ethylpentyl, 2- Ethyl-3-pentyl or various branched chain isomers thereof.
垸基可以是取代的或未取代的， 当被取代时， 取代基可以在任何可使用的连 接点上被取代， 优选为一个或多个以下基团， 独立地选自卤素、 羟基、 氰基、 硝 基、 CL8垸基、 ¾取代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 ¾取代 d.8垸氧 基、 C3.8环垸氧基、 -S(0)rR4、 -C(0)R4、 -C(0)OR4、 -0-C(0)R4、 -0-C(0)OR4、 - R5R6 -Ci-4- R5R6 -C(0) R5R6 -C1-4C(0) R5R6或 -N(R4)-C(0)R4取代基所取 代。 The fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano , nitro, CL 8 embankment group, a substituted ¾ d. 8 embankment, hydroxy substituted d. 8 embankment group, d. 8 embankment group, a substituted ¾ d. 8 embankment group, C 3. 8 cycloalkyl group embankment, -S(0)rR4, -C(0)R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR4, - R 5 R6 -Ci -4 - R 5 R6 -C(0)R 5 R6 -C 1-4 C(0) R 5 R6 or -N(R4)-C(0)R4 substituent is substituted.
"环垸基"指饱和或部分不饱和单环或多环环状烃取代基， "C3.8环垸基"指包括 3至 8个碳原子的环垸基， 例如： "Embankment ring group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent group, "C 3 8 cycloalkyl group embankment." Refers to a ring alkyl with 3-8 carbon atoms, for example:
单环环垸基的非限制性实施例包含环丙基、 环丁基、 环戊基、 环戊烯基、 环 己基、 环己烯基、 环己二烯基、 环庚基、 环庚三烯基、 环辛基等。  Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like.
多环环垸基包括螺环、 稠环和桥环的环垸基。 "螺环垸基"指单环之间共用一 个碳原子（称螺原子）的多环基团， 这些可以含有一个或多个双键， 但没有一个环 具有完全共轭的 π 电子系统。 根据环与环之间共用螺原子的数目将螺环垸基分为 单螺环垸基、 双螺环垸基基或多螺环垸基， 螺环垸基的非限制性实施例包含： "稠环垸基"指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全 碳多环基团， 其中一个或多个环可以含有一个或多个双键， 但没有一个环具有完 全共轭的 π电子系统。 根据组成环的数目可以分为双环、 三环、 四环或多环稠环 垸基， 稠环垸基的非限制性实施例包含：
Figure imgf000010_0001
Polycyclic fluorenyl groups include spiro, fused, and cyclic fluorenyl groups. "Spirocyclic thiol" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the individual rings. These may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. The spirocyclic fluorenyl group is divided into a single spiro fluorenyl group, a bispirocyclic fluorenyl group or a polyspirocyclic fluorenyl group according to the number of shared snail atoms between the ring and the ring. Non-limiting examples of the spiro fluorenyl group include: "Thick-ring thiol" means an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring fluorenyl groups, and non-limiting examples of fused ring fluorenyl groups include:
Figure imgf000010_0001
"桥环垸基"指任意两个环共用两个不直接连接的碳原子的全碳多环基团， 这 些可以含有一个或多个双键， 但没有一个环具有完全共轭的 π电子系统。 根据组 成环的数目可以分为双环、 三环、 四环或多环桥环垸基， 桥环垸基的非限制性实 施例
Figure imgf000010_0002
"Bridge ring thiol" refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded. These may contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged fluorenyl groups. Non-limiting examples of bridged ring fluorenyl groups
Figure imgf000010_0002
所述环垸基环可以稠合于芳基、 杂芳基或杂环垸基环上， 其中与母体结构连 接在一起的环为环垸基， 非限制性实施例包括茚满基、 四氢萘基、 苯并环庚垸基 等。  The cyclononyl ring may be fused to an aryl, heteroaryl or heterocyclic indenyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
环垸基可以是任选取代的或未取代的， 当被取代时， 取代基优选为一个或多 个以下基团， 独立地选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 - C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 - R5R6、 -C1-4- R5R6、 - C(0) R5R6 -CMCCC NRsRe或 -N(R4)-C(0)R4取代基所取代。 The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. .... - C(0)R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR4, -R 5 R 6 , -C 1-4 - R 5 R 6 , - C (0) Substituting R 5 R6 -CMCCC NRsRe or -N(R 4 )-C(0)R4.
"杂环基"指饱和或部分不饱和单环或多环环状烃取代基， 其中一个或多个环 原子选自氮、 氧或 S(0)i<其中 r是整数 0、 1、 2)的杂原子， 但不包括 -0-0-、 -0-S- 或 -S-S-的环部分， 其余环原子为碳。 "3-8元杂环基"指包含 3至 8个环原子的环基。  "Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0)i<where r is an integer 0, 1, 2 a hetero atom, but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. The "3-8 membered heterocyclic group" means a ring group containing 3 to 8 ring atoms.
单环环垸基的非限制性实施例包含吡咯垸基、 哌啶基、 哌嗪基、 吗啉基、 硫 代吗啉基、 高哌嗪基等。  Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
多环环垸基包括螺环、 稠环和桥环的杂环基。 "螺杂环基"指单环之间共用一 个原子 (称螺原子)的多环杂环基团， 其中一个或多个环原子选自氮、 氧或 S(0)r (其中 r是整数 0、 1、 2)的杂原子， 其余环原子为碳。 这些可以含有一个或多个双 键， 但没有一个环具有完全共轭的 π电子系统。 根据环与环之间共用螺原子的数 目将螺环垸基分为单螺杂环基、 双螺杂环基或多螺杂环基。 螺环垸基的非限制性 实施例包含：
Figure imgf000010_0003
"稠杂环基"指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环 杂环基团， 一个或多个环可以含有一个或多个双键， 但没有一个环具有完全共轭 的 π电子系统， 其中一个或多个环原子选自氮、 氧或 S(0)r(其中 r是整数 0至 2)的杂 原子， 其余环原子为碳。 根据组成环的数目可以分为双环、 三环、 四环或多环稠 杂环垸基， 稠杂环 Polycyclic fluorenyl groups include spiro, fused, and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0)r (where r is an integer) The heteroatoms of 0, 1, and 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocyclic thiol group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspiroheterocyclic group depending on the number of common snail atoms between the ring and the ring. Non-limiting examples of spirocyclic thiol groups include:
Figure imgf000010_0003
"Fused heterocyclic group" means that each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more double bonds, but none The ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0)r (wherein r is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic fluorenyl groups, fused heterocyclic rings.
Figure imgf000011_0001
Figure imgf000011_0001
"桥杂环基"指任意两个环共用两个不直接连接的原子的多环杂环基团， 这些 可以含有一个或多个双键， 但没有一个环具有完全共轭的 π电子系统， 其中一个 或多个环原子选自氮、 氧或 S(0)r(其中 r是整数 0、 1、 2)的杂原子， 其余环原子为 碳。 根据组成环的数目可以分为双环、 三环、 四环或多环桥环垸基， 桥环垸基的 非限制
Figure imgf000011_0002
"Bridge heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or a hetero atom of S(0)r (wherein r is an integer of 0, 1, 2), and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged fluorenyl groups.
Figure imgf000011_0002
所述杂环基环可以稠合于芳基、 杂芳基或环垸基环上， 其中与母体结构连接 在一起的环为杂环基，
Figure imgf000011_0003
The heterocyclyl ring may be fused to an aryl, heteroaryl or cyclodecyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group,
Figure imgf000011_0003
杂环基可以是任选取代的或未取代的， 当被取代时， 取代基优选为一个或多 个以下基团， 独立地选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 - C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 - R5R6、 -C1-4- R5R6、 - C(0) R5R6 -C1-4C(0)NR5R6或 -N(R4)-C(0)R4取代基所取代。 The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. .... - C(0)R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR4, -R 5 R 6 , -C 1-4 - R 5 R 6 , - C (0) R 5 R6 -C 1-4 C(0)NR 5 R6 or -N(R 4 )-C(0)R4 substituent is substituted.
"芳基 "指全碳单环或稠合多环 (也就是共享毗邻碳原子对的环）基团， 具有共 轭的 π 电子体系的多环 (即其带有相邻对碳原子的环;)基团， "C5.1Q芳基"指含有 5-10 个碳的全碳芳基， 例如苯基和萘基。 所述芳基环可以稠合于杂芳基、 杂环基或环 垸基环上， 其中与母体结构连接在一起的环为芳基环， 非限制性实施例包含： "Aryl" means an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated π-electron system (ie, a ring with adjacent pairs of carbon atoms) ;) group, "C 5 . 1Q aryl" refers to an all-carbon aryl group containing 5-10 carbons, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cyclodecyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
Figure imgf000011_0004
芳基可以是取代的或未取代的， 当被取代时， 取代基优选为一个或多个以下 基团， 独立地选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸基、 羟基取 代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 - C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 - R5R6、 -C1-4- R5R6、 - C(0) R5R6 -CMCCC NRsRe或 -N(R4)-C(0)R4取代基所取代。
Figure imgf000011_0004
The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halogen substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -.... C ( 0) R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR4, -R 5 R 6 , -C 1-4 - R 5 R 6 , - C(0 Substituting R 5 R6 -CMCCC NRsRe or -N(R 4 )-C(0)R4 substituent.
"杂芳基"指包含 1至 4个杂原子的杂芳族体系， 所述杂原子包括氮、 氧和 S(0)r(其中 r是整数 0、 1、 2) 的杂原子， 5-10元杂芳基指含有 5-10个环原子的杂芳 族体系， 例如呋喃基、 噻吩基、 吡啶基、 吡咯基、 N-垸基吡咯基、 嘧啶基、 吡嗪 基、 咪唑基、 四唑基等。 所述杂芳基环可以稠合于芳基、 杂环基或环垸基环上， 其中与母体结 一起的环为杂芳基环， 非限制性实施例包含：  "Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(0)r (wherein r is an integer 0, 1, 2), 5- A 10-membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, pyrrolyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring with the parent is a heteroaryl ring, non-limiting examples comprising:
Figure imgf000012_0001
Figure imgf000012_0001
杂芳基可以是任选取代的或未取代的， 当被取代时， 取代基优选为一个或多 个以下基团， 独立地选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 - C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 - R5R6、 -C1-4- R5R6、 - C(0) R5R6 -CMCCC NRsRe或 -N(R4)-C(0)R4取代基所取代。 The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. .... - C(0)R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR4, -R 5 R 6 , -C 1-4 - R 5 R 6 , - C (0) Substituting R 5 R6 -CMCCC NRsRe or -N(R 4 )-C(0)R4.
"烯基 "指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的垸基， C2.8链烯基指含有 2-8个碳的直链或含支链烯基。 例如乙烯基、 1-丙烯基、 2-丙烯 基、 1-， 2-或 3-丁烯基等。 "Alkenyl" refers to at least two carbon atoms and at least one carbon - carbon double bond as defined above consisting of alkyl with, C 2 8 alkenyl group means a straight chain comprising 2-8 carbon atoms or a branched alkylene. base. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
烯基可以是取代的或未取代的， 当被取代时， 取代基优选为一个或多个以下 基团， 独立地选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸基、 羟基取 代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 - C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 - R5R6、 -C1-4- R5R6、 - C(0) R5R6 -CMCCC NRsRe或 -N(R4)-C(0)R4取代基所取代。 The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -.... C ( 0) R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR4, -R 5 R 6 , -C 1-4 - R 5 R 6 , - C(0 Substituting R 5 R6 -CMCCC NRsRe or -N(R 4 )-C(0)R4 substituent.
"炔基"指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的垸基， C2.8链炔基指含有 2-8个碳的直链或含支链炔基。 例如乙炔基、 1-丙炔基、 2-丙炔 基、 1-， 2-或 3-丁炔基等。 "Alkynyl" means at least two carbon atoms and at least one carbon - carbon triple bond group as embankment composition as defined, C 2 8 alkynyl group means a straight chain comprising 2-8 carbon atoms or a branched alkynyl group. . For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
炔基可以是取代的或未取代的， 当被取代时， 取代基优选为一个或多个以下 基团， 独立地选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸基、 羟基取 代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 - C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 - R5R6、 -C1-4- R5R6、 - C(0) R5R6 -CMCCC NRsRe或 -N(R4)-C(0)R4取代基所取代。 "垸氧基"指 -O- (垸基)， 其中垸基的定义如上所述。 d.8垸氧基指含 1-8个碳的 垸基氧基， 非限制性实施例包含甲氧基、 乙氧基、 丙氧基、 丁氧基等。 The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl, halo substituted . d 8 embankment group, a hydroxyl-substituted alkyl with d 8, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) r R4, -.... C ( 0) R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR4, -R 5 R 6 , -C 1-4 - R 5 R 6 , - C(0 Substituting R 5 R6 -CMCCC NRsRe or -N(R 4 )-C(0)R4 substituent. "Alkoxy" means -O-(indenyl), wherein the definition of indenyl is as defined above. d. 8 decyloxy means decyloxy having 1-8 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy and the like.
垸氧基可以是任选取代的或未取代的， 当被取代时， 取代基， 优选为一个或 多个以下基团， 独立地选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸 基、 羟基取代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 - S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 撒 5R6、 -C1-4- R5R6 -C(0) R5R6 -CwC C NRsRe或 -N(R4)-C(0)R4取代基所取代。 The methoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8垸group, a halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -..... S (0) rR4, -C(0)R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR 4 , 5 R 6 , -C 1-4 - R 5 R6 -C( 0) R 5 R6 -CwC C NRsRe or -N(R4)-C(0)R4 substituent is substituted.
"环垸氧基"指和 -O- (未取代的环垸基)， 其中环垸基的定义如上所述。 。3.8环 垸氧基指含 3-8个碳的环垸基氧基， 非限制性实施例包含环丙氧基、 环丁氧基、 环 戊氧基、 环己氧基等。 "Cyclopentoxy" refers to and -O- (unsubstituted cyclodecyl), wherein cyclodecyl is as defined above. . 3.8 embankment cycloalkyl group refers to a 3-8 carbon cyclic embankment group, non-limiting embodiment includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
垸氧基可以是任选取代的或未取代的， 当被取代时， 取代基优选为一个或多 个以下基团， 独立地选自卤素、 羟基、 氰基、 硝基、 d.8垸基、 卤取代 d.8垸基、 羟基取代 d.8垸基、 d.8垸氧基、 卤取代 d.8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 - C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 - R5R6、 -C1-4- R5R6、 - C(0) R5R6 -CMCCC NRsRe或 -N(R4)-C(0)R4取代基所取代。 The methoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, d. 8 fluorenyl halogen-substituted alkyl with d 8, d 8 substituted alkyl with hydroxy, d 8 embankment group, a halogen-substituted alkoxy embankment d 8, C 3 8 cycloalkyl group embankment, -S (0) rR4,. .... - C(0)R4, -C(0)OR4, -0-C(0)R4, -0-C(0)OR4, -R 5 R 6 , -C 1-4 - R 5 R 6 , - C (0) Substituting R 5 R6 -CMCCC NRsRe or -N(R 4 )-C(0)R4.
"卤素"指氟、 氯、 溴或碘。  "Halogen" means fluoro, chloro, bromo or iodo.
"-S(0)rR4"指 R4取代的硫、 亚硫酰基、 硫酰基。  "-S(0)rR4" means a sulfur, a sulfinyl group or a sulfuryl group substituted by R4.
"-Ci-4-S(0)rR4"指 R4取代的 d.4垸基硫、 d.4垸基亚硫酰基、 d.4垸基硫酰基。"-Ci -4 -S(0)rR4" refers to an R4 substituted d. 4 mercaptosulfide, d. 4 mercaptosulfinyl, d. 4 mercaptosulfonyl.
"-C(C R4"指 取代的羰基。 "-C(C R4" refers to a substituted carbonyl group.
"-C1-4-C(0)R4"指 R4取代的 CM垸基羰基。 "-C 1-4 -C(0)R4" means an R 4 -substituted C M fluorenylcarbonyl group.
"-C(0)OR4 "指 取代的羰基氧基。 "-C(0)OR 4 " refers to a substituted carbonyloxy group.
"-C^- C OR^指 取代的 d.4垸基羰基氧基。 "-C^-C OR^ refers to a substituted d. 4 mercaptocarbonyloxy group.
"-0-C(0)R4"指 R4取代的氧基羰基。  "-0-C(0)R4" means an R4 substituted oxycarbonyl group.
"-C1-4-0-C(0)R4"指 R4取代的^.4垸基氧基羰基。 "-C 1-4 -0-C (0 ) R4" substituent refers to R4 ^ 4 alkyl with butoxycarbonyl.
"-NR5R6"指 R5、 R6取代的氨基。 "-NR 5 R6" refers to an amino group substituted with R 5 and R 6 .
"-Ci.4- R5R6"指 R5、 Re取代的 CL4垸基氨基。 "-Ci.4-R 5 R6" refers to a C 4 decylamino group substituted with R 5 and Re.
"-C(0) R5R6"指 R5、 Re取代的酰氨基。 "-C(0) R 5 R 6 " refers to an acylamino group substituted with R 5 and Re.
"-Ci-4C(0) R5R6"指 R5、 Re取代的 CL4垸基酰氨基。 "-Ci -4 C(0) R 5 R6" refers to a C 4 decyl amide group substituted with R 5 and Re.
"-N(R4)-C(0)R4"指 R4取代氨基酰基。  "-N(R4)-C(0)R4" refers to an R4 substituted amino group.
"-N(R4)-C(0)OR4"指 R4取代氨基酰基氧基。 "-N(R4)-C(0)OR 4 " refers to R4 substituted aminoacyloxy.
"-NH-NR5R6"指 R5、 R6取代的肼基。 "-NH-NR 5 R 6 " refers to a fluorenyl group substituted with R 5 and R 6 .
"任选 "或"任选地 "意味着随后所描述地事件或环境可以但不必发生， 该说明 包括该事件或环境发生或不发生地场合。 例如， "任选被垸基取代的杂环基团"意 味着垸基可以但不必须存在， 该说明包括杂环基团被垸基取代的情形和杂环基团 不被垸基取代的情形。 "取代的"指基团中的一个或多个氢原子， 优选为最多 5个， 更优选为 1〜3个氢 原子彼此独立地被相应数目的取代基取代。 不言而喻， 取代基仅处在它们的可能 的化学位置， 本领域技术人员能够在不付出过多努力的情况下确定 (通过实验或理 论)可能或不可能的取代。 例如， 具有游离氢的氨基或羟基与具有不饱和 (如烯属） 键的碳原子结合时可能是不稳定的。 "Optional" or "optionally" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by a thiol group" means that a fluorenyl group may be, but is not necessarily, present, including the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by a thiol group. . "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
"药物组合物 "表示含有一种或多种本文所述化合物或其生理学上 /可药用的盐 或前体药物与其他化学组分的混合物， 以及其他组分例如生理学 /可药用的载体 和赋形剂。 药物组合物的目的是促进对生物体的给药， 利于活性成分的吸收进而 发挥生物活性。  "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
下面实施例将进一步举例说明本发明。 这些实施例仅用于说明本发明， 但不 以任何方式限制本发明。  The following examples will further illustrate the invention. These examples are for illustrative purposes only and are not intended to limit the invention in any way.
实施例 1  Example 1
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸乙氧基碳氧基甲基酯的 制备
Figure imgf000014_0001
Preparation of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid ethoxycarbonyloxymethyl ester
Figure imgf000014_0001
L-焦谷氨醇 （50.0 g， 0.43 mol) 加入 500 mL二氯甲垸中， 冰水浴冷却后， 依次加入三乙胺 （120 mL， 0.86 mol) 以及对甲苯磺酰氯 （90.0 g， 0.47 mol) ， 室温反应过夜。 过滤， 浓缩， 粗产品用石油醚 -乙酸乙酯重结晶， 得灰白色固体 (S)-5-羰基-吡咯垸 -2-基甲基甲苯 -4-磺酸酯 （110.0 g，
Figure imgf000014_0002
L-pyroglutamine (50.0 g, 0.43 mol) was added to 500 mL of dichloromethane. After cooling in an ice water bath, triethylamine (120 mL, 0.86 mol) and p-toluenesulfonyl chloride (90.0 g, 0.47 mol) were added in that order. ), react at room temperature overnight. Filtration, concentrating, EtOAc (EtOAc:EtOAc:EtOAc:
Figure imgf000014_0002
称取镁屑 （10.9 g， 0.45 mol) 置于 2000 mL三颈瓶中， 4-溴联苯 （93.2 g， 0.40 mol) 溶于 400 mL四氢呋喃中， 然后缓慢滴加入三颈瓶中， 约两小时加完， 加完后继续回流反应两小时。 冷却至室温后加入 25 mLl,4-二氧六环， 然后冰水 浴冷却， 再加入氰化亚铜 （17.9 g， 0.20 mol) 。 随后将体系冷却至 -40 °C， 同时 将 (S)-5-氧杂吡咯 -2-亚甲基对甲基苯磺酸酯 （26.9 g， 0.10 mol) 加入 400 mL四氢 呋喃中， 再缓慢滴加入反应体系中。 加完后升至 35 °C， 反应过夜。 冷却至室温 后， 依次加入 200 mL饱和氨水以及 900 mL饱和氯化铵溶液， 分液， 有机相再用 饱和食盐水洗涤， 无水硫酸钠干燥， 浓缩。 柱层析分离， 得白色固体 (S)-5-联苯 基 -4-基甲基-吡咯垸 -2-酮 （15.8 g) 。
Figure imgf000014_0003
Weigh the magnesium chips (10.9 g, 0.45 mol) in a 2000 mL three-necked flask, and dissolve the 4-bromobiphenyl (93.2 g, 0.40 mol) in 400 mL of tetrahydrofuran, then slowly add to the three-necked flask, about two After the hour is added, the reaction is continued for two hours after the addition. After cooling to room temperature, 25 mL of 1,4-dioxane was added, followed by cooling in an ice water bath, followed by addition of cuprous cyanide (17.9 g, 0.20 mol). The system was then cooled to -40 ° C, while (S)-5-oxapyrrole-2-methylene p-toluenesulfonate (26.9 g, 0.10 mol) was added to 400 mL of tetrahydrofuran, and then slowly dripped Add to the reaction system. After the addition was completed, it was raised to 35 ° C and allowed to react overnight. After cooling to room temperature, 200 mL of saturated aqueous ammonia and 900 mL of a saturated aqueous solution of ammonium chloride were added, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. Column chromatography gave a white solid (S)-5-biphenyl-4-ylmethyl-pyrrole-2-one (15.8 g).
Figure imgf000014_0003
将 L-焦谷氨酸 (30.0 g, 0.23 mol) 、 N-羟基苯并三唑 (3.1 g, 0.023 mol) 以 环己基碳二亚胺 （48.0 g， 0.23 mol) 加入 170 mL二氯甲垸中， 冷却至 -15 °C 后， 加入吗啡啉 （20.3 mL， 0.23 mol ) 。 室温反应过夜。 过滤， 滤液浓缩后得淡 黄色糖浆 (S)
Figure imgf000015_0001
Add L-pyroglutamic acid (30.0 g, 0.23 mol), N-hydroxybenzotriazole (3.1 g, 0.023 mol) to cyclohexylcarbodiimide (48.0 g, 0.23 mol) to 170 mL of dichloroformamidine Medium, cooled to -15 °C After that, morpholine (20.3 mL, 0.23 mol) was added. The reaction was carried out at room temperature overnight. Filtration, the filtrate is concentrated to give a pale yellow syrup (S)
Figure imgf000015_0001
称取镁屑 （1.95 g， 80 mmol ) 置于 250 mL三颈瓶中， 4-溴联苯 （ 17.48 g， 75 mmol ) 溶于 80 mL四氢呋喃中， 然后缓慢滴加入三颈瓶中， 待反应引发后保 持微沸， 加完后继续回流两小时。  Weigh the magnesium chips (1.95 g, 80 mmol) in a 250 mL three-necked flask, dissolve the 4-bromobiphenyl (1748 g, 75 mmol) in 80 mL of tetrahydrofuran, and slowly add dropwise to the three-necked flask. After the initiation, the mixture was kept slightly boiled, and the reflux was continued for two hours after the addition.
(S)-5- (吗啉 -4-羰基)吡咯酮 （9.91 g， 50 mmol ) 溶于 80 mL四氢呋喃， 冰水浴 冷却后， 滴加入异丙基氯化镁 （24 mL， 2M四氢呋喃溶液） ， 再滴加上述联苯基 溴化镁溶液。 室温反应过夜。 加入饱和氯化铵溶液淬灭， 再用稀盐酸中和。 浓缩 除去四氢呋喃， 再用乙酸乙酯萃取， 无水硫酸钠干燥。 浓缩， 柱层析分离， 得白 色固体 (S)-5- (联苯
Figure imgf000015_0002
(S)-5-(morpholine-4-carbonyl)pyrrolidone (9.91 g, 50 mmol) dissolved in 80 mL of tetrahydrofuran, cooled in an ice water bath, and then added dropwise isopropylmagnesium chloride (24 mL, 2M in tetrahydrofuran). The above biphenyl magnesium bromide solution was added dropwise. The reaction was carried out at room temperature overnight. It was quenched by the addition of a saturated ammonium chloride solution and neutralized with dilute hydrochloric acid. The tetrahydrofuran was removed by concentration, extracted with ethyl acetate and dried over anhydrous sodium sulfate. Concentration, column chromatography, white solid (S)-5- (biphenyl)
Figure imgf000015_0002
(S)-5- (联苯基 -4-羰基)吡咯酮 （5.0 g， 18.8 mmol ) 溶于 100 mL四氢呋喃中， 加入浓硫酸 （0.2 mL) 以及钯 /碳 ( l .O g) ， 50 °C油浴加热， 3 bar氢气进行氢 化， 反应 2天。 冷却后， 过滤， 滤液中加入 2 N NaOH中和。 浓缩， 除去四氢呋 喃， 再用乙酸乙酯萃取， 无水硫酸钠干燥。 浓缩得白色固体 (S)-5-联苯基 -4-基甲 基-吡咯垸 -2-酮 （4.7 g，  (S)-5-(biphenyl-4-carbonyl)pyrrolidone (5.0 g, 18.8 mmol) dissolved in 100 mL of tetrahydrofuran, concentrated sulfuric acid (0.2 mL) and palladium/carbon (1.O g), 50 The oil was heated in a °C oil bath, hydrogenated at 3 bar of hydrogen, and reacted for 2 days. After cooling, it was filtered and the filtrate was neutralized with 2 N NaOH. After concentration, the tetrahydrofuran was removed, extracted with ethyl acetate and dried over anhydrous sodium sulfate. Concentrated to a white solid (S)-5-biphenyl-4-ylmethyl-pyrrole-2-one (4.7 g,
Figure imgf000015_0003
Figure imgf000015_0003
(S)-5- (联苯基 -4-亚甲基)吡咯酮 （4.7 g， 18.7 mmol ) 以及三乙胺 ( 7.8 mL, 56.1 mmol ) 加入 50 mL甲苯中， 加热至 60 °C， 再缓慢滴加特戊酰氯 （3.5 mL, 28.1 mmol ) ， 加热反应过夜。 冷却至室温后加入柠檬酸水溶液， 分液， 水相用甲 苯反萃， 合并有机相后用水洗涤。 浓缩， 柱层析分离， 得白色固体 (S)-5-联苯基- 4-基甲基 -1-(2,2-  (S)-5-(biphenyl-4-methylene)pyrrolidone (4.7 g, 18.7 mmol) and triethylamine (7.8 mL, 56.1 mmol) were added to 50 mL of toluene and heated to 60 °C. Pivaloyl chloride (3.5 mL, 28.1 mmol) was slowly added dropwise, and the reaction was heated overnight. After cooling to room temperature, an aqueous citric acid solution was added, and the mixture was separated. The aqueous phase was back-extracted with toluene, and the organic phases were combined and washed with water. Concentration, column chromatography, white solid (S)-5-biphenyl-4-ylmethyl-1-(2,2-
Figure imgf000015_0004
Figure imgf000015_0004
(S)-5-联苯基 -4-亚甲基 -1-(2,2-二甲基丙酰基)吡咯酮 （6.7 g， 20 mmol ) 溶于 (S)-5-biphenyl-4-methylene-1-(2,2-dimethylpropanoyl)pyrrolidone (6.7 g, 20 mmol)
30 mL 甲苯， 冰盐浴冷却下， 缓慢滴加入六甲基二硅基胺基钾 （37.1 mL , 26 mmol, 0.7 M甲苯溶液） ， 30分钟加完， 再滴加硫酸二甲酯 （2.8 mL， 5 mL甲苯 稀释） ， 40分钟加完。 加完后继续低温反应一小时， 然后加入饱和氯化铵溶液淬 灭。 甲苯萃取， 有机相用饱和食盐水洗涤。 浓缩后柱层析分离， 得到产物 (3R, 5S)-5-联苯基 -4-亚甲基 -1-(2,2-二甲基丙酰基 )-3-甲基吡咯酮 （3.2 g， 46%) 。 30 mL of toluene, ice-cold bath cooling, slowly add hexamethyldisilazide potassium (37.1 mL, 26 mmol, 0.7 M in toluene), add in 30 minutes, then add dimethyl sulfate (2.8 mL) , 5 mL of toluene Dilution), added in 40 minutes. After the addition was completed, the low temperature reaction was continued for one hour, and then quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted with toluene and the organic phase was washed with brine. After concentration and column chromatography, the product (3R, 5S)-5-biphenyl-4-methylene-1-(2,2-dimethylpropanoyl)-3-methylpyrrolidone (3.2 g) was obtained. , 46%).
1H MR (400 MHz, CDC13) δ 7.52 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 - 7.22 (m, 3H), 4.57-4.44 (m, 1H), 3.06 (dd, J = 13.2, 3.0 Hz, 1H), 2.63 (dd, = 13.0, 9.6 Hz, 1H), 2.61 - 2.51 (m, 1H), 2.05 (dd, = 12.8, 8.4 Hz, 1H), 1.57 (td, = 12.5, 8.6 Hz, 1H), 1.31 (s, 9H), 1.11 (d, = 6.8 Hz, 3H). 1H MR (400 MHz, CDC1 3 ) δ 7.52 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 - 7.22 ( m, 3H), 4.57-4.44 (m, 1H), 3.06 (dd, J = 13.2, 3.0 Hz, 1H), 2.63 (dd, = 13.0, 9.6 Hz, 1H), 2.61 - 2.51 (m, 1H), 2.05 (dd, = 12.8, 8.4 Hz, 1H), 1.57 (td, = 12.5, 8.6 Hz, 1H), 1.31 (s, 9H), 1.11 (d, = 6.8 Hz, 3H).
LC-MS: tR = 4.3 +: 350.0. LC-MS: t R = 4.3 +: 350.0.
Figure imgf000016_0001
Figure imgf000016_0001
(3R, 5S)-5-联苯基 -4-亚甲基 -1-(2,2-二甲基丙酰基 )-3-甲基吡咯酮 （3.5 g， 10.0 mmol) 溶于 50 mL甲苯， 再加入 4.0 g—水对甲苯磺酸。 加热至回流， 反应两小 时。 冷却至室温后， 加入饱和碳酸氢钠水溶液洗涤， 甲苯萃取。 有机相浓缩， 所 得粗产品 (3R,5S)-5-联苯基 -4-基甲基 -3-甲基-吡咯垸 -2-酮直接用于下步反应。  (3R, 5S)-5-biphenyl-4-methylene-1-(2,2-dimethylpropanoyl)-3-methylpyrrolidone (3.5 g, 10.0 mmol) dissolved in 50 mL of toluene , then add 4.0 g - water p-toluenesulfonic acid. Heat to reflux and allow to react for two hours. After cooling to room temperature, it was washed with a saturated aqueous solution of sodium hydrogen carbonate and extracted with toluene. The organic phase was concentrated and the crude product (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-pyrrole-2-one was used directly in the next step.
LC-MS: tR = 3.3 +: 266.0. LC-MS: t R = 3.3 +: 266.0.
Figure imgf000016_0002
Figure imgf000016_0002
将上述粗产品 (3R, 5S)-5-联苯基 -4-亚甲基 -3-甲基吡咯酮溶于 50 mL乙酸乙 酯， 再依次加入二碳酸二叔丁酯 （4.4 g， 20 mmol) ， Ν,Ν-二甲基 -4-氨基吡啶 The above crude product (3R, 5S)-5-biphenyl-4-methylene-3-methylpyrrolidone was dissolved in 50 mL of ethyl acetate, followed by the addition of di-tert-butyl dicarbonate (4.4 g, 20 Ment), hydrazine, hydrazine-dimethyl-4-aminopyridine
(0.6 g， 5.0 mol) ， 三乙胺 （2.8 mL， 20 mmol) ， 室温 50 °C反应一小时。 加水 淬灭， 乙酸乙酯萃取， 无水硫酸钠干燥。 过滤， 浓缩， 所得粗产品 (3R,5S)-5-联苯 基 -4-基甲基 -3-甲基 -2-羰基-吡咯垸 -1-羧酸叔丁基酯直接用于下步反应。 (0.6 g, 5.0 mol), triethylamine (2.8 mL, 20 mmol), and allowed to react at room temperature 50 ° C for one hour. Quenched with water, extracted with ethyl acetate and dried over anhydrous sodium sulfate. Filtration and concentration, the crude product (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-carbonyl-pyrrole-1-carboxylic acid tert-butyl ester was used directly in the next step reaction.
LC-MS: tR = +: 266.0. LC-MS: t R = +: 266.0.
Figure imgf000016_0003
Figure imgf000016_0003
将 (3R,5S)-5-联苯基 -4-亚甲基 -1-叔丁氧基羰基 -3-甲基吡咯酮溶于 20 mL四氢 呋喃， 再加入氢氧化锂水溶液 （20 mL， 2M) ， 室温反应一小时。 加入稀磷酸溶 液中和， 浓缩除去四氢呋喃， 然后用乙酸乙酯萃取， 无水硫酸钠干燥。 浓缩， 反 相柱层析分离， 得白色固体 (2R,4S)-5-联苯基 -4-基 -4-叔丁氧基羰基氨基 -2-甲基戊 酸 （1.8 g， 三步产率 47% ) 。 Dissolve (3R,5S)-5-biphenyl-4-methylene-1-tert-butoxycarbonyl-3-methylpyrrolidone in 20 mL of tetrahydrofuran, then add aqueous lithium hydroxide solution (20 mL, 2M) ), react at room temperature for one hour. The mixture was neutralized with a dilute phosphoric acid solution and concentrated to remove tetrahydrofuran, then extracted with ethyl acetate and dried over anhydrous sodium sulfate. Concentrated, anti The residue was purified by column chromatography to afford white crystals (2D, 4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1.8 g, three-step yield 47% ).
1H MR (400 MHz, DMSO-d6) δ 1 1.99 (s, 1H), 7.63 (d, = 7.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.72 (d, = 8.8 Hz, 1H), 3.78-3.57 (m, 1H), 2.68 (d, = 6.8 Hz, 2H), 2.46-2.35 (m, 1H), 1.74 (ddd, = 13.6, 9.6, 4.0 Hz, 1H), 1.43-1.26 (m, 10H), 1.05 (d, = 7.2 Hz, 3H).  1H MR (400 MHz, DMSO-d6) δ 1 1.99 (s, 1H), 7.63 (d, = 7.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 7.6 Hz) , 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.72 (d, = 8.8 Hz, 1H), 3.78-3.57 (m, 1H), 2.68 ( d, = 6.8 Hz, 2H), 2.46-2.35 (m, 1H), 1.74 (ddd, = 13.6, 9.6, 4.0 Hz, 1H), 1.43-1.26 (m, 10H), 1.05 (d, = 7.2 Hz, 3H).
LC-MS: tR = 3.66 min; [M-H]": 382.0. LC-MS: t R = 3.66 min; [MH] ": 382.0.
、0^0, 0^0
Figure imgf000017_0001
Figure imgf000017_0001
丁二酸酐 （2.4 g， 24 mmol ) 、 苯甲醇 （2.1 mL， 20 mmol ) 以及 N,N-二甲 基 -4-氨基吡啶 （2.4 g， 20 mmol ) 溶于 30 mL二氯甲垸， 室温反应过夜。 加入 5% 碳酸钠水溶液， 分液。 水相用 1M盐酸酸化， 再用乙酸乙酯萃取， 无水硫酸钠干 燥。 浓缩， 得白色固体琥珀酸单苯甲酯 （3.0 g， 72% ) 。  Succinic anhydride (2.4 g, 24 mmol), benzyl alcohol (2.1 mL, 20 mmol) and N,N-dimethyl-4-aminopyridine (2.4 g, 20 mmol) dissolved in 30 mL of dichloromethane, room temperature The reaction was overnight. Add 5% aqueous sodium carbonate solution and separate. The aqueous layer was acidified with EtOAc (EtOAc)EtOAc. Concentration gave a white solid monosuccinimide (3.0 g, 72%).
1H NMR (400 MHz, CDC13) δ 7.37-7.21 (m, 5H), 5.06 (s, 2H), 2.79-2.42 (m, 4H).
Figure imgf000017_0002
1H NMR (400 MHz, CDC1 3 ) δ 7.37-7.21 (m, 5H), 5.06 (s, 2H), 2.79-2.42 (m, 4H).
Figure imgf000017_0002
琥珀酸单苯甲基酯 （1041 mg， 5.0 mmol ) 、 N-羟基琥珀酰亚胺 （575 mg， 5.0 mmol ) 、 二环己基碳二亚胺 （1547 mg， 7.5 mmol ) 以及 Ν,Ν-二甲基 -4-氨基 吡啶 （61 mg， 0.5 mmol ) 溶于 10 mL二氯甲垸， 室温反应 3小时。 过滤， 滤液浓 缩后柱层析分离， 得白色固体琥珀酸苯甲基酯 2,5-二羰基-吡咯垸 -1-基酯 （1230 mg， 81%) 。  Monosyl succinate (1041 mg, 5.0 mmol), N-hydroxysuccinimide (575 mg, 5.0 mmol), dicyclohexylcarbodiimide (1547 mg, 7.5 mmol) and hydrazine, hydrazine-II Methyl-4-aminopyridine (61 mg, 0.5 mmol) was dissolved in 10 mL of dichloromethane and allowed to react at room temperature for 3 hours. Filtration and concentration of the filtrate were followed by column chromatography to yield white solid benzyl succinate 2,5-dicarbonyl-pyrrole-1-yl ester (1230 mg, 81%).
1H NMR (400 MHz, CDC13) δ 7.34-7.23 (m, 5H), 5.10 (s, 2H), 2.91 (t, = 7.1 Hz, 2H), 2.77 (brs, 4H), 2.73 (t, J = 1.0 Hz, 2H). 1H NMR (400 MHz, CDC1 3 ) δ 7.34-7.23 (m, 5H), 5.10 (s, 2H), 2.91 (t, = 7.1 Hz, 2H), 2.77 (brs, 4H), 2.73 (t, J = 1.0 Hz, 2H).
LC-MS: tR 3.12 + 327.9 LC-MS: t R 3.12 + 327.9
Figure imgf000017_0003
Figure imgf000017_0003
N-叔丁氧基羰基 -(2R, 4S)-5-联苯基 -4-氨基 -2-甲基戊酸 （1 165 mg， 3.04 mmol ) 溶于 10 mL二氯甲垸， 冰水浴冷却， 然后加入 5 mL三氟乙酸， 自然升至 室温， 反应两小时。 浓缩， 抽真空干燥， 得黄色糖浆， （2R, 4S)-5-联苯基 -4-氨基- N-tert-Butoxycarbonyl-(2R, 4S)-5-biphenyl-4-amino-2-methylpentanoic acid (1 165 mg, 3.04 mmol) dissolved in 10 mL of dichloromethane, cooled in ice water bath Then, 5 mL of trifluoroacetic acid was added, and the temperature was naturally raised to room temperature for two hours. Concentrated, vacuum dried to give a yellow syrup, (2R, 4S)-5-biphenyl-4-amino-
2-甲基戊酸三氟乙酸盐直接用于下步反应。 2-methylpentanoic acid trifluoroacetate was used directly in the next step.
Figure imgf000017_0004
(2R, 4S)-5-联苯基 -4-氨基 -2-甲基戊酸三氟乙酸盐 （3.04 mmol) 和琥珀酸苯甲 基酯 2,5-二羰基-吡咯垸 -1-基酯 （1113 mg， 3.65 mmol) 溶于 15 mL二氯甲垸， 再 加入二异丙基乙基胺 （1.1 mL， 6.08 mmol ) ， 室温反应过夜。 浓缩， 反相柱层析 分离， 得白色固体 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 ( 1120 mg, 78%) 。
Figure imgf000017_0004
(2R, 4S)-5-biphenyl-4-amino-2-methylpentanoic acid trifluoroacetate (3.04 mmol) and benzyl succinate 2,5-dicarbonyl-pyrrole-1- The ester (1113 mg, 3.65 mmol) was dissolved in 15 mL of dichloromethane, then diisopropylethylamine (1.1 mL, 6.08 mmol). Concentration, reverse phase column chromatography gave white solid (2R,4S)-4-(3-benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid ( 1120 mg, 78%).
1H MR (400 MHz, DMSO-d6) δ 12.00 (brs, 1Η), 7.79 (d, J = 8.4 Hz, 1H), 7.69- 7.61 (m, 2H), 7.56 (d, = 8.2 Hz, 2H), 7.44 (t, = 7.6 Hz, 2H), 7.43-7.29 (m, 5H), 7.25 (d, = 8.2 Hz, 2H), 5.07 (s, 2H), 4.03-3.88 (m, 1H), 3.32 (brs, 2H), 2.69 (d, = 6.4 Hz, 2H), 2.53 (d, = 7.2 Hz, 2H), 2.47-2.23 (m, 4H), 1.77 (ddd, J = 13.6, 9.2, 4.2 Hz, 1H), 1.42-1.27 (m, 1H), 1.04 (d, = 7.2 Hz, 3H).  1H MR (400 MHz, DMSO-d6) δ 12.00 (brs, 1Η), 7.79 (d, J = 8.4 Hz, 1H), 7.69- 7.61 (m, 2H), 7.56 (d, = 8.2 Hz, 2H), 7.44 (t, = 7.6 Hz, 2H), 7.43-7.29 (m, 5H), 7.25 (d, = 8.2 Hz, 2H), 5.07 (s, 2H), 4.03-3.88 (m, 1H), 3.32 (brs , 2H), 2.69 (d, = 6.4 Hz, 2H), 2.53 (d, = 7.2 Hz, 2H), 2.47-2.23 (m, 4H), 1.77 (ddd, J = 13.6, 9.2, 4.2 Hz, 1H) , 1.42-1.27 (m, 1H), 1.04 (d, = 7.2 Hz, 3H).
LC-MS: tR 4.39 min; [M+H]+ 474.0; [M-H]" 472.0. LC-MS: t R 4.39 min ; [M + H] + 474.0; [MH] "472.0.
J
Figure imgf000018_0001
J
Figure imgf000018_0001
乙醇 （1.4 mL， 25.0 mmol) 加入 25 mL二氯甲垸， 冰水浴冷却； 氯甲酸氯甲 酯 （2.2 mL， 25.0 mmol) 溶于 25 mL二氯甲垸， 缓慢滴加入反应体系中； 吡啶 Ethanol (1.4 mL, 25.0 mmol) was added to 25 mL of dichloromethane and cooled in an ice water bath; chloromethyl chloroformate (2.2 mL, 25.0 mmol) was dissolved in 25 mL of dichloromethane and slowly added dropwise to the reaction system;
(2.2 mL, 27.5 mmol) 稀释于 5 mL二氯甲垸， 再缓慢滴加入反应体系中。 室温 反应过夜。 加入二氯甲垸稀释， 水洗 3次， 无水硫酸钠干燥。 浓缩， 得无色液体 碳酸乙酯氯甲酯 （3.16 g， 91%) 。 (2.2 mL, 27.5 mmol) was diluted in 5 mL of dichloromethane and slowly added dropwise to the reaction system. The reaction was carried out at room temperature overnight. Diluted with dichloromethane, washed 3 times with water and dried over anhydrous sodium sulfate. Concentration gave a colorless liquid ethyl chloromethyl ester (3.16 g, 91%).
1H MR (400 MHz, CDC13) δ 5.67 (s, 2H), 4.22 (q, = 7.2 Hz, 2H), 1.28 (t, = 7.2 Hz, 3H). 1H MR (400 MHz, CDC1 3 ) δ 5.67 (s, 2H), 4.22 (q, = 7.2 Hz, 2H), 1.28 (t, = 7.2 Hz, 3H).
M* Nal, CH3CN M* Nal, CH 3 CN
r| ^。人。^\ ·" , ^^人 r | ^. people. ^\ ·" , ^^ people
U U U 40 °C, 20 h 1 0 0 UUU 40 °C, 20 h 1 0 0
碳酸乙酯氯甲酯 (3.1 g， 22.4 mmol) 溶于 25 mL乙腈， 再加入碘化钠 (6.7 g， 44.7 mmol) ， 室温反应 20小时。 过滤， 浓缩， 所得粗产品中加入乙醚溶解， 再次过滤， 浓缩， 得黄色油状物碳酸乙酯碘甲酯 （4.3 g， 84%) 。  Ethyl carbonate chloromethyl ester (3.1 g, 22.4 mmol) was dissolved in 25 mL of acetonitrile, then sodium iodide (6.7 g, 44.7 mmol) was added and allowed to react at room temperature for 20 hours. Filtration and concentrating. The obtained crude material was taken from ethyl ether.
1H MR (400 MHz, CDCI3) δ 5.89 (s, 2H), 4.22 (q, = 7.2 Hz, 2H), 1.27 (t, =  1H MR (400 MHz, CDCI3) δ 5.89 (s, 2H), 4.22 (q, = 7.2 Hz, 2H), 1.27 (t, =
Figure imgf000018_0002
Figure imgf000018_0002
(2R,4S)-4-(3-苄氧基羰基-丙酰氨基；) -5-联苯基 -4-基 -2-甲基戊酸 （331 mg， 0.70 mmol) 溶于 5 mL乙腈， 再依次加入 Cs2C03 ( 114 mg， 0.35 mmol) 和碳酸乙酯 碘甲酯 （322 mg， 1.40 mmol) ， 室温反应 4小时。 过滤， 浓缩， 反相柱层析分 离， 得无色糖浆 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸乙 氧基碳氧基甲基酯 （372 mg， 92%) 。 1H MR (400 MHz, CDC13) δ 7.55-7.48 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.32-7.22 (m, 6H), 7.16 (d, J = 8.0 Hz, 2H), 5.70 (d, J = 5.6 Hz, 1H),(2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino;)-5-biphenyl-4-yl-2-methylpentanoic acid (331 mg, 0.70 mmol) dissolved in 5 mL of acetonitrile Then, Cs 2 C0 3 (114 mg, 0.35 mmol) and ethyl bromoethyl iodide (322 mg, 1.40 mmol) were added, and the mixture was reacted at room temperature for 4 hours. Filtration, concentration, reverse phase column chromatography to give colorless syrup (2R,4S)-4-(3-benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methyl Ethoxy methoxymethyl valerate (372 mg, 92%). 1H MR (400 MHz, CDC1 3 ) δ 7.55-7.48 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.32-7.22 (m, 6H ), 7.16 (d, J = 8.0 Hz, 2H), 5.70 (d, J = 5.6 Hz, 1H),
5.66 (d, J = 5.6 Hz, 1H), 5.53 (d, = 8.8 Hz, 1H), 5.04 (s, 2H), 4.26-4.07 (m, 3H), 2.84-5.66 (d, J = 5.6 Hz, 1H), 5.53 (d, = 8.8 Hz, 1H), 5.04 (s, 2H), 4.26-4.07 (m, 3H), 2.84-
2.67 (m, 2H), 2.67-2.45 (m, 3H), 2.34 (t, = 6.8 Hz, 2H), 1.87 (ddd, = 13.2, 8.8, 4.2 Hz, 1H), 1.65-1.52 (m, 1H), 1.22 (t, = 7.2 Hz, 3H), 1.11 (d, = 7.2 Hz, 3H). 2.67 (m, 2H), 2.67-2.45 (m, 3H), 2.34 (t, = 6.8 Hz, 2H), 1.87 (ddd, = 13.2, 8.8, 4.2 Hz, 1H), 1.65-1.52 (m, 1H) , 1.22 (t, = 7.2 Hz, 3H), 1.11 (d, = 7.2 Hz, 3H).
十 576.0.  Ten 576.0.
Figure imgf000019_0001
Figure imgf000019_0001
(2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸乙氧基碳氧基 甲基酯 （372 mg， 0.65 mmol) 溶于 20 mL甲醇， 加入钯 /炭 (400 mg) ， 抽换 气， 常压氢化 2小时。 过滤， 浓缩， 反相柱层析分离， 得无色油状液体 (2R,4S)-5- 联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸乙氧基碳氧基甲基酯 （213 mg, 68%) 。  (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid ethoxycarbonyloxymethyl ester (372 mg, 0.65 mmol) dissolved in 20 mL of methanol, palladium on charcoal (400 mg), gas exchange, hydrogenation at atmospheric pressure for 2 hours. Filtration, concentration, reverse phase column chromatography to give a colorless oily liquid (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid Ethoxymethoxymethyl ester (213 mg, 68%).
¾ MR (400 MHz, CDCI3) δ 7.54-7.48 (m, 2Η), 7.45 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.32-7.24 (m, 1H), 7.16 (d, J = 8.2 Hz, 2H), 5.83 (brd, J = 8.6 Hz, 1H), 5.71 (d, = 5.6 Hz, 1H), 5.63 (d, = 5.6 Hz, 1H), 4.30-4.20 (m, 1H), 4.16 (q, = 7.2 Hz: 2H), 2.85-2.70 (m, 2H), 2.66-2.48 (m, 3H), 2.44-2.28 (m, 2H), 1.87 (ddd, = 13.2, 9.2, 4.0 Hz, 1H), 1.60 (ddd, = 14.4, 10.2, 4.0 Hz, 1H), 1.23 (t, = 7.2 Hz, 3H), 1.10 (d, = 7.2 Hz, 3H).  3⁄4 MR (400 MHz, CDCI3) δ 7.54-7.48 (m, 2Η), 7.45 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.32-7.24 (m, 1H) , 7.16 (d, J = 8.2 Hz, 2H), 5.83 (brd, J = 8.6 Hz, 1H), 5.71 (d, = 5.6 Hz, 1H), 5.63 (d, = 5.6 Hz, 1H), 4.30-4.20 (m, 1H), 4.16 (q, = 7.2 Hz: 2H), 2.85-2.70 (m, 2H), 2.66-2.48 (m, 3H), 2.44-2.28 (m, 2H), 1.87 (ddd, = 13.2 , 9.2, 4.0 Hz, 1H), 1.60 (ddd, = 14.4, 10.2, 4.0 Hz, 1H), 1.23 (t, = 7.2 Hz, 3H), 1.10 (d, = 7.2 Hz, 3H).
LC-MS: tR = 4.81 min; [M+H]+: 486.0. 实施例 2 LC-MS: t R = 4.81 min; [M + H] +: 486.0 Example 2.
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸环己氧基碳氧基甲基酯的
Figure imgf000019_0002
(2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid cyclohexyloxycarboxymethyl ester
Figure imgf000019_0002
环己醇 （2.50 g， 25.0 mmol) 加入 25 mL二氯甲垸， 冰水浴冷却； 氯甲酸氯 甲酯 （2.2 mL， 25.0 mmol) 溶于 25 mL二氯甲垸， 缓慢滴加入反应体系中； 吡啶 (2.2 mL, 27.5 mmol) 稀释于 5 mL二氯甲垸， 再缓慢滴加入反应体系中。 室温 反应过夜。 加入二氯甲垸稀释， 水洗 3次， 无水硫酸钠干燥。 浓缩， 得无色液体 碳酸环己酯氯甲酯 （4.80 g， 99%) 。  Cyclohexanol (2.50 g, 25.0 mmol) was added to 25 mL of dichloromethane, and cooled in an ice water bath; chloromethyl chloroformate (2.2 mL, 25.0 mmol) was dissolved in 25 mL of dichloromethane and slowly added dropwise to the reaction system; Pyridine (2.2 mL, 27.5 mmol) was diluted in 5 mL of dichloromethane and slowly added dropwise to the reaction system. The reaction was carried out at room temperature overnight. Diluted with dichloromethane, washed 3 times with water and dried over anhydrous sodium sulfate. Concentrated to give a colorless liquid chloromethyl cyclohexyl carbonate (4.80 g, 99%).
1H MR (400 MHz, CDC13) δ 5.66 (s, 2H), 4.72-4.58 (m, 1H), 1.93-1.80 (m, 2H), 1.76-1.63 (m, 2H), 1.54-1.39 (m, 3H), 1.37-1.15 (m, 3H).
Figure imgf000019_0003
碳酸环己酯氯甲酯 （4.8 g， 25.0 mmol) 溶于 25 mL乙腈， 再加入碘化钠 (7.5 g， 50.0 mmol) ， 室温反应 20小时。 过滤， 浓缩， 所得粗产品中加入乙醚 溶解， 再次过滤， 浓缩， 得黄色油状物碳酸环己酯碘甲酯 （7.1 g， 99%) 。 1H MR (400 MHz, CDC1 3 ) δ 5.66 (s, 2H), 4.72-4.58 (m, 1H), 1.93-1.80 (m, 2H), 1.76-1.63 (m, 2H), 1.54-1.39 (m, 3H), 1.37-1.15 (m, 3H).
Figure imgf000019_0003
The cyclohexyl carbonate chloromethyl ester (4.8 g, 25.0 mmol) was dissolved in 25 mL of acetonitrile, and then sodium iodide (7.5 g, 50.0 mmol) was added, and the mixture was reacted at room temperature for 20 hours. Filtration and concentrating. The obtained crude product was dissolved in diethyl ether, filtered again, and concentrated to give ethyl chloroformate (7.1 g, 99%).
1H MR (400 MHz, CDC13) δ 5.88 (s, 2H), 4.78-4.52 (m, 1H), 1.95-1.81 (m, 2H)， 1H MR (400 MHz, CDC1 3 ) δ 5.88 (s, 2H), 4.78-4.52 (m, 1H), 1.95-1.81 (m, 2H),
(m,3  (m, 3
Figure imgf000020_0001
Figure imgf000020_0001
(2R,4S)-4-(3-苄氧基羰基-丙酰氨基；) -5-联苯基 -4-基 -2-甲基戊酸 （331 mg， 0.70 mmol) 溶于 5 mL乙腈， 再依次加入 Cs2C03 ( 114 mg， 0.35 mmol) 和碳酸环己 酯碘甲酯 （398 mg， 1.40 mmol ) ， 室温反应 4小时。 过滤， 浓缩， 反相柱层析分 离， 得无色粘稠液体 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊 酸环己氧基碳氧基甲基酯 （404 mg， 92%) 。 (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino;)-5-biphenyl-4-yl-2-methylpentanoic acid (331 mg, 0.70 mmol) dissolved in 5 mL of acetonitrile Then, Cs 2 C0 3 (114 mg, 0.35 mmol) and cyclohexyl methyl iodide (398 mg, 1.40 mmol) were added in this order, and the mixture was reacted at room temperature for 4 hours. Filtration, concentration, reverse phase column chromatography to give a colorless viscous liquid (2R,4S)-4-(3-benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2- Cyclohexyloxycarbomethyl methyl valerate (404 mg, 92%).
1H MR (400 MHz, CDCI3) δ 7.54-7.48 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.32-7.22 (m, 6H), 7.16 (d, J = 8.0 Hz, 2H), 5.69 (d, J = 5.6 Hz, 1H), 5.66 (d, J = 5.6 Hz, 1H), 5.55 (d, = 8.8 Hz, 1H), 5.04 (s, 2H), 4.66-4.51 (m, 1H), 4.30- 4.11 (m, 1H), 3.42 (d, = 5.2 Hz, 1H), 2.84-2.67 (m, 2H), 2.59 (t, = 6.8 Hz, 2H), 2.57- 2.52 (m, 1H), 2.34 (t, = 6.8 Hz, 2H), 1.92-1.77 (m, 3H), 1.71-1.52 (m, 3H), 1.46-1.13 (m,  1H MR (400 MHz, CDCI3) δ 7.54-7.48 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.32-7.22 (m, 6H) , 7.16 (d, J = 8.0 Hz, 2H), 5.69 (d, J = 5.6 Hz, 1H), 5.66 (d, J = 5.6 Hz, 1H), 5.55 (d, = 8.8 Hz, 1H), 5.04 ( s, 2H), 4.66-4.51 (m, 1H), 4.30- 4.11 (m, 1H), 3.42 (d, = 5.2 Hz, 1H), 2.84-2.67 (m, 2H), 2.59 (t, = 6.8 Hz , 2H), 2.57- 2.52 (m, 1H), 2.34 (t, = 6.8 Hz, 2H), 1.92-1.77 (m, 3H), 1.71-1.52 (m, 3H), 1.46-1.13 (m,
Figure imgf000020_0002
Figure imgf000020_0002
(2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基 -戊酸乙氧基碳氧基 甲基酯 （372 mg， 0.65 mmol) 溶于 20 mL甲醇， 加入钯 /炭 (400 mg) ， 抽换 气， 常压氢化 2小时。 过滤， 浓缩， 反相柱层析分离， 得无色粘稠液体 (2R,4S)-5- 联苯基 -4-基 -4-(3-羧基 -丙酰氨基; )-2-甲基戊酸环己氧基碳氧基甲基酯 （252 mg, 73%) 。  (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methyl-pentanoic acid ethoxycarbonylmethyl ester (372 mg , 0.65 mmol) dissolved in 20 mL of methanol, palladium on charcoal (400 mg), gas exchange, hydrogenation at atmospheric pressure for 2 hours. Filtration, concentration, reverse phase column chromatography to give a colorless viscous liquid (2R, 4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino; )-2-methyl Cyclohexyloxycarbomethoxyvalerate (252 mg, 73%).
1H MR (400 MHz, CDCI3) δ 7.57-7.49 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 5.86 (d, J = 8.0 Hz, 1H), 5.72 (d, = 5.6 Hz, 1H), 5.63 (d, = 5.6 Hz, 1H), 4.66-4.53 (m, 1H), 4.31-4.17 (m, 1H), 2.83-2.68 (m, 2H), 2.64-2.49 (m, 3H), 2.46-2.30 (m, 3H), 1.93-1.77 (m, 4H), 1.74- 1.58 (m, 4H), 1.52-1.36 (m, 4H), 1.34-1.14 (m, 6H), 1.10 (d, = 7.2 Hz, 3H).  1H MR (400 MHz, CDCI3) δ 7.57-7.49 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (d, J = 7.2 Hz) , 1H), 7.16 (d, J = 8.0 Hz, 2H), 5.86 (d, J = 8.0 Hz, 1H), 5.72 (d, = 5.6 Hz, 1H), 5.63 (d, = 5.6 Hz, 1H), 4.66-4.53 (m, 1H), 4.31-4.17 (m, 1H), 2.83-2.68 (m, 2H), 2.64-2.49 (m, 3H), 2.46-2.30 (m, 3H), 1.93-1.77 (m , 4H), 1.74- 1.58 (m, 4H), 1.52-1.36 (m, 4H), 1.34-1.14 (m, 6H), 1.10 (d, = 7.2 Hz, 3H).
LC-MS: tR = 5.13 min; [M+H]+: 540.0. 实施例 3 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸异丙氧基碳氧基甲基酯的 制备
Figure imgf000021_0001
 LC-MS: t R = 5.13 min; [M + H] +: 540.0 Example 3. Preparation of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid isopropoxycarboxymethyl ester
Figure imgf000021_0001
异丙醇 （1.9 mL， 25.0 mmol) 加入 25 mL二氯甲垸， 冰水浴冷却； 氯甲酸氯 甲酯 （2.2 mL， 25.0 mmol) 溶于 25 mL二氯甲垸， 缓慢滴加入反应体系中； 吡啶 (2.2 mL, 27.5 mmol) 稀释于 5 mL二氯甲垸， 再缓慢滴加入反应体系中。 室温 反应过夜。 加入二氯甲垸稀释， 水洗 3次， 无水硫酸钠干燥。 浓缩， 得无色液体 碳酸异丙酯氯甲酯 （3.8 g， 99%) 。  Isopropanol (1.9 mL, 25.0 mmol) was added to 25 mL of dichloromethane and cooled in an ice water bath; chloromethyl chloroformate (2.2 mL, 25.0 mmol) was dissolved in 25 mL of dichloromethane and slowly added dropwise to the reaction system; Pyridine (2.2 mL, 27.5 mmol) was diluted in 5 mL of dichloromethane and slowly added dropwise to the reaction system. The reaction was carried out at room temperature overnight. Diluted with dichloromethane, washed 3 times with water and dried over anhydrous sodium sulfate. Concentrated to give a colorless liquid isopropyl chloroformate (3.8 g, 99%).
1H MR (400 MHz, CDC13) δ 5.66 (s, 2H), 4.89 (m, IH), 1.27 (d, 6H).
Figure imgf000021_0002
1H MR (400 MHz, CDC1 3 ) δ 5.66 (s, 2H), 4.89 (m, IH), 1.27 (d, 6H).
Figure imgf000021_0002
碳酸异丙酯氯甲酯 （3.8 g， 25.0 mmol) 溶于 25 mL乙腈， 再加入碘化钠 ( 18.7 g， 125.0 mmol) ， 室温反应 20小时。 过滤， 浓缩， 所得粗产品中加入乙 醚溶解， 再次过滤， 浓缩， 得黄色油状物碳酸异丙酯碘甲酯 （5.0 g， 83%) 。  Isopropyl chloroformate (3.8 g, 25.0 mmol) was dissolved in 25 mL of acetonitrile, then sodium iodide (1,7 g, 125.0 mmol) was added and allowed to react at room temperature for 20 hours. Filtration and concentrating. The obtained crude product was dissolved in ethyl ether, filtered again, and concentrated to afford ethyl isopropyl isopropyl ester (5.0 g, 83%).
4.89 (m, IH), 1.26 (d, 6H).  4.89 (m, IH), 1.26 (d, 6H).
Figure imgf000021_0003
Figure imgf000021_0003
(2R,4S)-4-(3-苄氧基羰基-丙酰氨基；) -5-联苯基 -4-基 -2-甲基戊酸 （323 mg， 0.68 mmol) 溶于 5 mL乙腈， 再依次加入 Cs2C03 ( 111 mg, 0.34 mmol) 和碳酸异丙 酯碘甲酯 （333 mg， 1.36 mmol ) ， 室温反应过夜。 过滤， 浓缩， 产物直接用于下 (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino;)-5-biphenyl-4-yl-2-methylpentanoic acid (323 mg, 0.68 mmol) dissolved in 5 mL of acetonitrile Then, Cs 2 C0 3 (111 mg, 0.34 mmol) and isopropyl iodide (333 mg, 1.36 mmol) were added in this order and allowed to react at room temperature overnight. Filtered, concentrated, product directly used
Figure imgf000021_0004
Figure imgf000021_0004
(2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸异丙氧基碳氧 基甲基酯溶于 20 mL甲醇， 加入钯 /炭 (400 mg) ， 抽换气， 常压氢化 2小时。 过 滤， 浓缩， 反相柱层析分离， 得无色油状液体 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基-丙 酰氨基 )-2-甲基戊酸异丙氧基碳氧基甲基酯 （166 mg， 49%) 。  (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid isopropoxycarboxymethyl ester dissolved in 20 In methanol, add palladium on charcoal (400 mg), exchange gas, and hydrogenate at atmospheric pressure for 2 hours. Filtration, concentration, reverse phase column chromatography to give a colorless oily liquid (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid Isopropoxy carboxymethyl ester (166 mg, 49%).
1H MR (400 MHz, CDCI3) δ 7.45 (dd, 4H), 7.33 (t, 2H), 7.24 (t, IH), 7.14 (d, 2H), 5.95 (s, IH), 5.64 (dd, 2H), 4.81 (m, IH), 4.19 (m, IH), 2.73 (m, 2H), 2.53 (m, 3H): 2.34 (m, 2H), 1.85 (m, IH), 1.56 (m, IH), 1.21 (d, 6H), 1.08 (d, 3H). 1H MR (400 MHz, CDCI3) δ 7.45 (dd, 4H), 7.33 (t, 2H), 7.24 (t, IH), 7.14 (d, 2H), 5.95 (s, IH), 5.64 (dd, 2H) , 4.81 (m, IH), 4.19 (m, IH), 2.73 (m, 2H), 2.53 (m, 3H) : 2.34 (m, 2H), 1.85 (m, IH), 1.56 (m, IH), 1.21 (d, 6H), 1.08 (d, 3H).
LC-MS: tR = 4.73 min; [M+H]+: 500.0. 实施例 4 LC-MS: t R = 4.73 min; [M + H] +: 500.0. Example 4
(2R,4S)-4-(3-羧基 -丙酰氨基; )-5-联苯基 -4-基 -2-甲基 -戊酸 2,2-二甲基-丙酰氧基甲基 酯的制备
Figure imgf000022_0001
(2R,4S)-4-(3-carboxy-propionylamino; )-5-biphenyl-4-yl-2-methyl-pentanoic acid 2,2-dimethyl-propionyloxymethyl Preparation of ester
Figure imgf000022_0001
2,2-二甲基-丙酸氯甲基酯 （1.4 mL， 10.0 mmol) 溶于 20 mL丙酮， 再加入碘 化钠 （3.7 g， 25.0 mmol) ， 室温反应过夜。 过滤， 浓縮， 所得粗产品中加入乙醚 溶解， 再次过滤， 浓縮， 得棕色油状物 2,2-二甲基丙酸碘甲基酯 （2.9 g) 。  2,2-Dimethyl-propionic acid chloromethyl ester (1.4 mL, 10.0 mmol) was dissolved in 20 mL of acetone, then sodium iodide (3.7 g, 25.0 mmol) was added and allowed to react overnight at room temperature. Filtration and concentrating. The obtained crude product was dissolved in diethyl ether, filtered again, and concentrated to give a white oil (2.
Figure imgf000022_0002
Figure imgf000022_0002
(2R,4S)-4-(3-苄氧基羰基-丙酰氨基；) -5-联苯基 -4-基 -2-甲基戊酸 （331 mg， 0.70 mmol) 溶于 5 mL乙腈， 再依次加入 Cs2C03 ( 114 mg， 0.35 mmol) 和 2,2-二甲 基-丙酸碘甲基酯 （339 mg， 1.40 mmol) ， 室温反应 4小时； 补力 B Cs2C03 ( 114 mg， 0.35 mmol) 禾 P 2,2-二甲基-丙酸碘甲基酯 （339 mg， 1.40 mmol) ， 继续反应 过夜。 过滤， 浓缩， 反相柱层析分离， 得无色油状液体 (2R,4S)-4-(3-苄氧基羰基- 丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 -2,2-二甲基-丙酰氧基甲基酯 （305 mg， 74%) 。 (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino;)-5-biphenyl-4-yl-2-methylpentanoic acid (331 mg, 0.70 mmol) dissolved in 5 mL of acetonitrile Then add Cs 2 C0 3 (114 mg, 0.35 mmol) and 2,2-dimethyl-propionic acid iodomethyl ester (339 mg, 1.40 mmol), and react at room temperature for 4 hours; make up B Cs 2 C0 3 (114 mg, 0.35 mmol) P 2,2-dimethyl-propionic acid iodomethyl ester (339 mg, 1.40 mmol). Filtration, concentration, reverse phase column chromatography to give a colorless oily liquid (2R,4S)-4-(3-benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-yl 2,2-dimethyl-propionyloxymethyl valerate (305 mg, 74%).
1H MR (400 MHz, CDC13) δ 7.50 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.33-7.24 (m, 6H), 7.16 (d, J = 8.0 Hz, 2H), 5.70 (d, J = 5.6 Hz, 1H), 5.64 (d, = 5.6 Hz, 1H), 5.58 (d, = 9.0 Hz, 1H), 5.04 (s, 2H), 4.25-4.12 (m, 1H), 2.75 (d, = 6.4 Hz, 2H), 2.59 (t, = 7.0 Hz, 2H), 2.58-2.48 (m, 1H), 2.35 (t, = 6.4 Hz, 2H 1.1 Hz, 3H). 1H MR (400 MHz, CDC1 3 ) δ 7.50 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.33-7.24 ( m, 6H), 7.16 (d, J = 8.0 Hz, 2H), 5.70 (d, J = 5.6 Hz, 1H), 5.64 (d, = 5.6 Hz, 1H), 5.58 (d, = 9.0 Hz, 1H) , 5.04 (s, 2H), 4.25-4.12 (m, 1H), 2.75 (d, = 6.4 Hz, 2H), 2.59 (t, = 7.0 Hz, 2H), 2.58-2.48 (m, 1H), 2.35 ( t, = 6.4 Hz, 2H 1.1 Hz, 3H).
Figure imgf000022_0003
Figure imgf000022_0003
(2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 2,2-二甲基-丙 酰氧基甲基酯 （305 mg， 0.65 mmol) 溶于 10 mL甲醇， 加入钯 /炭 (330 mg) ， 抽换气， 常压氢化 3 小时。 过滤， 浓缩， 反相柱层析分离， 得无色粘稠液体 (2R,4S)-4-(3-羧基 -丙酰氨基； )-5-联苯基 -4-基 -2-甲基戊酸 -2,2-二甲基-丙酰氧基甲基 酯 ( 194 mg, 75%) 。  (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid 2,2-dimethyl-propionyloxymethyl The base ester (305 mg, 0.65 mmol) was dissolved in 10 mL of methanol, palladium on charcoal (330 mg) was added, and the mixture was purged and hydrogenated at atmospheric pressure for 3 hours. Filtration, concentration, reverse phase column chromatography to give a colorless viscous liquid (2R,4S)-4-(3-carboxy-propionylamino; )-5-biphenyl-4-yl-2-methyl 2,2-Dimethyl-propionyloxymethyl valerate (194 mg, 75%).
1H NMR (400 MHz, CDCI3) δ 7.50 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.15 (d, = 8.0 Hz, 2H), 5.97 (d, J = 8.6 Hz, 1H), 5.72 (d, = 5.6 Hz, 1H), 5.59 (d, = 5.6 Hz, 1H), 4.27-4.14 (m, 1H), 2.86- 2.68 (m, 2H), 2.60-2.46 (m, 3H), 2.45-2.30 (m, 2H), 1.92-1.83 (m, 1H), 1.54 (ddd, J = 14.2, 10.4, 3.8 Hz, 1H), 1.14 (s, 9H), 1.08 (d, = 7.2 Hz, 3H). 1H NMR (400 MHz, CDCI3) δ 7.50 (d, J = 7.2 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.15 (d, = 8.0 Hz, 2H), 5.97 (d, J = 8.6 Hz, 1H), 5.72 (d, = 5.6 Hz, 1H), 5.59 (d, = 5.6 Hz, 1H), 4.27-4.14 (m, 1H), 2.86- 2.68 (m, 2H), 2.60-2.46 ( m, 3H), 2.45-2.30 (m, 2H), 1.92-1.83 (m, 1H), 1.54 (ddd, J = 14.2, 10.4, 3.8 Hz, 1H), 1.14 (s, 9H), 1.08 (d, = 7.2 Hz, 3H).
LC-MS: tR = 5.40 min; [M+H]+: 498.0. 实施例 5 LC-MS: t R = 5.40 min; [M + H] +: 498.0 Example 5.
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基-丙酰氨基；) -2-甲基戊酸 2-((2R,3R,4S,5S,6R)-3,4, 三羟基 -6-羟甲基 -四氢 -吡喃 -2-氧基)乙基酯的制备
Figure imgf000023_0001
(2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino;)-2-methylpentanoic acid 2-((2R,3R,4S,5S,6R)- Preparation of 3,4, trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-oxy)ethyl ester
Figure imgf000023_0001
2,3,4,6-四苄基-葡萄糖 （5407 mg， 10.0 mmol) 溶于 20 mL二氯甲垸， 冰水浴 冷却下依次加入三氯乙腈 （1.5 mL， 15.0 mmol) 以及 1滴 DBU， 自然升至室 温， 反应 4小时。 停止反应， 直接浓缩， 所得产物用于下步反应。
Figure imgf000023_0002
2,3,4,6-Tetrabenzyl-glucose (5407 mg, 10.0 mmol) was dissolved in 20 mL of dichloromethane, and trichloroacetonitrile (1.5 mL, 15.0 mmol) and 1 drop of DBU were added in an ice water bath. The mixture was naturally warmed to room temperature and allowed to react for 4 hours. The reaction was stopped, concentrated directly, and the resulting product was used in the next step.
Figure imgf000023_0002
化合物 2,2,2-三氯 -乙酰亚胺酸（4S ,5R)-3,4,5-三-苄氧基 -6-苄氧基甲基-四氢-吡 喃 -2-基酯 （5.0 mmol) 溶于 20 mL二氯甲垸， 加入约 3 g新活化的 4A分子筛， 再加入乙二醇 （0.55 mL, 10.0 mmol ) ， 室温搅拌 1 小时。 冰水浴冷却下加入 TMSOTf (97 0.5 mmol) ， 室温反应过夜。 加入 Et3N淬灭， 过滤， 浓缩。 柱 层析分离， 得白色固体 2- 2R,4S,5R)-3,4,5-三-苄氧基 -6-苄氧基甲基 -四氢 -吡喃 -2- 氧基) -乙醇 （850 mg， 29%) 。 Compound 2,2,2-trichloro-acetimidoic acid (4S , 5R)-3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl ester (5.0 mmol) Dissolved in 20 mL of dichloromethane, added about 3 g of freshly activated 4A molecular sieve, then added ethylene glycol (0.55 mL, 10.0 mmol) and stirred at room temperature for 1 hour. TMSOTf (97 0.5 mmol) was added to the ice water bath and allowed to react at room temperature overnight. Quenched with Et 3 N was added, filtered, and concentrated. Column chromatography to give a white solid 2- 2R,4S,5R)-3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yloxy)-ethanol (850 mg, 29%).
1H MR (400 MHz, CDC13) δ 7.37-7.15 (m, 22H), 7.07 (dd, J = 6.7, 2.9 Hz, 2H), 4.84 (t, = 11.1 Hz, 2H), 4.71 (dd, = 18.4, 10.6 Hz, 3H), 4.54-4.39 (m, 3H), 4.35 (d, J = 7.8 Hz, 1H), 3.96-3.85 (m, 1H), 3.83-3.68 (m, 2H), 3.68-3.56 (m, 3H), 3.56-3.35 (m, 1H MR (400 MHz, CDC1 3 ) δ 7.37-7.15 (m, 22H), 7.07 (dd, J = 6.7, 2.9 Hz, 2H), 4.84 (t, = 11.1 Hz, 2H), 4.71 (dd, = 18.4 , 10.6 Hz, 3H), 4.54-4.39 (m, 3H), 4.35 (d, J = 7.8 Hz, 1H), 3.96-3.85 (m, 1H), 3.83-3.68 (m, 2H), 3.68-3.56 ( m, 3H), 3.56-3.35 (m,
Figure imgf000023_0003
Figure imgf000023_0003
将化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 （284 mg， 0.60 mmol) ， 2-((2R,4S,5R)-3,4,5-三-苄氧基 -6-苄氧基甲基 -四氢 -吡喃 -2-氧 基) -乙醇 （351 mg， 0.60 mmol) ， EDCI ( 173 mg, 0.90 mmol ) 以及 Ν,Ν-二甲基 对氨基吡啶 （15 mg， 0.12 mmol) 溶于 5 mL二氯甲垸， 室温反应过夜。 浓缩后 反相柱层析分离， 得无色糖浆 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基- 2-甲基戊酸 -2-((2R,3R,4S,5R,6R )-3,4,5-三-苄氧基 -6-苄氧基甲基 -四氢 -吡喃 -2-氧 基)-乙基酯 （318 mg， 51%) 。 The compound (2R,4S)-4-(3-benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (284 mg, 0.60 mmol), 2- (2R,4S,5R)-3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yloxy)-ethanol (351 mg, 0.60 mmol), EDCI (173 mg, 0.90 mmol) and hydrazine, hydrazine-dimethyl-p-aminopyridine (15 mg, 0.12 mmol) dissolved in 5 mL of dichloromethane. After concentration, the reverse phase column chromatography was carried out to give a colorless syrup (2R,4S)-4-(3-benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl- 2-methylpentanoic acid-2-((2R,3R,4S,5R,6R )-3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2- Oxy))ethyl ester (318 mg, 51%).
1H MR (400 MHz, CDC13) δ 7.51-7.46 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.32 (t, = 7.5 Hz, 2H), 7.29-7.16 (m, 19H), 7.12 (d, = 8.2 Hz, 2H), 7.05 (dd, = 6.8, 2.8 Hz, 2H), 5.49 (d, = 8.8 Hz, 1H), 5.01 (s, 2H), 4.90-4.79 (m, 2H), 4.73-4.58 (m, 3H), 4.45 (dt, = 14.8, 11.6 Hz, 3H), 4.34 (d, = 7.8 Hz, 1H), 4.19 (d, = 7.2 Hz, 1H), 4.12-3.99 (m, 2H), 3.78-3.68 (m, 1H), 3.68-3.44 (m, 5H), 3.40-3.31 (m, 3H), 2.73 (dd, = 6.4, 3.2 Hz, 2H), 2.54 (t, = 6.8 Hz, 2H), 2.51-2.42 (m, 1H), 2.28 (t, = 6.8 Hz, 2H), 1.81 (ddd, 1H MR (400 MHz, CDC1 3 ) δ 7.51-7.46 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.32 (t, = 7.5 Hz, 2H), 7.29-7.16 (m, 19H) , 7.12 (d, = 8.2 Hz, 2H), 7.05 (dd, = 6.8, 2.8 Hz, 2H), 5.49 (d, = 8.8 Hz, 1H), 5.01 (s, 2H), 4.90-4.79 (m, 2H) ), 4.73-4.58 (m, 3H), 4.45 (dt, = 14.8, 11.6 Hz, 3H), 4.34 (d, = 7.8 Hz, 1H), 4.19 (d, = 7.2 Hz, 1H), 4.12-3.99 ( m, 2H), 3.78-3.68 (m, 1H), 3.68-3.44 (m, 5H), 3.40-3.31 (m, 3H), 2.73 (dd, = 6.4, 3.2 Hz, 2H), 2.54 (t, = 6.8 Hz, 2H), 2.51-2.42 (m, 1H), 2.28 (t, = 6.8 Hz, 2H), 1.81 (ddd,
Figure imgf000024_0001
Figure imgf000024_0001
化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 -2- Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid-2-
((2R,3R,4S,5R,6R )-3,4,5-三-苄氧基 -6-苄氧基甲基 -四氢 -吡喃 -2-氧基)-乙基酯 （318 mg， 0.31 mmol) 溶于 10 mL甲醇， 再加入 350 mg钯 /炭， 常压氢化 5天。 过滤， 浓缩， 反相柱层析分离， 得无色油状液体 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基-丙酰氨 基) -2-甲基戊酸 2-((2R,3R,4S,5S,6R)-3,4,5-三羟基 -6-羟甲基 -四氢 -吡喃 -2-氧基) -乙 基酯 (73 mg, 40%) 。 ((2R,3R,4S,5R,6R)-3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yloxy)-ethyl ester (318 Mg, 0.31 mmol) Dissolved in 10 mL of methanol, then added 350 mg of palladium on charcoal and hydrogenated at atmospheric pressure for 5 days. Filtration, concentration, reverse phase column chromatography to give a colorless oily liquid (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid 2-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-ethyl ester (73 mg, 40 %).
1H雇 R (400 MHz, MeOD) δ 7.72-7.60 (m, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.40-7.27 (m, 3H), 4.33 (d, = 7.8 Hz, 1H), 4.32-4.12 (m, 3H), 4.07 (ddd, = 11.3, 5.8, 3.5 Hz, 1H), 3.88 (d, = 12.0 Hz, 1H), 3.85-3.77 (m, 1H), 3.71-3.64 (m, 1H), 3.23 (dd, = 9.1, 7.8 Hz, 1H), 2.80 (d, = 6.8 Hz, 2H), 2.69-2.58 (m, 1H), 2.42 (s, 4H), 1.92 (ddd, = 13.9, 10.4, 3.5 Hz, 1H), 1.59-1.46 (m, 1H), 1.17 (d, = 7.2 Hz, 3H).  1H hire R (400 MHz, MeOD) δ 7.72-7.60 (m, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.40-7.27 (m, 3H ), 4.33 (d, = 7.8 Hz, 1H), 4.32-4.12 (m, 3H), 4.07 (ddd, = 11.3, 5.8, 3.5 Hz, 1H), 3.88 (d, = 12.0 Hz, 1H), 3.85- 3.77 (m, 1H), 3.71-3.64 (m, 1H), 3.23 (dd, = 9.1, 7.8 Hz, 1H), 2.80 (d, = 6.8 Hz, 2H), 2.69-2.58 (m, 1H), 2.42 (s, 4H), 1.92 (ddd, = 13.9, 10.4, 3.5 Hz, 1H), 1.59-1.46 (m, 1H), 1.17 (d, = 7.2 Hz, 3H).
LC-MS: tR = 2.85 min; [M-H]": 587.9. 实施例 6 LC-MS: t R = 2.85 min; [MH] ": 587.9 Example 6.
(2R,4S)-5-联苯基 -4-基 -4-0羧基 -丙酰氨基) -2-甲基戊酸 -3-( 2R,3R,4S,5S,6R)-3,4,5 三羟基 -6-羟甲基 -四氢 -吡喃 -2-氧基)丙基酯的制备
Figure imgf000024_0002
(2R,4S)-5-biphenyl-4-yl-4-0carboxy-propionylamino)-2-methylpentanoic acid-3-( 2R,3R,4S,5S,6R)-3,4 ,5 Preparation of trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-oxy)propyl ester
Figure imgf000024_0002
化合物 2,2,2-三氯 -乙酰亚胺酸 -(4S ,5R)-3,4,5-三-苄氧基 -6-苄氧基甲基-四氢- 吡喃 -2-基酯 （5.0 mmol) 溶于 20 mL二氯甲垸， 加入约 3 g新活化的 4A分子 筛， 再加入 1,3-丙二醇 （0.72 mL， 10.0 mmol) ， 室温搅拌 1小时。 冰水浴冷却 下加入 TMSOTf (97 μί， 0.5 mmol) ， 室温反应过夜。 加入 Et3N淬灭， 过滤， 浓缩。 柱层析分离， 得白色固体 （463 mg， 15%) 。 1H雇 R (400 MHz, CDCI3) δ 7.40-7.02 (m, 20H), 4.84 (dd, = 11.0, 5.4 Hz, 2H), 4.73 (dd, J = 10.8, 5.2 Hz, 2H), 4.66 (d, = 11.0 Hz, 1H), 4.55-4.46 (m, 2H), 4.44 (d, J = 10.8 Hz, 1H), 4.33 (d, = 7.8 Hz, 1H), 4.02-3.91 (m, 1H), 3.82-3.62 (m, 4H), 3.62- 3.52 (m, 2H), 3.47 (t, = 9.2 Hz, 1H), 3.45-3.30 (m, 2H), 2.09 (t, = 6.0 Hz, 1H), 1.79 (t, Compound 2,2,2-trichloro-acetimidate-(4S ,5R)-3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl The ester (5.0 mmol) was dissolved in 20 mL of dichloromethane, and about 3 g of freshly activated 4A molecular sieves were added, then 1,3-propanediol (0.72 mL, 10.0 mmol) was added and stirred at room temperature for 1 hour. TMSOTf (97 μί, 0.5 mmol) was added to the ice water bath and allowed to react at room temperature overnight. Quenched with Et 3 N was added, filtered, and concentrated. Column chromatography gave a white solid (463 mg, 15%). 1H hire R (400 MHz, CDCI3) δ 7.40-7.02 (m, 20H), 4.84 (dd, = 11.0, 5.4 Hz, 2H), 4.73 (dd, J = 10.8, 5.2 Hz, 2H), 4.66 (d, = 11.0 Hz, 1H), 4.55-4.46 (m, 2H), 4.44 (d, J = 10.8 Hz, 1H), 4.33 (d, = 7.8 Hz, 1H), 4.02-3.91 (m, 1H), 3.82- 3.62 (m, 4H), 3.62- 3.52 (m, 2H), 3.47 (t, = 9.2 Hz, 1H), 3.45-3.30 (m, 2H), 2.09 (t, = 6.0 Hz, 1H), 1.79 (t ,
Figure imgf000025_0001
Figure imgf000025_0001
将化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 （216 mg， 0.46 mmol) ， 3-((2R,4S,5R)-3,4,5-三-苄氧基 - 6-苄氧基甲基 -四氢 -吡喃 - 2-氧 基) -丙垸 -1-醇 (273 mg, 0.46 mmol) ， EDCI ( 131 mg, 0.68 mmol) 以及 Ν,Ν-二 甲基对氨基吡啶 （6 mg， 0.05 mmol) 溶于 5 mL二氯甲垸， 室温反应过夜。 反相  Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (216 mg, 0.46 mmol), 3-( (2R,4S,5R)-3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yloxy)-propan-1-ol (273 mg, 0.46 mmol), EDCI (131 mg, 0.68 mmol) and hydrazine, hydrazine-dimethyl-p-aminopyridine (6 mg, 0.05 mmol) were dissolved in 5 mL of dichloromethane and allowed to react overnight at room temperature. Inversion
Figure imgf000025_0002
Figure imgf000025_0002
化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基 -戊酸 -3- ((2R,3R,4S,5R,6R )-3,4,5-三-苄氧基 -6-苄氧基甲基 -四氢 -吡喃 -2-氧基) -丙基酯粗产 品溶于 10 mL甲醇， 再加入 300 mg钯 /炭， 常压氢化 3天。 反相柱层析分离， 得 无色糖浆（2R,4S)-5-联苯基 -4-基 -4-(3-羧基-丙酰氨基）-2-甲基戊酸 -3- ((2R,3R,4S,5S,6R)-3,4,5-三羟基 -6-羟甲基 -四氢 -吡喃 -2-氧基)-丙基酯 （13 mg , 10%) 。  Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methyl-pentanoic acid-3-((2R,3R,4S, 5R,6R )-3,4,5-tri-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-oxy)-propyl ester crude product is dissolved in 10 mL of methanol, then added 300 mg palladium on charcoal, hydrogenated at atmospheric pressure for 3 days. Separation by reverse phase column chromatography gave colorless syrup (2R, 4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid-3- (( 2R, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-oxy)-propyl ester (13 mg, 10%).
1H MR (400 MHz, MeOD) δ 7.67-7.58 (m, 2Η), 7.55 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.36-7.25 (m, 3H), 4.27 (d, J = 7.8 Hz, 1H), 4.25-4.09 (m, 3H), 3.96 (dt, J = 10.0, 6.0 Hz, 1H), 3.87 (dd, = 12.0, 1.6 Hz, 1H), 3.74-3.57 (m, 2H), 3.43-3.26 (m, 3H), 3.24-3.16 (m, 1H), 2.90-2.73 (m, 2H), 2.67-2.55 (m, 1H), 2.47 (brd, J = 8.0 Hz, 4H), 2.00-1.84 (m, 3H), 1.57-1.43 (m, 1H), 1.16 (d, = 7.2 Hz, 3H). 实施例 7  1H MR (400 MHz, MeOD) δ 7.67-7.58 (m, 2Η), 7.55 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.36-7.25 (m, 3H) , 4.27 (d, J = 7.8 Hz, 1H), 4.25-4.09 (m, 3H), 3.96 (dt, J = 10.0, 6.0 Hz, 1H), 3.87 (dd, = 12.0, 1.6 Hz, 1H), 3.74 -3.57 (m, 2H), 3.43-3.26 (m, 3H), 3.24-3.16 (m, 1H), 2.90-2.73 (m, 2H), 2.67-2.55 (m, 1H), 2.47 (brd, J = 8.0 Hz, 4H), 2.00-1.84 (m, 3H), 1.57-1.43 (m, 1H), 1.16 (d, = 7.2 Hz, 3H). Example 7
(2 备  (2 preparation
Figure imgf000025_0003
乙酰氯 （1 mL ) 加入 0 °C乙醇 （10 mL) 中， 室温反应 0.5小时， 加入化合 物 (3R, 5S)-5-联苯基 -4-亚甲基 -1-(2,2-二甲基丙酰基 )-3-甲基吡咯酮 （520 mg， 1.49 mmol ) ， 回流反应 3天。 冷却至室温后， 浓缩。 将上述反应混合物溶于 8 mL二 氯甲垸和吡啶的 1 : 1 混合溶液， 再加入丁二酸酐 （223 mg， 2.23 mmol ) 。 30 °C 反应过夜。 LC-MS 检测， 有少量原料剩余， 补加丁二酸酐 （75 mg， 0.74 mmol ) ， 继续反映 4小时。 浓缩， 反相柱层析分离， 得白色泡状固体（2R,4S)-5- 联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基 -戊酸乙基酯 a ( 355 mg， 58% ) 和白色固 体 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基 -戊酸 b ( 13 mg， 2.3% ) 。
Figure imgf000025_0003
Acetyl chloride (1 mL) was added to 0 °C ethanol (10 mL), reacted at room temperature for 0.5 hours, and compound (3R, 5S)-5-biphenyl-4-methylene-1-(2,2-di) was added. Methylpropionyl)-3-methylpyrrolidone (520 mg, 1.49 mmol) was refluxed for 3 days. After cooling to room temperature, it was concentrated. The above reaction mixture was dissolved in 8 mL of a 1:1 mixed solution of dichloromethane and pyridine, and then succinic anhydride (223 mg, 2.23 mmol) was added. The reaction was carried out at 30 °C overnight. LC-MS detected that a small amount of raw materials remained, supplemented with succinic anhydride (75 mg, 0.74 mmol) and continued to reflect for 4 hours. Concentration, reverse phase column chromatography to give a white foamy solid (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid Alkyl ester a (355 mg, 58%) and white solid (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid b ( 13 mg, 2.3%).
a: 1H MR (400 MHz, CDC13) δ 7.51 (d, = 7.8 Hz, 2H), 7.46 (d, = 7.8 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.2 Hz, IH), 7.17 (d, J = 7.9 Hz, 2H), 5.72 (d, J = 8.1 Hz, IH), 4.19 (brs, IH), 4.06 (q, J = 7.0 Hz, 2H), 2.87-2.72 (m, 2H), 2.62-2.54 (m, 2H), 2.49 (brs, IH), 2.43-2.33 (m, 2H), 1.88 (ddd, = 13.2, 9.5, 3.9 Hz, IH), 1.54-1.43 (m, IH), 1.18 (t, = 7.0 Hz, 3H), 1.10 (d, = 7.2 Hz, 3H). a: 1H MR (400 MHz, CDC1 3 ) δ 7.51 (d, = 7.8 Hz, 2H), 7.46 (d, = 7.8 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.2 Hz, IH), 7.17 (d, J = 7.9 Hz, 2H), 5.72 (d, J = 8.1 Hz, IH), 4.19 (brs, IH), 4.06 (q, J = 7.0 Hz, 2H) , 2.87-2.72 (m, 2H), 2.62-2.54 (m, 2H), 2.49 (brs, IH), 2.43-2.33 (m, 2H), 1.88 (ddd, = 13.2, 9.5, 3.9 Hz, IH), 1.54-1.43 (m, IH), 1.18 (t, = 7.0 Hz, 3H), 1.10 (d, = 7.2 Hz, 3H).
LC-MS: tR = 3.43 min; [M+H]+: 412.0. LC-MS: t R = 3.43 min; [M + H] +: 412.0.
b: 1H NMR (400 MHz, MeOD) δ 7.48 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H)， b: 1H NMR (400 MHz, MeOD) δ 7.48 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H),
7.30 (t, = 7.4 Hz, 2H), 7.23-7.15 (m, 3H), 4.07 (d, = 6.0 Hz, IH), 2.75-2.62 (m, 2H), 2.50-2.37 (m, 3H), 2.36-2.21 (m, 2H), 1.90-1.75 (m, IH), 1.45-1.31 (m, IH), 1.05 (d, J = 7.0 Hz, 3H). 7.30 (t, = 7.4 Hz, 2H), 7.23-7.15 (m, 3H), 4.07 (d, = 6.0 Hz, IH), 2.75-2.62 (m, 2H), 2.50-2.37 (m, 3H), 2.36 -2.21 (m, 2H), 1.90-1.75 (m, IH), 1.45-1.31 (m, IH), 1.05 (d, J = 7.0 Hz, 3H).
LC-MS: t = 3.09 min +: 384.0.  LC-MS: t = 3.09 min +: 384.0.
Figure imgf000026_0001
Figure imgf000026_0001
化合物 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基 -戊酸乙基酯 （ 155 mg， 0.38 mmol ) 溶于 5 mL乙酸酐， 再加入 50 mg醋酸钠。 加热回流， 反应 0.5 小时。 冷却至室温， 加入 10 mL水淬灭。 浓缩， 反相柱层析分离， 得无色油状液 体 (2R,4S)-5-联苯基 -4-基 -4-(2,5-二羰基-吡咯垸 -1-基) -2-甲基戊酸乙基酯 （ 134 mg, 85%) 。  Compound (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester (155 mg, 0.38 mmol) dissolved in 5 mL Acetic anhydride was added with 50 mg of sodium acetate. Heat to reflux and react for 0.5 hours. Cool to room temperature and quench by adding 10 mL of water. Concentration, reverse phase column chromatography to give a colorless oily liquid (2R,4S)-5-biphenyl-4-yl-4-(2,5-dicarbonyl-pyrrole-1-yl)-2- Ethyl methyl valerate (134 mg, 85%).
1H NMR (400 MHz, CDCI3) δ 7.49 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 1.6 Hz, 2H), 7.26 (t, = 7.6 Hz, IH), 7.13 (d, = 8.0 Hz, 2H), 4.48-4.32 (m, IH), 4.14-3.93 (m, 2H), 3.18 (dd, J = 13.6, 10.4 Hz, IH), 2.96 (dd, = 13.8, 6.0 Hz, 1H): 2.41 (brs, 4H), 2.30-2.19 (m, 2H), 2.05-1.94 (m, IH), 1.18 (t, = 7.2 Hz, 3H), 1.1 1 (d, J = 6.8 Hz, 3H). 1H NMR (400 MHz, CDCI3) δ 7.49 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 1.6 Hz, 2H), 7.26 (t, = 7.6 Hz, IH), 7.13 (d, = 8.0 Hz, 2H), 4.48-4.32 (m, IH), 4.14-3.93 (m, 2H), 3.18 (dd, J = 13.6, 10.4 Hz, IH), 2.96 (dd, = 13.8, 6.0 Hz, 1H) : 2.41 (brs, 4H), 2.30-2.19 (m, 2H), 2.05-1.94 (m, IH), 1.18 (t, = 7.2 Hz, 3H), 1.1 1 (d, J = 6.8 Hz, 3H).
LC-MS: tR = 3.824 min; [M+H]+: 394.0. 实施例 8 LC-MS: t R = 3.824 min; [M + H] +: 394.0 Example 8.
(2R,4S)-5-联苯基 -4-基 -4-(2,5-二羰基-吡咯垸 -1-基) -2-甲基戊酸的制备
Figure imgf000027_0001
Preparation of (2R,4S)-5-biphenyl-4-yl-4-(2,5-dicarbonyl-pyrrole-1-yl)-2-methylpentanoic acid
Figure imgf000027_0001
化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 (24 mg, 0.05 mmol)和 Cs2C03 (65 mg, 0.2 mmol)在 3毫升乙腈中加热至 40 °C反应 3.5小时 后， 将体系旋干， 用磷酸中和至 pH=6-7,反相柱层析纯化， 得 17.4 mg产物， 产 率为 95%。 Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (24 mg, 0.05 mmol) and Cs 2 C0 3 (65 mg, 0.2 mmol) After heating to 40 ° C for 3.5 hours in 3 ml of acetonitrile, the system was spun dry, neutralized with phosphoric acid to pH = 6-7, and purified by reverse-phase column chromatography to yield 17.4 mg of product. The yield was 95%.
1H MR: (400 MHz, CDC13), 7.51-7.45 (m, 2H), 7.40 (d, 2H), 7.34 (dd, 2H), 7.25 (d, 1H), 7.13 (d, 2H), 4.48 (dt, 1H), 3.20 (dd, 1H), 2.96 (dd, 1H), 2.46-2.22 (m, 6H), 2.02 (s, 1H), 1.15 (d, 3H).  1H MR: (400 MHz, CDC13), 7.51-7.45 (m, 2H), 7.40 (d, 2H), 7.34 (dd, 2H), 7.25 (d, 1H), 7.13 (d, 2H), 4.48 (dt , 1H), 3.20 (dd, 1H), 2.96 (dd, 1H), 2.46-2.22 (m, 6H), 2.02 (s, 1H), 1.15 (d, 3H).
LC-MS: 3.385 min, 366 (M+H+). 实施例 9  LC-MS: 3.385 min, 366 (M+H+). Example 9
(2R, 备  (2R, prepared
Figure imgf000027_0002
Figure imgf000027_0002
化合物 (2R,4S)-5-联苯基 -4-基 -4-叔丁氧基羰基氨基 -2-甲基戊酸 (383 mg, 1 mmol)溶解在 2 ml三氟丙醇中， 加热至 70°C， 缓慢将氯化亚砜滴加进去， 保持该 温度， 反应过夜， 然后将体系旋干， 加入 5毫升吡啶和 5毫升二氯甲垸， 然后将 丁二酸酐加入， 升温至 40°C， 反应 30 h， 将溶剂旋干， 过反相柱层析纯化， 得 147 mg黄色油状物。  Compound (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (383 mg, 1 mmol) dissolved in 2 ml of trifluoropropanol, heated To 70 ° C, slowly add thionyl chloride dropwise, keep the temperature, react overnight, then spin dry the system, add 5 ml of pyridine and 5 ml of dichloromethane, then add succinic anhydride, heat to 40 After reacting for 30 h at ° C, the solvent was evaporated to dryness and purified by reversed column chromatography to yield 147 mg of yellow oil.
1HNMR: (400 MHz, CDC13), 7.495 (d, 2H), 7.443 (d, 2H), 7.347 (t, 2H), 7.252 (t, 1H), 7.145 (d, 2H), 5.758 (s, 1H), 4.210 (s, 3H), 2.747 (s, 2H), 2.540 (m, 3H), 2.354 (m, 4H), 1.758 (m, 1H), 1.462 (m, 1H), 1.073 (d, 3H). 1 H NMR: (400 MHz, CDC1 3 ), 7.495 (d, 2H), 7.443 (d, 2H), 7.347 (t, 2H), 7.252 (t, 1H), 7.145 (d, 2H), 5.758 (s, 1H), 4.210 (s, 3H), 2.747 (s, 2H), 2.540 (m, 3H), 2.354 (m, 4H), 1.758 (m, 1H), 1.462 (m, 1H), 1.073 (d, 3H ).
LC-MS: 3.607 min, 480 (M+H) +. 实施例 10 LC-MS: 3.607 min, 480 (M+H) + . Example 10
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸 -2,2,2-三氟乙基酯的制备  Preparation of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid-2,2,2-trifluoroethyl ester
Figure imgf000027_0003
化合物（2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 (0.2 g, 0.42 mmol)和 HATU (193 mg, 0.46 mmol)溶解在 DMF中， 将三氟乙醇（1 ml)和 DIPEA C0.4 ml)加入，反应过夜， 将体系旋干， 反相柱层析纯化， 得 0.2 g白色固 体， 产率为 86%。
Figure imgf000027_0003
Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (0.2 g, 0.42 mmol) and HATU (193 mg , 0.46 mmol) was dissolved in DMF, trifluoroethanol (1 ml) and DIPEA C 0.4 ml) was added and the mixture was stirred overnight. The crystals were dried and purified by reverse column chromatography to give 0.2 g of white solid. 86%.
LC-MS: 4.072 min, 556 (M+H).  LC-MS: 4.072 min, 556 (M+H).
Figure imgf000028_0001
Figure imgf000028_0001
化合物（2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 -2,2,2- 三氟乙基酯 (0.2 g, 0.36 mmol)和 Pd/C (0.2 g)溶解在 MeOH中， H2氛围下室温反应 4 h左右， 将 Pd/C用硅藻土过滤掉， 滤液旋干， 反相柱层析纯化， 得 141 mg淡黄 色油状物 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸 -2,2,2-三氟乙基 酯， 产率为 84%。 Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid-2,2,2-trifluoroethyl ester (0.2 g, 0.36 mmol) and Pd/C (0.2 g) were dissolved in MeOH, and reacted at room temperature for about 4 h under H 2 atmosphere. Pd/C was filtered off with celite, and the filtrate was evaporated to dryness. Purification gave 141 mg of pale yellow oil (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid-2,2,2- Trifluoroethyl ester, yield 84%.
1HNMR: (400 MHz, CDC13), 7.47 (dd, 4H), 7.35 (t, 2H), 7.26 (t, 1H), 7.15 (dd, 2H), 5.64 (t, 1H), 4.4 (m, 1H), 2.76 (d, 2H), 2.55 (m, 2H), 2.32 (m, 2H), 1.85 (m, 1H), 1.51 (m, 1H), 1.12 (d, 3H); 19FNMR: (376 MHz, CDC13), -73.75 (dt, 3F). 1 H NMR: (400 MHz, CDC1 3 ), 7.47 (dd, 4H), 7.35 (t, 2H), 7.26 (t, 1H), 7.15 (dd, 2H), 5.64 (t, 1H), 4.4 (m, 1H), 2.76 (d, 2H), 2.55 (m, 2H), 2.32 (m, 2H), 1.85 (m, 1H), 1.51 (m, 1H), 1.12 (d, 3H); 19 FNMR: (376 MHz, CDC1 3 ), -73.75 (dt, 3F).
LC-MS: 3.579 min, 466 (M+H) +. 实施例 11 LC-MS: 3.579 min, 466 (M+H) + . Example 11
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸 -1-异丙氧基碳氧基乙基酉 ί
Figure imgf000028_0002
(2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid-1-isopropoxycarboxyethyl 酉
Figure imgf000028_0002
化合物 1-氯乙基氯甲酸酯（3 ml, 27.8 mmol)用 DCM (25 ml) 稀释， 冷却至 0°C， 将用 DCM (25 ml) 稀释的异丙醇 （2.1 ml, 27.8 mmol) 用恒压滴液漏斗缓 慢加入， 反应 15 min左右， 将用 DCM ( 5 ml) 稀释的吡啶 (2.4 ml, 30.6 mmol)同 样用恒压滴液漏斗缓慢加入， 该过程中保持低温不变， 加完后， 室温下反应过 夜， 然后加水稀释， 用 DCM萃取， 有机相干燥， 浓缩后得 3.74 g淡黄色液体， 产率为 81%。  The compound 1-chloroethyl chloroformate (3 ml, 27.8 mmol) was diluted with DCM (25 ml), cooled to 0 ° C, isopropyl alcohol (2.1 ml, 27.8 mmol) diluted with DCM (25 ml) Slowly add with a constant pressure dropping funnel, react for about 15 min, and slowly add pyridine (2.4 ml, 30.6 mmol) diluted with DCM (5 ml) with a constant pressure dropping funnel. After completion, the reaction was carried out at room temperature overnight, then diluted with water, extracted with DCM, and then dried and evaporated.
1H MR: (400MHz, CDCI3), 6.36 (q, 1H), 4.88 (m, 1H), 1.759 (dm, 3H), 1.26 (t, 6H).
Figure imgf000028_0003
1H MR: (400MHz, CDCI3), 6.36 (q, 1H), 4.88 (m, 1H), 1.759 (dm, 3H), 1.26 (t, 6H).
Figure imgf000028_0003
化合物 1-氯-乙基酯异丙基碳酸酯 (3.74 g, 22.4 mmol)溶解在乙腈 （20 ml ) 中， 加入碘化钠（16.8 g, 112.2 mmol), 升温至 50°C反应 6小时左右， 将溶剂旋 干， 固体用乙醚溶解， 过滤掉多余的碘化钠， 滤液旋干， 得 5.2 g棕褐色液体， 产率为 90%。 The compound 1-chloro-ethyl ester isopropyl carbonate (3.74 g, 22.4 mmol) was dissolved in acetonitrile (20 ml), sodium iodide (16.8 g, 112.2 mmol) was added, and the mixture was heated to 50 ° C for 6 hours. , swirling the solvent Dry, solid was dissolved in diethyl ether, excess sodium iodide was filtered off, and the filtrate was evaporated to dryness to give 5.2 g of tan.
1H MR: (400MHz, CDC13), 6.69 (m, IH), 4.87 (m, IH), 2.16 (m, 3H), 1.25 (m: 6H). 1H MR: (400MHz, CDC1 3 ), 6.69 (m, IH), 4.87 (m, IH), 2.16 (m, 3H), 1.25 (m : 6H).
Figure imgf000029_0001
Figure imgf000029_0001
化合物（2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 (284 mg: 0.6 mmol)和 Cs2C03 (391 mg, 1.2 mmol)在乙腈中反应 2.5小时后， 将化合物 1-碘- 乙基异丙基碳酸酯 (464 mg, 1.8 mmol)加入， 反应 3小时后， 补加化合物 1-碘 -乙基 异丙基碳酸酯 (464 mg, 1.8 mmol)和 Cs2C03 (391 mg, 1.2 mmol),反应过夜， 将体系 旋干， 反相柱层析纯化， 得 228 mg产物。 Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (284 mg : 0.6 mmol) and Cs 2 C0 3 After reacting (391 mg, 1.2 mmol) in acetonitrile for 2.5 hours, the compound 1-iodo-ethyl isopropyl carbonate (464 mg, 1.8 mmol) was added. After reacting for 3 hours, compound 1-iodo-B was added. The isopropyl carbonate (464 mg, 1.8 mmol) and Cs 2 C0 3 (391 mg, 1.2 mmol) were reacted overnight. The system was dried and purified by reversed column chromatography to yield 228 mg.
L +, 626 (M+Na) +.  L +, 626 (M+Na) +.
Figure imgf000029_0002
Figure imgf000029_0002
化合物（2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 -1-异丙 氧基碳氧基乙基酯（228 mg)和 Pd/C (0.2 g)溶解在 MeOH中， H2氛围下室温反应 4小时左右， 将 Pd/C用硅藻土过滤掉， 滤液旋干， 反相柱层析纯化得到 125 mg 淡黄色油状物 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸 -1-异丙氧基 碳氧基乙基酯。 Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid-1-isopropoxyoxyethyl The ester (228 mg) and Pd/C (0.2 g) were dissolved in MeOH, and reacted at room temperature for about 4 hours under H 2 atmosphere. The Pd/C was filtered off with celite, and the filtrate was evaporated to dryness. 125 mg light yellow oil (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid-1-isopropoxycarbonyl Ethyl ester.
1H MR: (400 MHz, CDC13), 7.49 (m, 2H), 7.41 (m, 2H), 7.35 (m, 2H), 7.25 (m, IH), 7.13 (m, 2H), 6.66 (m, IH), 4.82 (m, IH), 4.42 (m, IH), 3.20 (m, IH), 2.96 (m, IH), 2.4 (m, 6H), 2.01 (m, IH), 1.69 (m, IH), 1.44 (m, 3H), 1.23 (m, 6H), 1.12 (m, 3H). 1H MR: (400 MHz, CDC1 3 ), 7.49 (m, 2H), 7.41 (m, 2H), 7.35 (m, 2H), 7.25 (m, IH), 7.13 (m, 2H), 6.66 (m, IH), 4.82 (m, IH), 4.42 (m, IH), 3.20 (m, IH), 2.96 (m, IH), 2.4 (m, 6H), 2.01 (m, IH), 1.69 (m, IH) ), 1.44 (m, 3H), 1.23 (m, 6H), 1.12 (m, 3H).
LC-MS: 4.045 min, 518 (M+Na) +. 实施例 12  LC-MS: 4.045 min, 518 (M+Na) +. Example 12
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸 -1-环己氧基碳氧基乙基酉 ί 的制备
Figure imgf000029_0003
c 0 ci Preparation of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid-1-cyclohexyloxycarboethylethyl
Figure imgf000029_0003
c 0 ci
环己醇 （2.6 mL， 25.0 mmol) 加入 25 mL二氯甲垸， 冰水浴冷却； 氯甲酸 1- 氯乙酯 （2.2 mL， 25.0 mmol) 溶于 25 mL二氯甲垸， 缓慢滴加入反应体系中； 吡 啶 （2.2 mL, 27.5 mmol) 稀释于 5 mL二氯甲垸， 再缓慢滴加入反应体系中。 室 温反应过夜。 加入二氯甲垸稀释， 水洗 3次， 无水硫酸钠干燥。 浓缩， 得无色液 体 5.05 g。 Cyclohexanol (2.6 mL, 25.0 mmol) was added to 25 mL of dichloromethane and cooled in an ice water bath; 1-chloroethyl chloroformate (2.2 mL, 25.0 mmol) was dissolved in 25 mL of dichloromethane and slowly added dropwise to the reaction system. Middle; pyridine (2.2 mL, 27.5 mmol) was diluted in 5 mL of dichloromethane and slowly added dropwise to the reaction system. Room Warm reaction overnight. Diluted with dichloromethane, washed 3 times with water and dried over anhydrous sodium sulfate. Concentrated to give a colorless liquid of 5.05 g.
1H MR (400 MHz, CDC13) δ 6.36 (q, J = 5.8 Hz, 1H), 4.71-4.54 (m, 1H), 1.95 - 1.80 (m, 2H), 1.76 (d, J = 5.8 Hz, 3H), 1.74 - 1.65 (m, 2H), 1.54-1.37 (m, 3H), 1.37- 1.23 (m, 3H).
Figure imgf000030_0001
1H MR (400 MHz, CDC13) δ 6.36 (q, J = 5.8 Hz, 1H), 4.71-4.54 (m, 1H), 1.95 - 1.80 (m, 2H), 1.76 (d, J = 5.8 Hz, 3H) , 1.74 - 1.65 (m, 2H), 1.54-1.37 (m, 3H), 1.37- 1.23 (m, 3H).
Figure imgf000030_0001
碘化钠 （7495 mg， 50.0 mmol ) 溶于 50 mL乙腈， 碳酸 1-氯-乙基酯环己基醒 (2067 mg, 10.0 mmol) 溶于 5 mL乙腈， 再加入反应体系中， 50 oC反应过夜。 冷却至室温， 过滤， 浓缩， 所得粗产品中加入乙醚溶解， 再次过滤， 浓缩， 得黄 色油状物 （1920 mg， 64%) 。  Sodium iodide (7495 mg, 50.0 mmol) dissolved in 50 mL of acetonitrile, 1-chloro-ethyl carbonate cyclohexyl ketone (2067 mg, 10.0 mmol) dissolved in 5 mL of acetonitrile, added to the reaction system, reacted at 50 °C overnight . The mixture was cooled to room temperature, filtered and evaporated.
1H雇 R (400 MHz, CDC13), δ 6.697 (d, 1H), 4.623 (m, 1H), 2.171 (d, 3H), 1.874 (m, 2  1H employment R (400 MHz, CDC13), δ 6.697 (d, 1H), 4.623 (m, 1H), 2.171 (d, 3H), 1.874 (m, 2
Figure imgf000030_0002
Figure imgf000030_0002
化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 (300 mg, 0.63 mmol)和 Cs2C03 (103 mg, 0.32 mmol)在乙腈中反应 5 min后， 将 1-碘-乙基酯 环己基碳酸酯 (378 mg, 1.27 mmol)加入， 反应 3h后， 补加化合物 1-碘 -乙基酯环己 基碳酸酯 (378 mg, 1.27 mmol)和 Cs2C03 (103 mg, 0.32 mmol),反应过夜， 继续补加 Cs2C03 (103 mg, 0.32 mmol)和 1-碘-乙基酯环己基碳酸酯 (378 mg, 1.27 mmol), 反 应 3 h后结束， 将乙腈旋干， 反相柱层析纯化， 得 337 mg淡黄色油状物， 产率为 83%。 Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (300 mg, 0.63 mmol) and Cs 2 C0 3 (103 mg, 0.32 mmol) After reacting for 5 min in acetonitrile, 1-iodo-ethyl ester cyclohexyl carbonate (378 mg, 1.27 mmol) was added. After 3 h, the compound 1-iodo-ethyl ester was added. Cyclohexyl carbonate (378 mg, 1.27 mmol) and Cs 2 C0 3 (103 mg, 0.32 mmol), reacted overnight, and continued to add Cs 2 C0 3 (103 mg, 0.32 mmol) and 1-iodo-ethyl ester ring The hexyl carbonate (378 mg, 1.27 mmol) was quenched after 3 h.
LC +, 666 (M+Na) +.  LC +, 666 (M+Na) +.
Figure imgf000030_0003
Figure imgf000030_0003
化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 -1-环己 氧基碳氧基乙基酯 (337 mg, 0.52 mmol)和 Pd/C (0.3 g)溶解在 MeOH中， ¾氛围 下室温反应 4小时左右， 将 Pd/C用硅藻土过滤掉， 滤液旋干， 反相柱层析纯化得 到 202 mg淡黄色油状物 (2R,4S)-5-联苯基 -4-基 -4-P-羧基 -丙酰氨基) -2-甲基戊酸 -1- 环己氧基碳氧基乙基酯， 产率为 70%。  Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid-1-cyclohexyloxycarboethyl The ester (337 mg, 0.52 mmol) and Pd/C (0.3 g) were dissolved in MeOH, and reacted at room temperature for 4 hours at room temperature. Pd/C was filtered off with celite, and the filtrate was evaporated to dryness. Purification afforded 202 mg of pale yellow oil (2R,4S)-5-biphenyl-4-yl-4-P-carboxy-propionylamino)-2-methylpentanoic acid-1-cyclohexyloxycarbohydroxide Base ethyl ester, yield 70%.
1H MR: (400 MHz, CDC13), 7.477 (m, 2H), 7.421 (m, 2H), 7.325 (m, 2H), 7.23 (m, 1H), 7.144 (d, 2H), 6.668 (q, 0.5H), 6.499 (q, 0.5H), 6.439 (d, 0.5H), 5.978 (d, 0.5H), 4.536 (m, 1H), 4.208 (m, 1H), 2.523 (m, 7H), 1.732 (m, 6H), 1.411 (m, 6H), 1.209 (m, 3H), 1.059 (dd, 3H). 1H MR: (400 MHz, CDC1 3 ), 7.477 (m, 2H), 7.421 (m, 2H), 7.325 (m, 2H), 7.23 (m, 1H), 7.144 (d, 2H), 6.668 (q, 0.5H), 6.499 (q, 0.5H), 6.439 (d, 0.5H), 5.978 (d, 0.5H), 4.536 (m, 1H), 4.208 (m, 1H), 2.523 (m, 7H), 1.732 (m, 6H), 1.411 (m, 6H), 1.209 (m, 3H), 1.059 (dd, 3H).
LC-MS: 5.880 min, 554 (M+H)+, 576 (M+Na)+. 实施例 13  LC-MS: 5.880 min, 554 (M+H)+, 576 (M+Na)+. Example 13
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基戊酸 -1-乙氧基碳氧基乙基酯的 制备
Figure imgf000031_0001
〇 Preparation of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid-1-ethoxycarboxyethyl ester
Figure imgf000031_0001
〇
碘化钠 （7495 mg， 50.0 mmol) 溶于 50 mL乙腈， 1-氯-乙基乙基碳酸酯 （1.3 mL， 10.0 mmol) 溶于 5 mL乙腈， 再加入反应体系中， 60 °C反应过夜。 冷却至 室温， 过滤， 浓缩， 所得粗产品中加入乙醚溶解， 再次过滤， 浓缩， 得黄色油状 物 （970 mg， 40%) 。  Sodium iodide (7495 mg, 50.0 mmol) dissolved in 50 mL of acetonitrile, 1-chloro-ethylethyl carbonate (1.3 mL, 10.0 mmol) dissolved in 5 mL of acetonitrile, then added to the reaction system and reacted at 60 ° C overnight. . After cooling to room temperature, EtOAc (EtOAc):EtOAc:
1H MR (400 MHz, CDC13) δ 6.70 (q, J = 6.0 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.18 ( Hz, 3H).  1H MR (400 MHz, CDC13) δ 6.70 (q, J = 6.0 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.18 (Hz, 3H).
Figure imgf000031_0002
Figure imgf000031_0002
化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 (331 mg, 0.7 mmol)和 Cs2C03 (111 mg, 0.35 mmol)在乙腈中反应 5分钟后， 将 1-碘-乙基酯 乙基碳酸酯（341 mg, 1.4 mmol)加入， 反应 3小时后， 补加 1-碘-乙基酯乙基碳酸 酯 （341 mg, 1.4 mmol)禾 P Cs2C03 (111 mg, 0.35 mmol), 反应过夜， 继续补加 Cs2C03 (111 mg, 0.35 mmol)和 1-碘 -乙基酯乙基碳酸酯（341 mg, 1.4 mmol), 反应 3小时后结束， 将乙腈旋干， 反相柱层析纯化， 得 287 mg淡黄色油状物， 产率为 70%。 Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (331 mg, 0.7 mmol) and Cs 2 C0 3 After reacting (111 mg, 0.35 mmol) in acetonitrile for 5 minutes, 1-iodo-ethyl ester ethyl carbonate (341 mg, 1.4 mmol) was added, and after reacting for 3 hours, 1-iodo-ethyl ester was added. Ethyl carbonate (341 mg, 1.4 mmol) and P Cs 2 C0 3 (111 mg, 0.35 mmol), react overnight, continue to add Cs 2 C0 3 (111 mg, 0.35 mmol) and 1-iodo-ethyl ester Ethyl carbonate (341 mg, 1.4 mmol), mp mp EtOAc (EtOAc)
+, +Na)+. +, +Na) + .
Figure imgf000031_0003
Figure imgf000031_0003
化合物 (2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 -1-乙氧 基碳氧基乙基酯 (287 mg, 0.49 mmol)和 Pd/C (0.2 g)溶解在 MeOH中， ¾氛围下 室温反应 4 h左右， 将 Pd/C用硅藻土过滤掉， 滤液旋干， 直接过反相柱 （40%- 60%) 得到 216 mg淡黄色油状物 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲 基戊酸 -1-乙氧基碳氧基乙基酯， 产率为 88%。 1H MR: (400 MHz, CDC13), 7.430 (m, 4H), 7.316 (q, 2H), 7.228 (q, IH), 7.132 (d, 2H), 6.654 (q, 0.5H), 6.547 (s, 0.5H), 6.483 (q, 0.5H), 6.342 (s, 0.5H), 4.1 17 (m, 3H), 2.755 (m, IH), 2.631 (m, IH), 2.418 (m, 5H), 1.804 (m, IH), 1.618 (m, 0.5H), 1.389 (m: 3.5H), 1.170 (m, 3H), 1.041 (dd, 3H). Compound (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid-1-ethoxycarboxyethyl ester (287 mg, 0.49 mmol) and Pd/C (0.2 g) were dissolved in MeOH, and reacted at room temperature for 4 h at room temperature. Pd/C was filtered off with celite, and the filtrate was dried and passed through a reversed phase column. 40% - 60%) 216 mg of pale yellow oil (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methylpentanoic acid-1- Ethoxymethoxyethyl ester, yield 88%. 1H MR: (400 MHz, CDC1 3 ), 7.430 (m, 4H), 7.316 (q, 2H), 7.228 (q, IH), 7.132 (d, 2H), 6.654 (q, 0.5H), 6.547 (s , 0.5H), 6.483 (q, 0.5H), 6.342 (s, 0.5H), 4.1 17 (m, 3H), 2.755 (m, IH), 2.631 (m, IH), 2.418 (m, 5H), 1.804 (m, IH), 1.618 (m, 0.5H), 1.389 (m : 3.5H), 1.170 (m, 3H), 1.041 (dd, 3H).
LC-MS: 3.552 min, 500 (M+H) +, 522 (M+Na) +. 实施例 14  LC-MS: 3.552 min, 500 (M+H) +, 522 (M+Na) +. Example 14
(2R,4S)-5-联苯基 -4-基 -4-p-羧基-丙酰氨基;) -2-甲基 -戊酸 -1-异丙氧基碳氧基 -1-甲 基-乙基酯的制备
Figure imgf000032_0001
(2R,4S)-5-biphenyl-4-yl-4-p-carboxy-propionylamino;)-2-methyl-pentanoic acid-1-isopropoxycarbonyl-1-methyl -Preparation of ethyl ester
Figure imgf000032_0001
氯甲酸 -2-丙烯酯（2.0, 16.6 mmol)溶于 20 mL的干燥 CH2C12中， 依次加入异 丙醇（1.0 g, 16.6 mmol)和吡啶（1.4g, 17.7 mmol), 室温反应 2小时。 将体系倒入2-propenyl chloroformate (2.0, 16.6 mmol) was dissolved in 20 mL of dry CH 2 C1 2 , then isopropanol (1.0 g, 16.6 mmol) and pyridine (1.4 g, 17.7 mmol) were added, and the reaction was carried out at room temperature 2 hour. Pour the system
20 mL冰水中， 有机相经硫酸钠干燥， 过滤， 滤液蒸干得无色透明状液体。 向该 液体中加入 10 mL乙醚， 然后缓慢滴加 4 N盐酸 /乙醚 50 mL, 加完后室温搅拌过 夜， 蒸出得无色液体 （0.7 g, 23%)。 In 20 mL of ice water, the organic phase was dried over sodium sulfate, filtered, and evaporated to dryness. To the liquid, 10 mL of diethyl ether was added, and then 50 mL of 4 N hydrochloric acid / diethyl ether was slowly added dropwise, and the mixture was stirred at room temperature overnight, and evaporated to give a colorless liquid (0.7 g, 23%).
¾ MR (400 MHz, CDC13) δ 4.84 (hept, J = 6.3 Hz, IH), 1.96 (s, 6H), 1.25 (d, J 3⁄4 MR (400 MHz, CDC1 3 ) δ 4.84 (hept, J = 6.3 Hz, IH), 1.96 (s, 6H), 1.25 (d, J
Figure imgf000032_0002
Figure imgf000032_0002
(2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 （1289 mg， 2.72 mmol ) 溶于 10 mL干燥 CH2C12中， 再依次加入 4A分子筛 （ 1 g) 和 Ag2C03 ( 375 mg， 1.36 mmol ) ， 室温搅拌过夜。 1-氯 -1-甲基-乙基酯异丙基碳酸酯 ( 590 mg， 3.27 mmol ) 溶于 2 mL CH2C12， 再滴加入反应体系中， 室温反应 30小时。 过滤， 浓缩。 粗产品经柱层析分离， 得无色粘稠液体 （421 mg， 25%) 。 (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (1289 mg, 2.72 mmol) dissolved in 10 mL dry CH In 2 C1 2 , 4A molecular sieves (1 g) and Ag 2 C0 3 (375 mg, 1.36 mmol) were added in this order, and stirred at room temperature overnight. 1-Chloro-1-methyl-ethyl ester isopropyl carbonate (590 mg, 3.27 mmol) was dissolved in 2 mL of CH 2 C1 2 , then added dropwise to the reaction mixture and allowed to react at room temperature for 30 hours. Filter and concentrate. The crude product was separated by column chromatography to give a colourless viscous liquid (421 mg, 25%).
1H MR (400 MHz, CDCI3) δ 7.53-7.47 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 (t, = 7.5 Hz, 2H), 7.31-7.21 (m, 6H), 7.17 (d, = 8.2 Hz, 2H), 5.82 (d, = 8.6 Hz, IH), 5.04 (s, 2H), 4.80-4.70 (m, IH), 4.17-4.04 (m, IH), 2.83 (dd, = 13.7, 6.6 Hz, IH), 2.73 (dd, = 13.7, 6.6 Hz, IH), 2.62-2.56 (m, 2H), 2.52-2.44 (m, IH), 2.39-2.32 (m, 2H), 1.86-1.71 (m, 7H), 1.69-1.59 (m, IH), 1.20 (d, = 6.3 Hz, 6H), 1.08 (d, = 7.1 Hz, 3H).  1H MR (400 MHz, CDCI3) δ 7.53-7.47 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.35 (t, = 7.5 Hz, 2H), 7.31-7.21 (m, 6H), 7.17 (d, = 8.2 Hz, 2H), 5.82 (d, = 8.6 Hz, IH), 5.04 (s, 2H), 4.80-4.70 (m, IH), 4.17-4.04 (m, IH), 2.83 (dd , = 13.7, 6.6 Hz, IH), 2.73 (dd, = 13.7, 6.6 Hz, IH), 2.62-2.56 (m, 2H), 2.52-2.44 (m, IH), 2.39-2.32 (m, 2H), 1.86-1.71 (m, 7H), 1.69-1.59 (m, IH), 1.20 (d, = 6.3 Hz, 6H), 1.08 (d, = 7.1 Hz, 3H).
LC-MS : tR = 4.87 min, [M+Na]+ = 640.2. LC-MS : t R = 4.87 min, [M+Na] + = 640.2.
Figure imgf000032_0003
(2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基 -戊酸 1-异丙氧基碳 氧基 -1-甲基-乙基酯 （330 mg， 0.53 mmol) 溶于 10 mL四氢呋喃， 加入 Pd/C
Figure imgf000032_0003
(2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methyl-pentanoic acid 1-isopropoxycarbonyl-1- Methyl-ethyl ester (330 mg, 0.53 mmol) dissolved in 10 mL of tetrahydrofuran, added to Pd/C
(400 mg) ， 常温常压氢化 3小时。 反应完全后过滤， 浓缩。 粗产品经反相柱层 析分离， 得无色糖浆状粘稠液体 （208 mg， 74%) 。 (400 mg), hydrogenation at room temperature and atmospheric pressure for 3 hours. After the reaction was completed, it was filtered and concentrated. The crude product was separated by a reversed-phase column to give a colorless syrupy viscous liquid (208 mg, 74%).
1H MR (400 MHz, CDC13) δ 7.50 (d, J = 7.4 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.35 (t, J =1.5 Hz, 2H), 7.25 (t, = 7.3 Hz, 1H), 7.16 (d, = 7.9 Hz, 2H), 6.13 (d, = 8.5 Hz, 1H), 4.75 (dt, = 12.4, 6.2 Hz, 1H), 4.17-4.07 (m, 1H), 2.85 (dd, = 13.6, 6.7 Hz, 1H), 2.74 (dd, = 13.7, 6.5 Hz, 1H), 2.65-2.44 (m, 3H), 2.36 (t, = 6.2 Hz, 2H), 1.94-1.61 (m, 8H), 1.21 (d, = 6.2 Hz, 6H), 1.08 (d, =7.0Hz, 3H). 1H MR (400 MHz, CDC1 3 ) δ 7.50 (d, J = 7.4 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 1.5 Hz, 2H), 7.25 (t, = 7.3 Hz, 1H), 7.16 (d, = 7.9 Hz, 2H), 6.13 (d, = 8.5 Hz, 1H), 4.75 (dt, = 12.4, 6.2 Hz, 1H), 4.17-4.07 (m, 1H) , 2.85 (dd, = 13.6, 6.7 Hz, 1H), 2.74 (dd, = 13.7, 6.5 Hz, 1H), 2.65-2.44 (m, 3H), 2.36 (t, = 6.2 Hz, 2H), 1.94-1.61 (m, 8H), 1.21 (d, = 6.2 Hz, 6H), 1.08 (d, =7.0Hz, 3H).
LC-MS: tR= 4.38 min, [M+Na]+= 550.2. 实施例 15 LC-MS:. T R = 4.38 min, [M + Na] + = 550.2 Example 15
(2R,4S)-5-联苯基 -4-基 -4-p-羧基 -丙酰氨基) -2-甲基 -戊酸 -1-异丙氧基碳氧基新戊  (2R,4S)-5-biphenyl-4-yl-4-p-carboxy-propionylamino)-2-methyl-pentanoic acid-1-isopropoxycarbonyl neopentyl
Figure imgf000033_0001
Figure imgf000033_0001
(2R,4S)-4-(3-苄氧基羰基 -丙酰氨基) -5-联苯基 -4-基 -2-甲基戊酸 （1421 mg， 3.0 mmol) 、 新戊二醇 （625 mg, 6.0 mmol) 、 EDCI (690 mg, 3.6 mmol) 以及 DMAP (73 mg, 0.6 mmol) ， 溶于 20 mL二氯甲垸， 室温反应 24小时。 饱和食 盐水洗涤， 二氯甲垸萃取， 无水 Na2S04干燥。 柱层析分离， 得 (2R,4S)-5-联苯基- 4-基 -4-P-羧基-丙酰氨基；) -2-甲基-戊酸新戊二醇基单酯 （1.37g， 82%) 。 (2R,4S)-4-(3-Benzyloxycarbonyl-propionylamino)-5-biphenyl-4-yl-2-methylpentanoic acid (1421 mg, 3.0 mmol), neopentyl glycol ( 625 mg, 6.0 mmol), EDCI (690 mg, 3.6 mmol) and DMAP (73 mg, 0.6 mmol), dissolved in 20 mL of dichloromethane, and allowed to react at room temperature for 24 hours. It was washed with saturated brine, extracted with dichloromethane, dried over anhydrous Na 2 SO 4 . Separation by column chromatography gave (2R,4S)-5-biphenyl-4-yl-4-P-carboxy-propionylamino;)-2-methyl-pentanoic acid neopentyl glycol monoester (1.37 g, 82%).
L 十 = 560.2.
Figure imgf000033_0002
L ten = 560.2.
Figure imgf000033_0002
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基) -2-甲基 -戊酸新戊二醇基酯 （ 1315 mg, 2.35 mmol) 溶于 10 mL 干燥二氯甲垸， 再加入吡啶 （0.21 mL, 2.58 mmol) ， 冰水浴冷却下滴加氯甲酸异丙酯 /甲苯溶液 （ 2.6 mL， 1M， 2.58 mmol) ， 反应过夜。 饱和食盐水洗涤， 二氯甲垸萃取， 无水 Na2S04干燥。 柱层 析分离， 得无色糖浆 （1.18 g， 78%) 。 (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid neopentyl glycol ester (1315 mg, 2.35 mmol) 10 mL of dry dichloromethane was added, and pyridine (0.21 mL, 2.58 mmol) was added, and isopropyl chloroformate/toluene solution (2.6 mL, 1M, 2.58 mmol) was added dropwise under ice-cooling, and allowed to react overnight. It was washed with saturated brine, extracted with dichloromethane, dried over anhydrous Na 2 SO 4 . Column chromatography separated to give a colorless syrup (1.18 g, 78%).
LC-MS: tR = 4.93 min; [M +H]+ = 646.3. LC-MS: t R = 4.93 min; [M + H] + = 646.3.
Figure imgf000033_0003
将上一步反应得到的糖浆样产物 （1180 mg， 1.83 mmol ) 溶于 THF ( 15 mL) ， 再加入 Pd/C ( 1.2 g， 10%) ， 常温常压氢化过夜。 过滤， THF反复洗涤 滤饼。 滤液浓缩， 反相柱层析分离， 得无色糖浆 （618 mg， 61%) 。
Figure imgf000033_0003
The syrup-like product obtained by the reaction of the previous step (1180 mg, 1.83 mmol) was dissolved in THF (15 mL), then Pd/C (1.2 g, 10%) was added and hydrogenated at room temperature and atmospheric pressure overnight. Filter and wash the filter cake repeatedly with THF. The filtrate was concentrated and separated by reverse phase column chromatography to give colorless syrup (618 mg, 61%).
1H MR (400 MHz, CDC13) δ 7.50 (d, J = 7.3 Hz, 2H), 7.45 (d, = 8.1 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.16 (d, = 8.1 Hz, 2H), 5.72 (d, J = 8.7 Hz, 1H), 4.76 (dt, = 12.4, 6.2 Hz, 1H), 4.26-4.08 (m, 1H), 3.97-3.73 (m, 4H), 2.91- 2.70 (m, 2H), 2.70-2.46 (m, 3H), 2.44-2.25 (m, 2H), 1.92-1.81 (m, 1H), 1.53 (ddd, J = 14.2, 10.5, 3.8 Hz, 1H), 1.21 (d, = 6.2 Hz, 6H), 1.11 (d, = 7.1 Hz, 3H), 0.91 (s, 6H). 1H MR (400 MHz, CDC1 3 ) δ 7.50 (d, J = 7.3 Hz, 2H), 7.45 (d, = 8.1 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.16 (d, = 8.1 Hz, 2H), 5.72 (d, J = 8.7 Hz, 1H), 4.76 (dt, = 12.4, 6.2 Hz, 1H), 4.26-4.08 (m, 1H) ), 3.97-3.73 (m, 4H), 2.91- 2.70 (m, 2H), 2.70-2.46 (m, 3H), 2.44-2.25 (m, 2H), 1.92-1.81 (m, 1H), 1.53 (ddd , J = 14.2, 10.5, 3.8 Hz, 1H), 1.21 (d, = 6.2 Hz, 6H), 1.11 (d, = 7.1 Hz, 3H), 0.91 (s, 6H).
LC-MS: tR = 4.43 min; [M+H]+ = 556.3. 实施例 16 LC-MS: t R = 4.43 min; [M + H] + = 556.3 Example 16.
N-((1 S,3R)-1 胺酸的制备  Preparation of N-((1 S,3R)-1 Amino Acid
Figure imgf000034_0001
Figure imgf000034_0001
(2R,4S)-5-联苯基 -4-基 -4-叔丁氧基羰基氨基 -2-甲基戊酸 （1150 mg， 3.0 mmol ) ， 乙硫醇 （0.33 mL, 4.5 mmol ) ， 溶于干燥 CH2C12 ( 10 mL) ， 再依次 加入 EDCI ( 863 mg， 4.5 mmol ) 禾 P DMAP ( 37 mg， 0.3 mmol ) ， 室温反应过 夜。 加入饱和食盐水洗涤， CH2C12萃取。 合并有机相， 无水 Na2S04干燥。 过 滤， 浓缩， 粗品经柱层析分离， 得化合物 (2R,4S)-5-联苯基 -4-基 -4-叔 -丁氧基羰基 氨基 -2-甲基-戊硫酸 S-乙基酯 （950 mg， 74%) 。 (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1150 mg, 3.0 mmol), ethanethiol (0.33 mL, 4.5 mmol) Dissolve in dry CH 2 C1 2 (10 mL), then add EDCI ( 863 mg, 4.5 mmol) and P DMAP (37 mg, 0.3 mmol), and react overnight at room temperature. It was washed with saturated brine and extracted with CH 2 C1 2 . The organic phases were combined and dried over anhydrous Na 2 SO 4 . Filtration, concentration, and crude product were purified by column chromatography to give compound (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentyl sulfate S-ethyl Ester (950 mg, 74%).
LC-MS: t + = 328.1. LC-MS: t + = 328.1.
Figure imgf000034_0002
Figure imgf000034_0002
(2R,4S)-5-联苯基 -4-基 -4-叔-丁氧基羰基氨基 -2-甲基-戊硫酸 S-乙基酯 （950 mg， 2.22 mmol ) 溶于 CH2C12 ( 10 mL) ， 再加入 TFA (4 mL) ， 室温反应 1小 时。 浓缩， 干燥， 得粗产品。 上述粗品溶于 20 mL 乙腈， 再依次加入丁二酸酐 (2100 mg, 21.0 mmol ) 以及 K2C03 (290 mg, 2.1 mmol ) ， 室温反应过夜。 反 应液浓缩后， 直接反相柱层析分离， 得糖浆状化合物 （335 mg， 37%) 。 (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentyl sulfate S-ethyl ester (950 mg, 2.22 mmol) dissolved in CH 2 C1 2 (10 mL), add TFA (4 mL), and react at room temperature for 1 hour. Concentrate, dry, and obtain a crude product. The above crude product was dissolved in 20 mL of acetonitrile, and then succinic anhydride (2100 mg, 21.0 mmol) and K 2 C0 3 (290 mg, 2.1 mmol) were added, and allowed to react overnight at room temperature. After concentrating the reaction mixture, it was directly separated by reverse phase column chromatography to give a syrupy compound (335 mg, 37%).
1H NMR (400 MHz, CDCI3) δ 7.56-7.47 (m, 2Η), 7.45 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 1.6 Hz, 2H), 7.26 (ddd, = 7.4, 3.9, 1.2 Hz, 1H), 7.14 (d, = 8.2 Hz, 2H), 5.66 (d, J = 8.6 Hz, 1H), 4.20-4.03 (m, 1H), 2.84-2.74 (m, 4H), 2.72-2.64 (m, 1H), 2.61-2.52 (m, 2H), 2.34 (t, = 6.5 Hz, 2H), 1.91 (ddd, = 13.9, 9.1, 4.5 Hz, 1H), 1.51 (ddd, = 14.2, 9.5, 4.5 Hz, 1H), 1.16 (t, = 7.4 Hz, 3H), 1.11 (d, = 7.0 Hz, 3H).  1H NMR (400 MHz, CDCI3) δ 7.56-7.47 (m, 2 Η), 7.45 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 1.6 Hz, 2H), 7.26 (ddd, = 7.4, 3.9 , 1.2 Hz, 1H), 7.14 (d, = 8.2 Hz, 2H), 5.66 (d, J = 8.6 Hz, 1H), 4.20-4.03 (m, 1H), 2.84-2.74 (m, 4H), 2.72- 2.64 (m, 1H), 2.61-2.52 (m, 2H), 2.34 (t, = 6.5 Hz, 2H), 1.91 (ddd, = 13.9, 9.1, 4.5 Hz, 1H), 1.51 (ddd, = 14.2, 9.5 , 4.5 Hz, 1H), 1.16 (t, = 7.4 Hz, 3H), 1.11 (d, = 7.0 Hz, 3H).
LC-MS: tR = 4.19 min; [M-Boc+H]+= 428.2. 实施例 17 LC-MS: t R = 4.19 min; [M-Boc + H] + = 428.2. Example 17
N-((1S,3R)-1 胺酸的制备  Preparation of N-((1S,3R)-1 Amino Acid
Figure imgf000035_0001
Figure imgf000035_0001
(2R,4S)-5-联苯基 -4-基 -4-叔丁氧基羰基氨基 -2-甲基戊酸 （1917 mg， 5.0 mmol) ， 甲硫醇钠 （701 mg， 10.0 mmol) ， EDCI (2400 mg， 12.5 mmol) 以及 DMAP (61 mg， 0.5 mmol) 溶于干燥 CH2C12 (20 mL) 和 DMF ( 5 mL) ， 室温 反应一天。 加入饱和食盐水洗涤， CH2C12萃取。 合并有机相， 无水 Na2S04干 燥。 过滤， 浓缩， 粗品经柱层析分离， 得无色粘稠液体 （900 mg， 44%) 。 (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1917 mg, 5.0 mmol), sodium thiomethoxide (701 mg, 10.0 mmol) EDCI (2400 mg, 12.5 mmol) and DMAP (61 mg, 0.5 mmol) were dissolved in dry CH 2 C1 2 (20 mL) and DMF (5 mL). It was washed with saturated brine and extracted with CH 2 C1 2 . The organic phases were combined and dried over anhydrous Na 2 SO 4 . Filtration, concentration, and crude material were purified by column chromatography to afford coloured viscous liquid (900 mg, 44%).
LC-MS: tR + = 314.1. LC-MS: t R + = 314.1.
Figure imgf000035_0002
Figure imgf000035_0002
(2R,4S)-5-联苯基 -4-基 -4-叔-丁氧基羰基氨基 -2-甲基-戊硫酸 S-甲基酯 （900 mg， 2.18 mmol) 溶于 CH2C12 ( 5 mL) ， 再加入 TFA (2 mL) ， 室温反应 1小 时。 浓缩， 干燥， 得粗产品， 取上述粗品溶于 20 mL乙腈， 再依次加入丁二酸酐 ( 1900 mg, 19.0 mmol) 以及 K2C03 (263 mg, 1.9 mmol) ， 室温反应过夜。 反 应液浓缩后， 直接反相柱层析分离， 得糖浆状化合物 （313 mg， 40%) 。 (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentyl sulfate S-methyl ester (900 mg, 2.18 mmol) dissolved in CH 2 C1 2 (5 mL), add TFA (2 mL), and react at room temperature for 1 hour. Concentrated, dried to give a crude product. The crude material was dissolved in 20 mL of acetonitrile, then succinic anhydride ( 1900 mg, 19.0 mmol) and K 2 C0 3 (263 mg, 1.9 mmol) were added and allowed to react overnight at room temperature. After concentrating the reaction mixture, it was directly separated by reverse phase column chromatography to give a syrupy compound (313 mg, 40%).
1H MR (400 MHz, CDC13) δ 7.65-7.56 (m, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.38-7.31 (m, 1H), 7.22 (d, J = 8.2 Hz, 2H), 5.69 (d, J = 8.5 Hz, 1H), 4.28-4.10 (m, 1H), 2.85 (d, = 6.3 Hz, 2H), 2.83-2.75 (m, 1H), 2.71-2.59 (m, 2H), 2.43 (t, = 6.4 Hz, 2H), 2.29 (s, 3H), 2.01 (ddd, = 13.9, 9.2, 4.4 Hz, 1H), 1.62 (ddd, = 14.2, 9.7, 4.4 Hz, 1H), 1.20 (d, = 7.0 Hz, 3H). 1H MR (400 MHz, CDC1 3 ) δ 7.65-7.56 (m, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.38-7.31 (m, 1H) ), 7.22 (d, J = 8.2 Hz, 2H), 5.69 (d, J = 8.5 Hz, 1H), 4.28-4.10 (m, 1H), 2.85 (d, = 6.3 Hz, 2H), 2.83-2.75 ( m, 1H), 2.71-2.59 (m, 2H), 2.43 (t, = 6.4 Hz, 2H), 2.29 (s, 3H), 2.01 (ddd, = 13.9, 9.2, 4.4 Hz, 1H), 1.62 (ddd , = 14.2, 9.7, 4.4 Hz, 1H), 1.20 (d, = 7.0 Hz, 3H).
LC-MS: tR = 4.04 min; [M-Boc+H]+ = 414.1. 实施例 18 LC-MS: t R = 4.04 min; [M-Boc + H] + = 414.1 Example 18.
N-((1S,3 酸的制备  Preparation of N-((1S,3 acid)
Figure imgf000035_0003
Figure imgf000035_0003
(2R,4S)-5-联苯基 -4-基 -4-叔丁氧基羰基氨基 -2-甲基戊酸 （1917 mg， 5.0 mmol) ， 异丙硫醇 （0.7 mL， 7.5 mmol) ， 溶于干燥 CH2C12 (20 mL) ， 再依次 加入 EDCI ( 1150 mg， 6.0 mmol ) 禾口 DMAP ( 61 mg， 0.5 mmol ) ， 室温反应过 夜。 加入饱和食盐水洗涤， CH2C12萃取。 合并有机相， 无水 Na2S04干燥。 过 滤， 浓缩， 粗品经柱层析分离， 得化无色粘稠液体 （1780 mg， 80%) 。 (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1917 mg, 5.0 mmol), isopropylthiol (0.7 mL, 7.5 mmol) , dissolved in dry CH 2 C1 2 (20 mL), and then EDCI (1150 mg, 6.0 mmol) and DMAP (61 mg, 0.5 mmol) were added and allowed to react at room temperature overnight. It was washed with saturated brine and extracted with CH 2 C1 2 . The organic phases were combined and dried over anhydrous Na 2 SO 4 . Filtration, concentration, and crude material were separated by column chromatography to give a colorless viscous liquid (1780 mg, 80%).
十 = 342.1.  Ten = 342.1.
Figure imgf000036_0001
Figure imgf000036_0001
步得到的无色粘稠液体 （1460 mg， 3.31 mmol ) 溶于 CH2C12 ( 10 mL) ， 再加入 TFA ( 5 mL) ， 室温反应 3小时。 浓缩， 干燥， 得粗产品。 上述 粗品溶于 20 mL乙腈， 再依次加入丁二酸酐 （3312 mg， 33.1 mmol ) 以及 K2C03 (457 mg， 3.31 mmol ) ， 室温反应过夜。 反应液浓缩后， 直接反相柱层析分离， 得白色固体 （845 mg， 58%) 。 The obtained colorless viscous liquid (1460 mg, 3.31 mmol) was dissolved in CH 2 C1 2 (10 mL), then TFA (5 mL) was added and reacted at room temperature for 3 hours. Concentrate, dry, and obtain a crude product. The above crude product was dissolved in 20 mL of acetonitrile, then succinic anhydride (3312 mg, 33.1 mmol) and K 2 C0 3 (457 mg, 3.31 mmol). After concentrating the reaction mixture, it was purified by reversed column chromatography to afford white solid ( 845 mg, 58%).
1H MR (400 MHz, CDC13) δ 7.54-7.48 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 1.1 Hz, 2H), 7.26 (t, = 7.3 Hz, 1H), 7.15 (d, = 8.1 Hz, 2H), 5.58 (d, = 8.6 Hz, 1H), 4.18-4.06 (m, 1H), 3.63-3.48 (m, 1H), 2.79 (d, = 6.3 Hz, 2H), 2.72-2.62 (m, 1H), 2.62-2.52 (m, 2H), 2.43-2.31 (m, 2H), 1.91 (ddd, = 13.9, 9.1, 4.5 Hz, 1H), 1.61-1.48 (m, 1H), 1.23 (t, = 6.8 Hz, 6H), 1.11 (d, = 7.0 Hz, 3H). 1H MR (400 MHz, CDC1 3 ) δ 7.54-7.48 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 1.1 Hz, 2H), 7.26 (t, = 7.3 Hz) , 1H), 7.15 (d, = 8.1 Hz, 2H), 5.58 (d, = 8.6 Hz, 1H), 4.18-4.06 (m, 1H), 3.63-3.48 (m, 1H), 2.79 (d, = 6.3 Hz, 2H), 2.72-2.62 (m, 1H), 2.62-2.52 (m, 2H), 2.43-2.31 (m, 2H), 1.91 (ddd, = 13.9, 9.1, 4.5 Hz, 1H), 1.61-1.48 (m, 1H), 1.23 (t, = 6.8 Hz, 6H), 1.11 (d, = 7.0 Hz, 3H).
LC-MS: tR = 4.32 min; [M+H]+ = 442.1. 生物学实验例 1、 EP酶抑制测试 LC-MS: t R = 4.32 min; [M+H]+ = 442.1. Biological Experiment 1, EP Enzyme Inhibition Test
下面的体外试验可用来测定本发明化合物对于大鼠血浆中 EP酶的抑制活 性， 其活性可用 IC5Q值来表示。 化合物的半数抑制浓度 IC5Q(将一定浓度的酶活性 抑制至 50%时所需的化合物浓度；)是通过将一定量的酶与特定的底物及不同浓度的待 测化合物混合反应后测定计算出的。 本实验所用的 NEP酶体系是取自正常 SD大鼠 的新鲜血液， 置于含肝素钠抗凝剂的管中， 5000rpm， 4°C离心 lOmin后， 收集血 浆； 配制不同浓度的 EP抑制剂， 其中， EP抑制剂的最高终浓度为 100 μΜ,并 以 3倍梯度依次稀释 10次； 每孔加 60 μΐ新鲜的大鼠血浆于 384孔板； 随后， 每 孔再加入 10 μΐ梯度稀释的 ΕΡ抑制剂； 37°C， 孵育 30min后， 每孔加入 10 μΐ ΙΟμΜ的底物 （SenoLyte 520 Neprilysin Activity Assay Kit, AnaSpec, 72223 ) ； 在 37°C孵育 18h(±lh);在激发光 490nm和发射光 520nm的波长下， 测定荧光信号； 并采用 Prism 5.0软件求得 IC50。 The following in vitro assays can be used to determine the inhibitory activity of the compounds of the invention against EP enzymes in rat plasma, the activity of which can be expressed as IC 5Q values. The half-inhibitory concentration of the compound IC 5Q (the concentration of the compound required to inhibit a certain concentration of the enzyme activity to 50%) is determined by mixing a certain amount of the enzyme with a specific substrate and a different concentration of the test compound. Out. The NEP enzyme system used in this experiment is fresh blood taken from normal SD rats, placed in a tube containing heparin sodium anticoagulant, collected at 5000 rpm, centrifuged at 4 ° C for 10 min, and plasma is collected; different concentrations of EP inhibitors are prepared. Among them, the EP inhibitor had a maximum final concentration of 100 μΜ and was diluted 10 times in a 3-fold gradient; 60 μL of fresh rat plasma was added to each well in a 384-well plate; then, 10 μΐ of a gradient dilution of ΕΡ was added to each well. Inhibitor; 37 ° C, after incubation for 30 min, add 10 μΐ ΙΟμΜ substrate per well (SenoLyte 520 Neprilysin Activity Assay Kit, AnaSpec, 72223); incubate at 37 ° C for 18 h (±lh); at excitation light 490 nm and emission The fluorescence signal was measured at a wavelength of 520 nm; and the IC 50 was determined using Prism 5.0 software.
本发明化合物的 EP酶抑制活性通过以上的试验进行测定， 测得的 IC5Q值见 下表。 The EP enzyme inhibitory activity of the compound of the present invention was measured by the above test, and the measured IC 5Q value is shown in the following table.
化合物名称  Compound name
LBQ657 (2R,4S)-5-联苯基 -4-基 -4-P-羧基 -丙酰氨基) -2-甲基 -戊酸 0.043 (2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基） 实施例 3 0.042 LBQ657 (2R,4S)-5-biphenyl-4-yl-4-P-carboxy-propionylamino)-2-methyl-pentanoic acid 0.043 (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino) Example 3 0.042
-2-甲基戊酸异丙氧基碳氧基甲基酯  2-methylpentanoic acid isopropoxy carboxymethyl ester
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基） 实施例 9 0.065  (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino) Example 9 0.065
-2-甲基戊酸 -3,3,3-三氟丙基酯  -2-methylpentanoic acid -3,3,3-trifluoropropyl ester
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基） 实施例 11 0.047  (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino) Example 11 0.047
-2-甲基戊酸 -1-异丙氧基碳氧基乙基酯  -2-methylpentanoic acid-1-isopropoxyoxyethyl ester
(2R,4S)-5-联苯基 -4-基 -4-(3-羧基 -丙酰氨基） 实施例 14 0.044  (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino) Example 14 0.044
-2-甲基 -戊酸 1-异丙氧基碳氧基 -1-甲基-乙基酯 结论： 本发明实施例化合物在 SD大鼠血浆中对 EP酶均有明显地抑制作用。 生物学实验例 2、 大鼠药代动力学研究试验  2-Methyl-pentanoic acid 1-isopropoxycarbonyl-1-methyl-ethyl ester Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on EP enzymes in the plasma of SD rats. Biological Experiments 2. Rat Pharmacokinetic Study
1.研究目的  1. Research purposes
以大鼠为受试动物， 研究 EP系列前药化合物例 2， 例 3， 例 4， 例 5， 例 Taking rats as test animals, study EP series of prodrug compounds, examples 2, 3, 4, 5, and
9， 例 11， 例 13在大鼠体内的药代动力学行为， 评价其药动学特征。 9. Pharmacokinetic behavior of rats in Example 11, Example 13 in rats.
2.试验方案  2. Test plan
2.1试验动物  2.1 test animals
每例使用 SD大鼠 3只， 雄性， 由西普尔-必凯实验动物有限公司提供， 动物生 产许可证号 SCXK (沪) 2008-0016。  Three SD rats were used in each case, male, supplied by Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number SCXK (Shanghai) 2008-0016.
2.2药物配制  2.2 drug preparation
样品全取 (按 30 mg计)， 力口 1 ml乙醇使溶解， 后依次加入 1 ml (温水适当加热使 融化） Solutol HS15和 8 ml pH 4.63醋酸盐缓冲液， 制成 3 mg/ml溶液， 剩余药液留 样用于定量分析。  Take all the samples (according to 30 mg), dissolve in 1 ml of ethanol, then add 1 ml (heated with warm water to melt) Solutol HS15 and 8 ml of pH 4.63 acetate buffer to make 3 mg/ml solution. The remaining drug solution is used for quantitative analysis.
2.3给药  2.3 administration
SD大鼠 3只， 雄性； 禁食一夜后分别灌胃给药， 剂量为 30 mg/kg, 给药体积 10 ml/kg  SD rats, 3 males; administered intragastrically overnight after fasting, dose 30 mg/kg, dose 10 ml/kg
2.4样品采集  2.4 sample collection
于给药前和给药后 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24.0 h采血 0.1 ml, 置于肝素化试 管中， 4°C 3500 rpm离心 10 min分离血浆， 乎 20°C保存； 给药后 2 h进食。 因待测 物在血浆中不稳定， 血样采集后迅速置于冰水浴中， 血样采集及处理、 分析的全 过程保持低温状态。  Before the administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24.0 h after the administration, 0.1 ml of blood was collected, placed in a heparinized test tube, and centrifuged at 3,500 rpm for 10 min to separate the plasma, and stored at 20 ° C; Eat 2 h after administration. Because the test object is unstable in plasma, the blood sample is quickly placed in the ice water bath after collection, and the whole process of blood sample collection, processing and analysis is kept at a low temperature.
3.分析方法  3. Analysis method
3.1仪器设备  3.1 Instrumentation
API 4000三重四级杆质谱仪， 美国 Applied Biosy stems公司；  API 4000 Triple Quadrupole Mass Spectrometer, Applied Biosy stems, USA;
Shimadzu LC-20AD高效液相色谱系统， 日本 Shimadzu公司。 3.2色谱条件 Shimadzu LC-20AD High Performance Liquid Chromatography System, Shimadzu Corporation, Japan. 3.2 chromatographic conditions
Figure imgf000038_0001
Figure imgf000038_0001
3.4 血浆样品预处理  3.4 Plasma sample pretreatment
同时检测前药及代谢产物 LBQ657 : 取给药后各时刻的大鼠血浆 25 μ1， 加入 内标 SHR133162 (200 ng/ml , 甲醇配制） 50 μ1， 甲醇 175 μ1， 涡旋混合 3 min, 离 心 10 min (13500 rpm), 取上清液 10 μΐ进行 LC/MS/MS分析。  Simultaneous detection of prodrugs and metabolites LBQ657: Take 25 μl of rat plasma at each time after administration, add internal standard SHR133162 (200 ng/ml, methanol) 50 μl, methanol 175 μl, vortex for 3 min, centrifuge 10 Min (13500 rpm), the supernatant was taken 10 μΐ for LC/MS/MS analysis.
3.5标准曲线制备  3.5 standard curve preparation
同时检测前药及代谢产物 LBQ657 : 取大鼠空白血浆 25 μ1， 加入混合标准系 列溶液 25 μ1， 使血药浓度为 1.00, 2.00, 5.00, 25.0, 100, 500, 2000, 5000, 20000和 40000 ng/ml , 加入内标 SHR133162 (200 ng/ml， 甲醇配制） 50 μ1， 甲醇 150 μ1， 按 Simultaneous detection of prodrugs and metabolites LBQ657: Take 25 μl of rat blank plasma, add 25 μl of mixed standard series solution, and make blood concentration 1.00, 2.00, 5.00, 25.0, 100, 500, 2000, 5000, 20000 and 40000 ng /ml , add internal standard SHR133162 (200 ng/ml, prepared in methanol) 50 μl, methanol 150 μ1, press
"血浆样品预处理"项下操作。 Operation under "Plasma sample pretreatment".
以血药浓度为横坐标， 样品与内标色谱峰面积比为纵坐标， 以加权最小二乘 法 (w=l/x2)进行线性回归， 获得典型标准曲线方程如下表： Taking the plasma concentration as the abscissa, the ratio of the peak area of the sample to the internal standard is the ordinate, and the linear regression is performed by the weighted least squares method (w=l/x 2 ). The typical standard curve equation is obtained as follows:
样品名称 标准曲线方程 相关系数（r) 实施例 1 y = 0.000770x + 0.00437 0.9994 实施例 2 y = 0.00244x + 0.00159 0.9997 实施例 3 y=0.00170x + 0.00108 0.9978 实施例 4 y=0.00313x + 0.0295 0.9948 实施例 5 y=0.000237x + 0.0000607 0.9988 实施例 9 y=0.00537x + 0.000953 0.9972 实施例 11 y=0.000942x + 0.00116 0.9989 实施例 13 y = 0.000737x + 0.00866 0.9956 Sample name standard curve equation correlation coefficient (r) Example 1 y = 0.000770x + 0.00437 0.9994 Example 2 y = 0.00244x + 0.00159 0.9997 Example 3 y=0.00170x + 0.00108 0.9978 Example 4 y=0.00313x + 0.0295 0.9948 Example 5 y=0.000237x + 0.0000607 0.9988 Example 9 y=0.00537x + 0.000953 0.9972 Example 11 y = 0.000942x + 0.00116 0.9989 Example 13 y = 0.000737x + 0.00866 0.9956
4. EP化合物大鼠药代动力学研究  4. Study on pharmacokinetics of EP compound rats
4.1.试验结果表明， 大鼠灌胃给予 30 mg/kg前药例 1后， 实施例 1化合物的血 药浓度达峰时间 tmaX为 (4.67±2.31)h， 峰浓度 Cmax为 (87.6±76.0)ng/ml， 血药浓度-时 间曲线下面积 AUCQ.t为 (312±424) ng/ml-h; 代谢产物 LBQ657的血药浓度达峰时间 1 为(0.83±0.29；)11， 峰浓度。 为(9042±2319 ¾/1^， 血药浓度-时间曲线下面积 AUC0-t为 (21028±7237) ng/ml-h, 消除半衰期 t1/2为（1.03±0.08)h。 4.1. The results showed that, 30 mg / kg in rats orally administered prodrug Example 1, the time to peak plasma concentration of the compound of Example 1 tma X is (4.67 ± 2.31) h, peak concentration C max was (87.6 ± 76.0) ng/ml, the area under the blood concentration-time curve AUC Q . t is (312 ± 424) ng / ml - h; the blood product concentration peak time 1 of the metabolite LBQ657 is (0.83 ± 0.29;) 11, Peak concentration. For (9042±2319 3⁄4/1^, the area under the blood concentration-time curve AUC 0-t is (21028±7237) ng/ml-h, and the elimination half-life t 1/2 is (1.03±0.08)h.
4.2. 大鼠灌胃给予 30.0 mg/kg前药例 2后， 实施例 2化合物在大鼠体内各时刻 血药浓度均低于定量下限， 推测该前药被酶快速水解； 代谢产物 LBQ657的血药 浓度达峰时间 1 为(0.67±0.29)11， 峰浓度。 为(8145±2101 ¾/1^， 血药浓度 -时间 曲线下面积 AUC0-t为 (20301±3404) ng/ml-h, 消除半衰期 t1/2为（1.63±1.56)h。 4.2. Rats were intragastrically administered with 30.0 mg/kg of prodrug 2, and the blood concentration of the compound of Example 2 was lower than the lower limit of quantification in rats at all times. It is speculated that the prodrug was rapidly hydrolyzed by the enzyme; the blood of metabolite LBQ657 The drug concentration peak time 1 is (0.67 ± 0.29) 11, peak concentration. (8145±2101 3⁄4/1^, the area under the blood concentration-time curve AUC 0-t is (20301±3404) ng/ml-h, and the elimination half-life t 1/2 is (1.63±1.56)h.
4.3.大鼠灌胃给予 30 mg/kg前药实施例例 3化合物后， 给药后各时刻前药的血 药浓度均低于 10 ng/ml， 推测该前药在大鼠体内快速被酶水解； 代谢产物 LBQ657 的血药浓度达峰时间 tmax为 (0.50±0.00)h， 峰浓度 Cmax为 (30041±13427)ng/ml， 血药 浓度-时间曲线下面积 AUCQ.t为（78570±31469)ng/ml-h， 消除半衰期 t1/2为 (2.36±0.39)h。 4.3. After administration of 30 mg/kg of the prodrug of the compound of Example 3 by intragastric administration, the blood concentration of the prodrug at each time after administration is less than 10 ng/ml, and it is speculated that the prodrug is rapidly enzyme-enzymed in rats. Hydrolysis; the peak concentration t max of the metabolite LBQ657 is (0.50±0.00) h, the peak concentration C max is (30041±13427) ng/ml, and the area under the plasma concentration-time curve is AUC Q. t ( 78570±31469) ng/ml-h, elimination half-life t 1/2 is (2.36±0.39)h.
4.4.试验结果表明， 大鼠灌胃给予 30.0 mg/kg前药实施例 4化合物后， 实施例 4化合物在大鼠体内各时刻血药浓度均低于定量下限， 推测该前药被酶快速水 解； 代谢产物 LBQ657的血药浓度达峰时间 t x为 (0.833±0.289)h， 峰浓度。„^为 (13308±3949)ng/ml , 血药浓度-时间曲线下面积 AUCo-t为（35276±16283)ng/ml-h， 消除半衰期 t1/2为 (4.54±1.77)h。 4.4. The test results showed that after the rats were administered with 30.0 mg/kg of the prodrug of the compound of Example 4 by intragastric administration, the blood concentration of the compound of Example 4 was lower than the lower limit of quantification in the rats at all times, and it was speculated that the prodrug was rapidly hydrolyzed by the enzyme. The blood product concentration peak time t x of the metabolite LBQ657 is (0.833±0.289) h, peak concentration. „^ is (13308±3949) ng/ml, the area under the blood concentration-time curve is AUCo- t (35276±16283) ng/ml-h, and the elimination half-life t 1/2 is (4.54±1.77)h.
4.5. 大鼠灌胃给予 30.0 mg/kg前药实施例 5化合物后， 实施例 5化合物在大鼠 体内各时刻血药浓度均低于 30 ng/ml， 推测该前药被酶快速水解； 代谢产物 LBQ657的血药浓度达峰时间 tmax为（1.67±0.58)h， 峰浓度 Cmax为（1040±703)ng/ml， 血药浓度-时间曲线下面积 AUCQ.t为（5237±2776)ng/ml_h， 消除半衰期 t1/2为 (2.74±0.53)h。 4.5. After the rats were administered with 30.0 mg/kg of the prodrug of the compound of Example 5 by intragastric administration, the blood concentration of the compound of Example 5 was lower than 30 ng/ml at various times in the rat, and it was speculated that the prodrug was rapidly hydrolyzed by the enzyme; The peak concentration t max of the product LBQ657 was (1.67±0.58) h, the peak concentration C max was (1040±703) ng/ml, and the area under the plasma concentration-time curve was AUC Q. t was (5237±2776). ) ng/ml_h, elimination half-life t 1/2 is (2.74 ± 0.53) h.
4.6. 大鼠灌胃给予 30.0 mg/kg前药实施例 9化合物后， 实施例 9化合物的血药 浓度达峰时间 tmax为 (0.667±0.289)h， 峰浓度 CmaX为 (4178±2633)ng/ml， 血药浓度-时 间曲线下面积 AUC。.t为 (6150±314i;>ng/ml i， 消除半衰期 t1/2为 (4.03±0.88)1ι; 代谢 产物 LBQ657的血药浓度达峰时间 tmax为（0.833±0.289)h， 峰浓度 CmaX为 (18657±6062)ng/ml, 血药浓度-时间曲线下面积 AUCo-t为 (42298±9756)ng/ml'h， 消 除半衰期11/2为 (4.61±1.18)h。 4.6. After administration of 30.0 mg/kg of the prodrug of the compound of Example 9 by intragastric administration, the peak concentration tmax of the compound of Example 9 was (0.667±0.289) h, and the peak concentration Cma X was (4178±2633) ng. /ml, blood concentration-time The area under the curve AUC. t is (6150±314i;>ng/ml i, elimination half-life t 1/2 is (4.03±0.88) 1ι ; metabolite LBQ657 blood concentration peak time t max is (0.833±0.289)h, peak concentration The Cma X was (18657±6062) ng/ml, and the area under the plasma concentration-time curve was AUCo- t (42298±9756) ng/ml'h, and the elimination half-life 1 1/2 was (4.61±1.18) h.
4.7.大鼠灌胃给予 30 mg/kg前药实施例 11化合物后， 各时刻实施例 11化合物 血药浓度均低于定量下限， 推测该前药在大鼠体内快速被酶水解； 代谢产物 LBQ657 的 血 药浓度 达 峰 时 间 tmax为 （0.83±0.29)h ， 峰浓度 C^为 (36393±15243)ng/ml, 血药浓度-时间曲线下面积 AUC0-t为（99618±54682)ng/ml-h， 消除半衰期 t1/2为 (2.29±0.26)h。 4.7. After administration of 30 mg/kg of the prodrug of the compound of Example 11 by intragastric administration, the blood concentration of the compound of Example 11 at each time was lower than the lower limit of quantification, and it was speculated that the prodrug was rapidly hydrolyzed in the body of the rat; metabolite LBQ657 The blood concentration peak time t max was (0.83±0.29) h, the peak concentration C^ was (36393±15243) ng/ml, and the area under the plasma concentration-time curve AUC 0-t was (99618±54682) ng. /ml-h, elimination half-life t 1/2 is (2.29 ± 0.26) h.
4.8. 大鼠灌胃给予 30 mg/kg前药实施例 13化合物后， 实施例 13化合物在大鼠 体内各时刻血药浓度均低于定量下限， 推测该前药被酶快速水解； 代谢产物 LBQ657 的 血 药浓度 达 峰 时 间 tmax为 （0.83±0.29)h ， 峰浓度 C^为 (12466±5106)ng/ml， 血药浓度-时间曲线下面积 AUCo-t为（33505±14118)ng/ml-h， 消除半衰期 t1/2为 (1.91±1.50)h。 4.8. After administration of 30 mg/kg of the prodrug of the compound of Example 13 by intragastric administration, the blood concentration of the compound of Example 13 at each time in the rat is lower than the lower limit of quantification, and the prodrug is presumed to be rapidly hydrolyzed by the enzyme; metabolite LBQ657 The blood concentration peak time t max was (0.83±0.29) h, the peak concentration C^ was (12466±5106) ng/ml, and the area under the plasma concentration-time curve was AUCo- t (33505±14118) ng/ Ml-h, elimination half-life t 1/2 is (1.91 ± 1.50) h.
结论： 本发明实施例化合物均可以在大鼠体内代谢成活性药物成分 LBQ657。  Conclusion: The compounds of the examples of the present invention can be metabolized into the active pharmaceutical ingredient LBQ657 in rats.

Claims

权利要求书: Claims:
1、 一种如式 （I) 所示的联 丁酸衍生物， 1. A bibutyric acid derivative represented by formula (I),
其中 Z选自氧或硫； Where Z is selected from oxygen or sulfur;
R选自碱金属、 碱土金属、
Figure imgf000041_0001
R is selected from alkali metals, alkaline earth metals,
Figure imgf000041_0001
Ri R2各自独立的选自氢、 卤素、 羟基、 氰基、 硝基、 _8垸基、 C2_8链烯 基、 C2.8链炔基、 .8环垸基、 .8垸氧基、 C3.8环垸氧基、 3-8元杂环基、 3-8元 杂环基氧基、 C5.1Q芳基、 C5.1Q芳基氧基、 5- 10元杂芳基、 5-10元杂芳基氧基、 - S(0)rR4、 -Ci-4-S(0)rR4 -C(0)R4、 -C1-4-C(0)R4、 -C(0)OR4、 -C1-4-C(0)OR4、 -O- C(0)R4、 -Ci-4-0-C(0)R4、 -0-C(0)OR4、 -C1-4-0-C(0)OR4、 -NR5R6、 -C1-4- NR5R6、 -C(0)NR5R6、 -C1-4C(0)NR5R6、 -N(R4)-C(0)R4或- NH-NR5R6; Ri R 2 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, _8 alkyl, C 2 _ 8 alkenyl, C 2.8 alkynyl, .8 cycloalkyl, .8 alkyl Oxygen group, C 3. 8 ring alkyloxy group, 3-8 membered heterocyclyl group, 3-8 membered heterocyclyl oxygen group, C 5 . 1Q aryl group, C 5 . 1Q aryloxy group, 5- 10 membered Heteroaryl, 5-10 membered heteroaryloxy, -S(0)rR4, -Ci -4 -S(0)rR4 -C(0)R 4 , -C 1-4 -C(0)R4 , -C(0)OR4, -C 1-4 -C(0)OR 4 , -O- C(0)R4, -Ci -4 -0-C(0)R4, -0-C(0) OR 4 , -C 1-4 -0-C(0)OR 4 , -NR 5 R 6 , -C 1-4 - NR 5 R 6 , -C(0)NR 5 R 6 , -C 1-4 C(0)NR 5 R 6 , -N(R4)-C(0)R4 or -NH-NR 5 R 6 ;
其中所述的 _8垸基、 C3_8环垸基、 3-8元杂环基、 C^。芳基或 5- 10元杂芳基各 自独立任选进一步被一个或多个选自卤素、 羟基、 氰基、 硝基、 _8垸基、 卤取 代 d_8垸基、 羟基取代 _8垸基、 _8垸氧基、 卤取代 _8垸氧基、 C3_8环垸氧基、 - S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 -NR5R6、 -C1-4- NR5R6、 -C(0)NR5R6、 -C1-4C(0)NR5R6或 -N(R4)-C(0)R4取代基所取代； The _8 alkyl group, C 3 _ 8 cycloalkyl group, 3-8 membered heterocyclic group, C^. The aryl group or the 5-10 membered heteroaryl group is each independently optionally further substituted by one or more selected from the group consisting of halogen, hydroxyl, cyano, nitro, _8 alkyl, halogen substituted d_ 8 alkyl, hydroxyl substituted _ 8 alkyl , _ 8 alkyloxy group, halogen substituted _ 8 alkyloxy group, C 3 _ 8 cycloalkyloxy group, - S(0)rR4, -C(0)R4, -C(0)OR4, -0-C( 0)R4, -0-C(0)OR 4 , -NR 5 R 6 , -C 1-4 - NR 5 R 6 , -C(0)NR 5 R 6 , -C 1-4 C(0) NR 5 R 6 or -N(R4)-C(0)R4 substituent substituted;
R3选自氢、 卤素、 羟基、 氰基、 硝基、 _8垸基、 C2_8链烯基、 C2_8链炔基、 3.8环垸基、 .8垸氧基、 C3.8环垸氧基、 3-8元杂环基、 3-8元杂环基氧基、 C5.10 芳基、 CWQ芳基氧基、 5- 10元杂芳基、 5- 10元杂芳基氧基、 -S(0)rR4、 -Ci-4- S(0)rR4、 -C(0)R4、 -Ci-4-C(0)R4 -C(0)OR4、 -C1-4-C(0)OR4、 -0-C(0)R4、 -C1-4- 0-C(0)R4 、 -0-C(0)OR4 、 -Ci-4-0-C(0)OR4 、 -NR5R6 、 -C1-4-NR5R6 、 - C(0)NR5R6、 -C1-4C(0)NR5R6、 -N(R4)-C(0)R4或- NH-NR5R6; R 3 is selected from hydrogen, halogen, hydroxyl, cyano, nitro, _ 8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, 3.8 cycloalkyl, . 8 alkyloxy, C 3. 8- ring alkyloxy, 3-8-membered heterocyclyl, 3-8-membered heterocyclyloxy, C 5. 10 aryl, CWQ aryloxy, 5-10-membered heteroaryl, 5- 10-membered heteroaryloxy, -S(0)rR4, -Ci -4 - S(0)rR4, -C(0)R4, -Ci -4 -C(0)R4 -C(0)OR4, -C 1-4 -C(0)OR4, -0-C(0)R4, -C 1-4 - 0-C(0)R 4 , -0-C(0)OR4, -Ci -4 - 0-C(0)OR4, -NR 5 R 6 , -C 1-4 -NR 5 R 6 , - C(0)NR 5 R 6 , -C 1-4 C(0)NR 5 R 6 , - N(R 4 )-C(0)R4 or-NH-NR 5 R 6 ;
其中所述的 C^垸基、 C3_8环垸基、 3-8元杂环基、 C^。芳基或 5- 10元杂芳基各 自独立任选进一步被一个或多个选自卤素、 羟基、 氰基、 硝基、 d_8垸基、 卤取 代 d_8垸基、 羟基取代 _8垸基、 _8垸氧基、 ¾取代 _8垸氧基、 C3_8环垸氧基、 - S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 -NR5R6、 -C1-4- NR5R6、 -C(0)NR5R6、 -C1-4C(0)NR5R6或 -N(R4)-C(0)R4取代基所取代； The C^ alkyl group, C 3_8 cycloalkyl group, 3-8 membered heterocyclic group, C^. The aryl group or the 5-10 membered heteroaryl group is each independently optionally further substituted by one or more halogen, hydroxyl, cyano, nitro, d- 8 alkyl, halogen-substituted d- 8 alkyl, hydroxyl-substituted d- 8 alkyl. , _ 8 alkyloxy group, ¾ substituted _ 8 alkyloxy group, C 3 _ 8 cycloalkyloxy group, -S(0)rR4, -C(0)R4, -C(0)OR4, -0-C( 0)R4, -0-C(0)OR 4 , -NR 5 R 6 , -C 1-4 - NR 5 R 6 , -C(0)NR 5 R 6 , -C 1-4 C(0) NR 5 R 6 or -N(R4)-C(0)R4 substituent substituted;
R4、 R5、 R6选自氢、 CM垸基、 C3_8环垸基; r为 0、 1、 2。 R4, R5 , R6 are selected from hydrogen, C M alkyl group, C 3_8 cycloalkyl group; r is 0, 1, 2.
2、 根据权利要求 1所述的联芳基取代的 4-氨基丁酸衍生物， 其特征在于， R 选自钠、 钾、 镁、 钙、 铵。 2. The biaryl-substituted 4-aminobutyric acid derivative according to claim 1, wherein R is selected from sodium, potassium, magnesium, calcium, and ammonium.
3、 根据权利要求 1所述的联芳基取代的 4-氨基丁酸衍生物， 其特征在于， 其选自式 （II) 化合物： 3. The biaryl-substituted 4-aminobutyric acid derivative according to claim 1, characterized in that it is selected from compounds of formula (II):
Figure imgf000042_0001
Figure imgf000042_0001
( TT ) (TT)
其中 R3、 R4、 R5、 R6、 r如权利要求 1所定义。 Wherein R 3 , R4 , R 5 , R 6 and r are as defined in claim 1.
4、 根据权利要求 1所述的联芳基取代的 4-氨基丁酸衍生物， 其特征在于， R3选自氢、 卤素、 CL8垸基、 卤取代 d.8垸基、 C3.8环垸基、 -Cw-O-C O)!^ -0- C(0)OR4、 -C1-4-0-C(0)OR4; R4、 R5、 R6、 r如权利要求 1所定义。 5、 一种制备如权利要求 1所述的如式 （I) 所示的联芳基取代的 4-氨基丁酸 衍生物的中间体， 其具有如通 （III) 所示的结构： 4. The biaryl-substituted 4-aminobutyric acid derivative according to claim 1, wherein R 3 is selected from hydrogen, halogen, CL 8 alkyl, halogen-substituted d. 8 alkyl, C 3 . 8- ring alkyl, -Cw-OC O)!^ -0- C(0)OR 4 , -C 1-4 -0-C(0)OR4; R4, R 5 , R 6 , r as claimed in claim 1 defined. 5. An intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative represented by formula (I) as claimed in claim 1, which has a structure represented by general (III):
Figure imgf000042_0002
其中 Z选自氧或硫
Figure imgf000042_0002
where Z is selected from oxygen or sulfur
R选自碱金属、 碱土金属、 铵或
Figure imgf000042_0003
R is selected from alkali metals, alkaline earth metals, ammonium or
Figure imgf000042_0003
、 R2各自独立的选自氢、 卤素、 羟基、 氰基、 硝基、 _8垸基、 C2_8链烯 基、 C2.8链炔基、 .8环垸基、 .8垸氧基、 C3.8环垸氧基、 3-8元杂环基、 3-8元 杂环基氧基、 C5.1Q芳基、 C5.1Q芳基氧基、 5-10元杂芳基、 5-10元杂芳基氧基、 - S(0)rR4、 -Ci-4-S(0)rR4 -C(0)R4、 -C1-4-C(0)R4、 -C(0)OR4、 -C1-4-C(0)OR4、 -O- C(0)R4、 -Ci-4-0-C(0)R4、 -0-C(0)OR4、 -C1-4-0-C(0)OR4、 -NR5R6、 -C1-4- NR5R6、 -C(0)NR5R6、 -C1-4C(0)NR5R6、 -N(R4)-C(0)R4或- NH-NR5R6; 其中所述的 _8垸基、 C3_8环垸基、 3-8元杂环基、 C^。芳基或 5-10元杂芳基各 自独立任选进一步被一个或多个选自卤素、 羟基、 氰基、 硝基、 _8垸基、 卤取 代 d_8垸基、 羟基取代 _8垸基、 _8垸氧基、 ¾取代 _8垸氧基、 C3_8环垸氧基、 - S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 -NR5R6、 -C1-4- NR5R6、 -C(0)NR5R6、 -C1-4C(0)NR5R6或 -N(R4)-C(0)R4取代基所取代； , R 2 is each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, _ 8 alkyl, C 2 _ 8 alkenyl, C 2. 8 alkynyl, . 8 cycloalkyl, . 8 alkyl Oxygen group, C 3. 8 ring alkyloxy group, 3-8 membered heterocyclyl group, 3-8 membered heterocyclyloxy group, C 5 . 1Q aryl group, C 5 . 1Q aryloxy group, 5-10 membered Heteroaryl, 5-10 membered heteroaryloxy, -S(0)rR4, -Ci -4 -S(0)rR4 -C(0)R 4 , -C 1-4 -C(0)R4 , -C(0)OR4, -C 1-4 -C(0)OR 4 , -O- C(0)R4, -Ci -4 -0-C(0)R4, -0-C(0) OR 4 , -C 1-4 -0-C(0)OR 4 , -NR 5 R 6 , -C 1-4 - NR 5 R 6 , -C(0)NR 5 R 6 , -C 1-4 C(0)NR 5 R 6 , -N(R4)-C(0)R4 or -NH-NR 5 R 6 ; The _8 alkyl group, C 3 _ 8 cycloalkyl group, 3-8 membered heterocyclic group, C^. The aryl group or the 5-10 membered heteroaryl group is each independently optionally further substituted by one or more selected from the group consisting of halogen, hydroxyl, cyano, nitro, _8 alkyl, halogen substituted d_ 8 alkyl, hydroxyl substituted _ 8 alkyl , _ 8 alkyloxy group, ¾ substituted _ 8 alkyloxy group, C 3 _ 8 cycloalkyloxy group, -S(0)rR4, -C(0)R4, -C(0)OR4, -0-C( 0)R4, -0-C(0)OR 4 , -NR 5 R 6 , -C 1-4 - NR 5 R 6 , -C(0)NR 5 R 6 , -C 1-4 C(0) NR 5 R 6 or -N(R4)-C(0)R4 substituent substituted;
R3选自氢、 卤素、 羟基、 氰基、 硝基、 _8垸基、 C2_8链烯基、 C2_8链炔基、 3.8环垸基、 .8垸氧基、 C3.8环垸氧基、 3-8元杂环基、 3-8元杂环基氧基、 C5.10 芳基、 C5.1()芳基氧基、 5-10元杂芳基、 R 3 is selected from hydrogen, halogen, hydroxyl, cyano, nitro, _ 8 alkyl, C 2 _ 8 alkenyl, C 2 _ 8 alkynyl, 3.8 cycloalkyl, . 8 alkyloxy, C 3. 8- ring alkyloxy group, 3-8 membered heterocyclyl group, 3-8 membered heterocyclyloxy group, C 5. 10 aryl group, C 5. 1() aryloxy group, 5-10 membered heterocyclic group Aryl,
5-10元杂芳基氧基、 -S(0)rR4、 -Ci-4- S(0)rR4、 -C(0)R4、 -Ci-4-C(0)R4 -C(0)OR4、 -C1-4-C(0)OR4、 -0-C(0)R4、 -C1-4- 0-C(0)R4 、 -0-C(0)OR4 、 -Ci-4-0-C(0)OR4 、 -NR5R6 、 -C1-4-NR5R6 、 - C(0)NR5R6、 -C1-4C(0)NR5R6、 -N(R4)-C(0)R4或- NH-NR5R6; 5-10 membered heteroaryloxy, -S(0)rR4, -Ci -4 - S(0)rR4, -C(0)R4, -Ci -4 -C(0)R4 -C(0) OR4, -C 1-4 -C(0)OR4, -0-C(0)R4, -C 1-4 - 0-C(0)R 4 , -0-C(0)OR4, -Ci - 4 -0-C(0)OR4 , -NR 5 R 6 , -C 1-4 -NR 5 R 6 , -C(0)NR 5 R 6 , -C 1-4 C(0)NR 5 R 6 , -N(R 4 )-C(0)R4 or -NH-NR 5 R 6 ;
其中所述的 _8垸基、 C3_8环垸基、 3-8元杂环基、 C^。芳基或 5-10元杂芳基各 自独立任选进一步被一个或多个选自卤素、 羟基、 氰基、 硝基、 _8垸基、 卤取 代 C^垸基、 羟基取代 d_8垸基、 d_8垸氧基、 ¾取代 d_8垸氧基、 C3_8环垸氧基、 - S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -0-C(0)R4、 -0-C(0)OR4、 -NR5R6、 -C1-4- NR5R6、 -C(0)NR5R6、 -C1-4C(0)NR5R6或 -N(R4)-C(0)R4取代基所取代； The _8 alkyl group, C 3 _ 8 cycloalkyl group, 3-8 membered heterocyclic group, C^. The aryl group or the 5-10 membered heteroaryl group is each independently optionally further substituted by one or more halogen, hydroxyl, cyano, nitro, alkyl, halogen -substituted alkyl, hydroxyl -substituted alkyl. , d_8 alkyloxy group, ¾ substituted d_8 alkyloxy group, C 3_8 ring alkyloxy group, -S(0)rR4, -C(0)R4, -C(0)OR4, -0-C( 0)R4, -0-C(0)OR 4 , -NR 5 R 6 , -C 1-4 - NR 5 R 6 , -C(0)NR 5 R 6 , -C 1-4 C(0) NR 5 R 6 or -N(R4)-C(0)R4 substituent substituted;
R4、 R5、 R6选自氢、 CM垸基、 C3.8环垸基； R4, R5 , R6 are selected from hydrogen, C M alkyl group, C 3.8 cycloalkyl group;
R7选自羟基、 巯基、 _8垸氧基、 _8垸基硫基、 C3_8环垸氧基、 C3_8环垸硫 基、 -S(0)rR12、 -0-C(0)R12、 -NR13R14、 -OM, 所述 M为碱金属、 碱土金属、 铵； 其中所述的 d_8垸基、 C3_8环垸基各自独立任选进一步被一个或多个选自卤 素、 羟基、 氰基、 硝基、 C^垸基、 卤取代 d_8焼基、 羟基取代 d_8垸基、 d_8垸氧 基、 卤取代 CL8垸氧基、 C3.8环垸氧基、 -S(0)rR4、 -C(0)R4、 -C(0)OR4 、 -O- C(0)R4、 -0-C(0)OR4、 -NR5R6、 -C1-4-NR5R6、 -C(0)NR5R6、 -C1-4C(0)NR5R6或- N(R4)-C(0)R4取代基所取代； R 7 is selected from hydroxyl group, mercapto group, _ 8 alkyloxy group, _ 8 alkylthio group, C 3 _ 8 cycloalkyl oxy group, C 3 _ 8 cycloalkyl sulfide group, -S(0)rR 12 , -0- C( 0 )R 12 , -NR 13 R 14 , -OM, the M is an alkali metal, an alkaline earth metal, ammonium; wherein the d_8 alkyl group and the C 3_8 cycloalkyl group are each independently optionally further optionally One or more are selected from halogen, hydroxyl, cyano, nitro, C alkyl, halogen-substituted d- 8 alkyl, hydroxyl-substituted d- 8 alkyl, d- 8 alkyloxy, halogen-substituted d -8 alkyloxy, C 3. 8- ring alkyloxy group, -S(0)rR4, -C(0)R4, -C(0)OR 4 , -O- C(0)R4, -0-C(0)OR4, -NR 5 R 6 , -C 1-4 -NR 5 R 6 , -C(0)NR 5 R 6 , -C 1-4 C(0)NR 5 R 6 or - N(R4)-C(0)R Substituted by 4 substituents;
r为 0、 1、 2。 r is 0, 1, 2.
6、 如权利要求 5所述的制备如权利要求 1所述的如式 （I) 所示的联芳基取 代的 4-氨基丁酸衍生物的中间体， 其特征在于， R7选自钠、 钾、 镁、 钙、 铵。 6. The intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative represented by formula (I) as claimed in claim 1, wherein R 7 is selected from sodium , potassium, magnesium, calcium, ammonium.
7、 如权利要求 5所述的制备如权利要求 1所述的如式 （I) 所示的联芳基取 代的 4-氨基丁酸衍生物的中间 其特征在于， 其选自式 （IV) 化合物： 7. The method of claim 5 for preparing the biaryl-substituted 4-aminobutyric acid derivative shown in formula (I) as claimed in claim 1, characterized in that it is selected from the group consisting of formula (IV) Compounds:
Figure imgf000043_0001
Figure imgf000043_0001
(IV) 其中 Z、 Ri R2、 R3、 R4、 R5、 R6、 r如权利要求 5所定义。 (IV) Where Z, Ri R 2 , R 3 , R4, R 5 , R 6 and r are as defined in claim 5.
8、 如权利要求 7所述的制备如权利要求 1所述的如式 （I) 所示的联芳基取 代的 4-氨基丁酸衍生物的中间体， 其特征在于， 、 R2各自独立的选自氢、 卤 素、 d.8垸基、 ^.8环垸基、 .8垸氧基、 C3.8环垸氧基； Z、 R3、 R4、 R5、 R6、 r 如权利要求 5所定义。 8. The intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative represented by formula (I) as claimed in claim 1, characterized in that, and R 2 are each independent is selected from hydrogen, halogen, d.8 alkyl group, ^ .8 cycloalkyl group, .8 alkyloxy group, C 3.8 cycloalkyloxy group; Z, R 3 , R4 , R 5 , R 6 , r such as As defined in claim 5.
9、 如权利要求 8所述的制备如权利要求 1所述的如式 （I) 所示的联芳基取 代的 4-氨基丁酸衍生物的中间体， 其特征在于， R3选自氢、 卤素、 _8垸基、 卤 取代 d_8垸基、 C3_8环垸基、 -Ci-4-0-C(0)R4 -0-C(0)OR4、 -C1-4-0-C(0)OR4 ; Z、 Ri R2、 R4、 R5、 R6、 r如权利要求 8所定义。 9. The intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative represented by formula (I) as claimed in claim 1, wherein R 3 is selected from hydrogen , Halogen, _ 8 alkyl group, halogen substituted d_ 8 alkyl group, C 3 _ 8 cycloalkyl group, -Ci -4 -0-C(0)R4 -0-C(0)OR4, -C 1-4 - 0-C(0)OR 4 ; Z, Ri R 2 , R4, R 5 , R 6 , r are as defined in claim 8.
10、 如权利要求 5所述的制备如权利要求 1所述的如式 （I) 所示的联芳基取 代的 4-氨基丁酸衍生物的中间体， 其特征在于， 所述中间体选自如下化合物： 10. The intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative represented by formula (I) as claimed in claim 1, characterized in that, the intermediate is selected from From the following compounds:
Figure imgf000044_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0001
Figure imgf000045_0002
11、 如权利要求 5所述的制备如权利要求 1所述的如式 （I) 所示的联芳基取 代的 4-氨基丁酸衍生物的中间体， 其特征在于， 所述中间体 （III) 具有与终产物 式 （I) 的化合物类似的医药活性。 种制备如权利要求 5-11中任一项所述的中间体的方法， 其包括如下步 11. The intermediate for preparing the biaryl-substituted 4-aminobutyric acid derivative represented by formula (I) as claimed in claim 1, characterized in that, the intermediate ( III) Have similar medicinal activity to the final product compound of formula (I). A method for preparing the intermediate according to any one of claims 5-11, which includes the following steps
Figure imgf000045_0003
Figure imgf000045_0003
( V ) (VI) ( V ) (VI)
步骤 2: 式 （VI) 的化合物脱保护基后得到式 （III) 的化合物； Step 2: The compound of formula (VI) is deprotected to obtain the compound of formula (III);
其中 R与权利要求 5的 R定义相同， 但 R不为氢； X为卤原子。 Wherein R has the same definition as R in claim 5, but R is not hydrogen; X is a halogen atom.
13、 一种制备如权利要求 1-4中任一项所述的联芳基取代的 4-氨基丁酸衍生 物的方法， 其特征在于， 使权利要求 12中制得的中间体式 （III) 的化合物经环 合反应得到式 （I) 的化合物。 13. A method for preparing the biaryl-substituted 4-aminobutyric acid derivative according to any one of claims 1 to 4, characterized in that the intermediate formula (III) prepared in claim 12 The compound of formula (I) is obtained through a cyclization reaction.
14、 一种用于预防和 /或治疗与 NEP异常有关的疾病的药物组合物， 其特征 在于， 所述药物组合物中含有治疗有效量的如权利要求 1-4 中任一项所述的联芳 基取代的 4-氨基丁酸衍生物或如权利要求 5-11中任一项所述的中间体， 以及至少 一种药学上可接受的载体。 14. A pharmaceutical composition for preventing and/or treating diseases related to abnormal NEP, characterized in that the pharmaceutical composition contains a therapeutically effective amount of the drug as described in any one of claims 1-4 A biaryl-substituted 4-aminobutyric acid derivative or an intermediate according to any one of claims 5-11, and at least one pharmaceutically acceptable carrier.
15、 如权利要求 14所述的用于预防和 /或治疗与 NEP异常有关的疾病的药物 或组合物， 其特征在于， 所述与 NEP异常有关的疾病是高血压、 肺动脉高压、 心 衰以及肾脏疾病。 15. The drug or composition for preventing and/or treating diseases related to abnormal NEP as claimed in claim 14, wherein the diseases related to abnormal NEP are hypertension, pulmonary hypertension, heart failure and Kidney disease.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106365997A (en) * 2016-08-23 2017-02-01 陕西思尔生物科技有限公司 Preparation method of 1-iodoethylisopropylcarbonate
WO2017033128A1 (en) * 2015-08-25 2017-03-02 Novartis Ag Biphenyl-substitued 4-amino-butyric acid derivatives and their use in the synthesis of nep inhibitors
US10668035B2 (en) 2018-02-07 2020-06-02 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016086798A1 (en) * 2014-12-03 2016-06-09 上海翰森生物医药科技有限公司 Nep inhibitor crystalline free acid, calcium salt polymorph of same, preparation method for same, and applications thereof
CN107072977B (en) * 2014-12-03 2019-11-22 上海翰森生物医药科技有限公司 Nep inhibitor pharmaceutical composition and its application
CN104557600B (en) * 2015-01-26 2016-05-04 苏州明锐医药科技有限公司 Sha Ku is than bent preparation method
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CN106496055A (en) * 2016-10-09 2017-03-15 杭州科巢生物科技有限公司 A kind of key component sand storehouse of anti-heart failure new drug is than bent novel synthesis
CN107216277B (en) * 2017-06-22 2020-04-24 东南大学 Preparation method of LCZ696 medicine impurity
CN109206419B (en) * 2017-06-29 2023-07-14 上海迪赛诺化学制药有限公司 Sakubi koji intermediate and preparation method and application thereof
CN110041217B (en) * 2019-03-29 2022-05-17 东北制药集团股份有限公司 Preparation method of shakubikojic acid
JP7389414B2 (en) * 2020-09-09 2023-11-30 南京海融医薬科技股▲フン▼有限公司 Method for preparing arylpropionic acid derivatives

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1615134A (en) * 2002-01-17 2005-05-11 诺瓦提斯公司 Pharmaceutical compositions comprising valsartan and NEP inhibitors
CN101516831A (en) * 2006-09-13 2009-08-26 诺瓦提斯公司 Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors
CN101631765A (en) * 2007-01-12 2010-01-20 诺瓦提斯公司 Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
CN102448928A (en) * 2009-05-28 2012-05-09 诺瓦提斯公司 Substituted Aminobutyric Derivatives as Neprilysin Inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217996A (en) * 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
WO2007045663A2 (en) * 2005-10-19 2007-04-26 Novartis Ag Combination of an ati receptor antagonist and a np inhibitor fro treating ia hypertension and heartfailure

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1615134A (en) * 2002-01-17 2005-05-11 诺瓦提斯公司 Pharmaceutical compositions comprising valsartan and NEP inhibitors
CN101516831A (en) * 2006-09-13 2009-08-26 诺瓦提斯公司 Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors
CN101631765A (en) * 2007-01-12 2010-01-20 诺瓦提斯公司 Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
CN102448928A (en) * 2009-05-28 2012-05-09 诺瓦提斯公司 Substituted Aminobutyric Derivatives as Neprilysin Inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KSANDER, G.M. ET AL.: "Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 38, no. 10, 31 May 1995 (1995-05-31), pages 1689 - 1700, XP008154341, DOI: doi:10.1021/jm00010a014 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017033128A1 (en) * 2015-08-25 2017-03-02 Novartis Ag Biphenyl-substitued 4-amino-butyric acid derivatives and their use in the synthesis of nep inhibitors
CN106365997A (en) * 2016-08-23 2017-02-01 陕西思尔生物科技有限公司 Preparation method of 1-iodoethylisopropylcarbonate
US10668035B2 (en) 2018-02-07 2020-06-02 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors
US11426375B2 (en) 2018-02-07 2022-08-30 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors

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