TW201738251A - Phosphamide derivative, method for manufacturing the same, and uses thereof - Google Patents

Abstract

Disclosed are a phosphamide derivative, a method for manufacturing the same, and uses thereof Particularly disclosed are a compound shown by general formula (I) as well as a pharmaceutically acceptable salt or stereisomer (I) thereof, wherein, G, L, Q and s are as defined in the description.

Description

Phosphonium derivative, preparation method and use thereof

The present invention relates to a phosphoniumamine derivative, an intermediate thereof and a process for the preparation thereof, and to the use thereof in the preparation of a medicament.

Some of the drugs currently on the market or researched have some physicochemical and biological defects, such as poor solubility, low stability, easy moisture absorption, poor odor, unsuitable preparation of preparations, difficulty in penetrating the blood-brain barrier, and inability to Oral, liver first pass effect, oral bioavailability, high dose and frequency of administration, body distribution can not meet the treatment needs, food impact, safety window is small, gastrointestinal irritation, tissue irritation, non-target Organ distribution causes problems such as toxic reactions, excessive metabolism, or long-term retention. Therefore, it is necessary to develop new technologies to improve the physical and chemical properties of drugs and eliminate bad odors, improve the absorption, distribution, transport and metabolism of drugs in the body, improve bioavailability, improve the selectivity of drugs to target sites, and reduce drugs. Technical effects such as toxic side effects and prolonged action time.

The present inventors have found that the introduction of phosphoniumamine can change the physical and chemical properties of the drug, such as the traits, stability, fat solubility, P-gp matrix properties, etc. of the drug, thereby changing the characteristics of the absorption and metabolism distribution in the body. After the phosphonium-modified drug enters the body, the hydrolyzed enzyme acts in the water. Release the original drug. By controlling the rate of hydrolysis of the phosphonamine drug, the time of the drug can be prolonged, and the specific action of the drug on the target site can be achieved by the distribution of the hydrolase.

One of the objects of the present invention is to provide an intermediate for preparing a phosphoniumamine derivative and a process for the preparation thereof.

Another object of the present invention is to provide a novel phosphonamine derivative which has an increased solubility, improved drug stability, improved drug taste, is more suitable for preparing a formulation, improves oral bioavailability, reduces dosage, and Frequency, improve patient compliance, improve the specificity of drugs on target sites, reduce food effects, avoid drug tolerance, reduce drug gastrointestinal irritation, reduce toxic side effects, improve safety, prolong half-life, prolong action time, etc. .

The present invention provides a compound of the formula (Z) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

Y is selected from O or S; R ¹ and R ² are each independently selected from H, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _{1- a 10} alkyl or amino acid side chain which, when said amino acid side chain contains a hydroxyl group, a thiol group or a carboxyl group, is selectively esterified, said CH ₂ , alkyl group, carbocyclic ring or heterocyclic ring Optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, thiol, carboxyl, amino, thiol or ester groups, the heterocycle containing from 1 to 6 selected from N, a hetero atom of O or S; optionally, R ¹ and R ² together with the atom to which they are attached may form a 3 to 6 membered ring, optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I Substituted by a substituent of a hydroxyl group, a carboxyl group or an amino group, the ring containing 0 to 6 hetero atoms selected from N, O or S; R ^{3 being} selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m- C _3-10 carbocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m -3 to 10 membered heterocyclic ring or -(CH ₂ ) _m -OC _1-4 alkyl group, said CH ₂ , alkenyl group Alkynyl, alkyl, carbocyclic or hetero Optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxy, amino, 1-cyclopropylethyl, C _1-4 alkyl, C _1-4 alkoxy, OC Substituted by a substituent of (=O)OR ^3a or OC(=O)R ^3a containing from 1 to 6 heteroatoms selected from N, O or S; R ^{3a is} selected from C _1-4 alkyl a C _3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C Substituted by a substituent of _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbocyclic or 3 to 10 membered heterocyclic ring containing from 1 to 6 selected from N, O or S a hetero atom; M _{2 is} selected from H, OH, L-OH, a leaving group or an L-releasing group; L is selected from a bond or a linking group; R ^{5 is} selected from H or C _1-10 alkyl; And R ¹ and R ⁵ together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S, optionally further to 0 to 4 Substituted by a substituent selected from H, F, Cl, Br, I, OH, amino, carboxyl, C _1-4 alkyl or C _1-4 alkoxy; R ⁶ and R ⁷ are each independently selected from H or C _1-10 alkyl, preferably H or C _1-4 alkyl; selective , R ⁶ and R ⁷ and the atoms to which they are attached form a 3-6 ring, said ring containing from 0 to 3 heteroatoms selected from N, O, or S heteroatoms, wherein the ring is optionally further selected from 0-4 Substituted from a substituent of H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; X is selected from the group consisting of absent, -O-, -S- or -NR ^8a R ^{8 is} selected from the group consisting of H, C _1-6 alkyl, -(CH ₂ ) _m C _3-6 carbocyclic ring, -(CH ₂ ) _m 3 to 6 membered heterocyclic ring, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p O(CH ₂ ) _p R ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , the alkane a group, a carbocyclic ring, a heterocyclic ring, optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; The heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S; R ^8a and R ^8b are each independently selected from H or C _1-6 alkyl, and the alkyl group is optionally further further 0 to 6 Substituted by a substituent selected from H, F, Cl, Br, I, OH, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl; optionally, R ^8a and R ^8b may form a 3 to 6 membered ring together with the atom to which it is attached, said ring containing 1 to 3 heteroatoms selected from N, O or S, The ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; R ^8c , R ^{8d are} selected From H, C _1-6 alkyl, C _3-6 carbocyclic or 3 to 6 membered heterocyclic ring, the alkyl, carbocyclic or heterocyclic ring optionally further from 0 to 6 selected from H, F, Cl, Substituted by a substituent of Br, I, OH, a carboxyl group, a C _1-4 alkyl group or a C _1-4 alkoxy group containing from 1 to 3 hetero atoms selected from N, O or S; p is each independently selected from 0, 1, 2 or 3; n is selected from 1, 2, 3, 4 or 5.

The present invention provides a compound of the formula (Z) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Not tridecyl, 2-aminoethyl; or M _{2 is} not trifluoroethoxy.

The present invention provides a compound of the formula (Z) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein M ^{2 is} selected from the group consisting of R ^M , H, L-halogen or L-OH; and R ^{M is} selected from the group consisting of F , Cl, Br, I or OH; L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N (C _{1 -6} alkyl)-, -C(=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S (=O) ₂ -, -S(=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl) -; W is selected from optionally substituted 0-10 W ^a phenyl group, the C _1-25 alkylene, C _2-25 alkenylene or C _2-25 alkynylene group, the a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, O, S, wherein 0 to 10 carbon atoms in the alkylene, alkenylene or alkynylene group are optionally substituted by 0 to 10 W ^a Substituting N, (C=O), the divalent group formed above is optionally further substituted by 0 to 10 W ^a ; the heterocyclic ring containing 0 to 4 hetero atoms selected from O, S or N ;W ^a each independently selected from phenyl, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _{1- 6} alkoxy, C _3-6 cycloalkyl, -OC(=O)C _1-6 alkyl, -(=O)OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _1-6 alkylthio, azido, cyano, nitro, halogen, amino, hydroxy, Substituted by a substituent of (=O), a carboxyl group, a C _3-10 carbocyclic ring, a 3 to 10 membered heterocyclic ring, a -OC _3-10 carbocyclic ring or a -O-3 to 10 membered heterocyclic ring; 0-4 selected from O, S or N heteroatoms; form 3-6 ring atoms, W ^a selective two together can be connected thereto, said ring comprising a carbocyclic or heterocyclic ring, optionally further 0 to 4 substituents selected from H, F, Cl, Br, I, OH, amino, carboxyl, C _1-4 alkyl or C _1-4 alkoxy, said ring containing 0 to 4 a hetero atom selected from O, S or N; m, p are each independently selected from 0, 1, 2 or 3; n is selected from 1, 2, 3, 4 or 5.

The present invention provides a compound of the formula (Z) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the compounds represented by the formula (Z-1) or (Z`-1), among them:

L is selected from a bond or L ₁ -W; L _{1 is} selected from -O- or -S-, and W is selected from phenyl or C _1-10 alkylene groups, and 0 to 10 carbons in said alkylene group The atom is optionally substituted with a substituted or unsubstituted phenyl, O, S, N or (C=O), and the divalent group formed above or the phenyl group is optionally further selected from 0 to 5 From F, Cl, Br, I, azido, cyano, nitro, amino, hydroxy, (=O), carboxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyl Substituted by an oxy or cyclopropyl substituent.

The present invention provides a compound of the formula (Z-1) or (Z`-1) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the formula (Z-1-1) or Compounds shown by (Z`-1-1):

The present invention provides a compound of the formula (Z), (Z-1), (Z'-1), (Z-1-1) or (Z'-1-1) or a pharmaceutically acceptable salt thereof Or a stereoisomer wherein: L is selected from a bond or L ₁ -W; L _{1 is} selected from -O- or -S-; W is selected from phenyl, C _1-10 alkylene, C _2-12 An alkenylene group or a C _2-12 alkynylene group, preferably a phenyl group or a C _1-10 alkylene group, and 0 to 10 carbon atoms in the alkylene group, alkenylene group or alkynylene group. Substituted by a substituted or unsubstituted phenyl, O, S, N or (C=O), the divalent group formed above or the phenyl group is further further selected from 0 to 5 selected from F , Cl, Br, I, azido, cyano, nitro, amino, hydroxy, (=O), carboxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy Or substituted with a cyclopropyl substituent; L is preferably selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC(=O), O- phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ ) OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further from 0 to 4 selected from H, F, Cl, Br, I, OH NH ₂ Substituted by a substituent of CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy.

The present invention provides a compound of the formula (Z), (Z-1), (Z`-1), (Z-1-1) or (Z`-1-1) and a pharmaceutically acceptable compound thereof a salt or a stereoisomer wherein: R ¹ and R ² are each independently selected from H, -(CH ₂ ) _m -C _3-10 carbocyclic, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _{a 1-10} alkyl or amino acid side chain, wherein when the amino acid side chain contains a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group is selectively esterified, the CH ₂ , an alkyl group, a carbocyclic ring or The heterocyclic ring is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, thiol, carboxyl, amino, thiol or ester groups, the heterocyclic ring having 1 to 6 selected from a hetero atom of N, O or S; optionally, R ¹ and R ⁵ together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S, The ring is optionally further substituted with from 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, OH, amino, carboxyl, C _1-4 alkyl or C _1-4 alkoxy; The amino acid is selected from the group consisting of lysine, methionine, isoleucine, valine, threonine, tryptophan, serine, and cysteine. Acid, tyrosine, aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine, and Said amino acid is D-form or L-form; optionally, R ¹ and R ² may form a C _3-6 cycloalkyl group together with the atom to which they are attached, said cycloalkyl optionally further being from 0 to 3 Substituted by a substituent selected from F, Cl, Br, I, a hydroxyl group, a carboxyl group or an amino group.

The present invention provides a compound of the formula (Z), (Z-1), (Z`-1), (Z-1-1) or (Z`-1-1) and a pharmaceutically acceptable compound thereof a salt or a stereoisomer wherein: R ¹ and R ² are each independently selected from the side chain of H, methyl, ethyl, isopropyl or amino acid, and when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, the thiol group a hydroxyl group or a carboxyl group is selectively esterified; optionally, R ¹ and R ⁵ may, together with the atom to which they are attached, form azacyclopropyl, azetidinyl or azacyclopentyl, said aza The cyclopropyl, azetidinyl or azacyclopentyl group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, methyl, ethyl, methoxy, ethoxy, carboxy Substituted by a substituent of an amino group selected from the group consisting of lysine, methionine, isoleucine, valine, threonine, tryptophan, serine, cysteine, tyrosine, aspartic Amino acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine, and the amino acid is D-form or L- type; selectivity, R ¹ and R ² may be The attached atoms together form a cyclopropyl, cyclobutyl or cyclopentyl group, optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy Substituted by a substituent of a carboxyl group or an amino group.

The present invention provides a compound of the formula (Z), (Z-1), (Z`-1), (Z-1-1) or (Z`-1-1) and a pharmaceutically acceptable compound thereof a salt or a stereoisomer wherein: R ¹ and R ² are each independently selected from the side chain of H, methyl, ethyl, isopropyl or amino acid, and when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, the thiol group a hydroxyl group or a carboxyl group is selectively esterified; the amino acid is selected from the group consisting of glycine, alanine, leucine, isoleucine, serine or valine, and the amino acid is D-form or L- Alternatively, R ¹ and R ² may form a cyclopropyl or cyclobutyl group together with the atom to which they are attached; alternatively, R ¹ and R ⁵ may form an azacyclopropyl group together with the atom to which they are attached, Azacyclobutyl or azacyclopentyl.

The present invention provides a compound of the formula (Z), (Z-1), (Z`-1), (Z-1-1) or (Z`-1-1) and a pharmaceutically acceptable compound thereof a salt or stereoisomer wherein: R ^{3 is} selected from substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl , -(CH ₂ ) _m -O-methyl or -(CH ₂ ) _m -O-ethyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, OC(=O)OR ^3a or OC (= O) R ^3a group substituted with a substituent; R & lt ^3a is selected from substituted or unsubstituted methyl, ethyl, propyl or isopropyl group, when substituted, optionally further substituted 1-4 Substituted with a substituent selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R ^{M is} selected from F, Cl, Br, I or OH; ^{5 is} selected from H, methyl, ethyl, isopropyl or propyl; R ⁶ and R ⁷ are each independently selected from H, methyl, ethyl, isopropyl or propyl; optionally, R ⁶ and R ⁷ atom to which they are attached a Forming a cyclopropyl, cyclobutyl or cyclopentyl group, the cyclopropyl, cyclobutyl or cyclopentyl group optionally further being from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, methyl Substituted by a substituent of ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy; X is selected from the absence, -O-, -S- or -NR ^8a R ^{8 is} selected from substituted or unsubstituted H, methyl, ethyl, isopropyl, propyl, phenyl, acridinyl, pyridazinyl, morpholinyl, azacyclopentyl, oxacyclohexane Pentyl, oxaheterocyclyl, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p OR ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , when substituted, optionally further from 1 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, A Substituted by a substituent of an oxy group, an ethoxy group, an isopropoxy group or a propoxy group; R ^8a and R ^8b are each independently selected from a substituted or unsubstituted H, methyl, ethyl, isopropyl or propyl group. When substituted, optionally further from 1 to 6 selected from the group consisting of H, F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, iso , Propoxy or C _3-6 cycloalkyl substituted with a substituent; selective, R ^8a and R ^8b form a 3 to 6-membered ring together with the atoms to which they are attached, the ring contains 1-3 a hetero atom selected from N, O or S, optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy Substituted by a substituent; R ^8c , R ^{8d are} selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, phenyl, acridinyl, pyridazinyl, morpholinyl, aza Cyclopentyl or oxolyl, when substituted, optionally further from 1 to 6 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, C Substituted by a substituent of a methoxy group, an ethoxy group, an isopropoxy group or a propoxy group.

The present invention provides a compound of the formula (Z), (Z-1), (Z`-1), (Z-1-1) or (Z`-1-1) and a pharmaceutically acceptable compound thereof a salt or a stereoisomer wherein: Y is selected from O or S; R ¹ and R ² are each independently selected from H, -(CH ₂ ) _m -C _3-10 carbocycle, -(CH ₂ ) _m -3 a 10-membered heterocyclic ring, a C _1-10 alkyl group or an amino acid side chain, wherein when the amino acid side chain contains a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group is selectively esterified, the CH ₂ Or an alkyl group, a carbocyclic ring or a heterocyclic ring is optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, decyl, carboxyl, amino, decyl or ester groups, said heterocyclic ring Containing from 1 to 6 heteroatoms selected from N, O or S; optionally, R ¹ and R ² together with the atom to which they are attached may form a 3 to 6 membered ring, optionally further 0 to 3 Substituted by a substituent selected from the group consisting of F, Cl, Br, I, a hydroxyl group, a carboxyl group or an amino group, the ring containing 0 to 6 hetero atoms selected from N, O or S; preferably, R ¹ and R ² A cyclopropyl, cyclobutyl or cyclopentyl group may be formed together with the atom to which it is attached, said cyclopropyl, cyclobutyl group Cyclopentyl optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, carboxy or amino substituents; more preferably, R ¹ and R ² may form a ring together with the atoms to which they are attached a propyl or cyclobutyl group; preferably, the amino acid is selected from the group consisting of lysine, methionine, isoleucine, valine, threonine, tryptophan, serine, cysteine, tyrosine , aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine, preferably the amino acid is Glycine, alanine, leucine, isoleucine, serine or valine, and the amino acid is D-form or L-form; and the amino acid is D-form or L-form; Preferably, R ¹ and R ² are each independently selected from the side chain of H, methyl, ethyl, isopropyl or amino acid, and when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, the thiol group, hydroxyl group or carboxyl group is selectively selected. esterified substituted; more preferably, R ¹ and R ² are each independently selected from side chains of H, methyl, ethyl, isopropyl or amino group, when the amino acid side chain containing a mercapto group, When the carboxyl group or the mercapto group, a hydroxyl group or a carboxyl group optionally esterified; R ³ is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, - (CH _{2) m} - C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m- C _3-10 carbocyclic ring, -(CH ₂ ) _m - O-(CH ₂ ) _m -3 to 10 membered heterocyclic ring or -(CH ₂ ) _m -OC _1-4 alkyl group, optionally CH ₂ , alkenyl, alkynyl, alkyl, carbocyclic or heterocyclic ring Further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, C _1-4 alkyl, C _1-4 alkoxy, OC (= O) Substituted by a substituent of OR ^3a or OC(=O)R ^3a which contains from 1 to 6 heteroatoms selected from N, O or S; preferably, R ^{3 is} selected from substituted or unsubstituted Methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl, -(CH ₂ ) _m -O-methyl or -(CH _{2 m} -O-ethyl, when substituted, optionally further from 1 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, OC (= O) oR ^3a, or OC (= O) R ^3a is Substituted with a substituent; R ^3a is selected from substituted or unsubstituted methyl, ethyl, propyl or isopropyl group, when substituted, optionally further substituted by 1 to 4 substituents selected from H, F, Cl, Br, Substituted by a substituent of I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R ^{3a is} selected from C _1-4 alkyl, C _3-10 carbocyclic or 3 to 10 membered heterocyclic ring, The alkyl group, carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, C Substituted by a substituent of a _3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring containing from 1 to 6 heteroatoms selected from N, O or S; M _{2 is} selected from the group consisting of H, OH, L-OH, a leaving group or an L- leaving group; preferably, M ^{2 is} selected from R ^M , H, L-halogen or L-OH; R ^{M is} selected from F, Cl, Br, I or OH; a bond or a linking group; preferably, L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N (C _{1 -6} alkyl)-, -C(=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S (=O) ₂ -, -S(=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl) -; further more preferably, L is selected from a bond or L ₁ -W; L ₁ is selected from -O- -S-; Still further preferably, L is selected from a bond, O- phenyl _{-CH 2 -OC (= O),} O- phenyl _{-CH (CH 3) -OC (=} O), O- phenyl -C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ ) OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group is optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl Substituted with a substituent of NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy; selected from optionally substituted 0-10 W ^a phenyl group, C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group, the alkylene group, ^a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, O, S, N or (C=) of 0 to 10 carbon atoms in the alkenylene or alkynylene group, optionally substituted by 0 to 10 W ^a O) Alternatively, the divalent group formed above is optionally further substituted by 0 to 10 W ^a , the heterocyclic ring containing 0 to 4 hetero atoms selected from O, S or N; W ^{a is} selected from C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, -OC(=O)C _1-6 Group, - (= O) OC _1-6 alkyl, -NHC (= O) C _1-6 alkyl, -C (= O) NHC _1-6 alkyl, C _1-6 alkylthio, azido Base, cyano, nitro, halogen, amino, hydroxy, (=O), carboxyl, C _3-10 carbocyclic, 3 to 10 membered heterocyclic ring, -OC _3-10 carbocyclic ring or -O-3 to 10 member heterocyclic substituents, the heterocycle containing from 0 to 4 heteroatoms selected from O, S or N heteroatoms; 3-6 ring formed together with two atoms of W ^a can be selectively connected thereto, the The ring includes a carbocyclic or heterocyclic ring, and optionally further from 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy Substituted, the ring contains 0 to 4 hetero atoms selected from O, S or N; preferably, W is selected from phenyl or C _1-10 alkylene groups, in the alkylene group 0 to 10 carbon atoms are optionally substituted with a substituted or unsubstituted phenyl, O, S, N or (C=O), and the divalent group formed above or the phenyl group optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, azido, cyano, nitro, amino, hydroxy, (=O), carboxyl, methyl, ethyl, isopropyl, methoxy, B Oxyl, isopropoxy or cyclopropane Substituted by a substituent; R ^{5 is} selected from H or C _1-10 alkyl; preferably, R ^{5 is} selected from H, methyl, ethyl, isopropyl or propyl; optionally, R ¹ and R ⁵ together with the atom to which it is attached forms a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S, said ring optionally further being from 0 to 4 selected from H, F Substituted with a substituent of Cl, Br, I, OH, amino, carboxy, C _1-4 alkyl or C _1-4 alkoxy; preferably, R ¹ and R ⁵ may form together with the atom to which they are attached Azacyclopropyl, azetidinyl or azacyclopentyl, optionally alkoxypropyl, azetidinyl or azacyclopentyl, further optionally from 0 to 4 selected from F, Cl Substituted with a substituent of Br, I, hydroxy, methyl, ethyl, methoxy, ethoxy, carboxy or amino; more preferably, R ¹ and R ⁵ may form a nitrogen heterocycle together with the atom to which they are attached a propyl, azetidinyl or azacyclopentyl; R ⁶ and R ⁷ are each independently selected from H or C _1-10 alkyl; preferably, R ⁶ and R ⁷ are each independently selected from H, methyl. , ethyl, isopropyl or propyl; optionally, R ⁶ and R ⁷ together with the atom to which they are attached Forming a 3 to 6 membered ring containing 0 to 3 heteroatoms selected from N, O or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH Substituted with a substituent of a C _1-4 alkyl group or a C _1-4 alkoxy group; preferably, optionally, R ⁶ and R ⁷ together with the atom to which they are attached form a cyclopropyl group, a cyclobutyl group or a ring With pentyl, the cyclopropyl, cyclobutyl or cyclopentyl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, methyl, ethyl, isopropyl, propyl. Substituted by a substituent of a methoxy, ethoxy, isopropoxy or propoxy group; X is selected from the group consisting of absent, -O-, -S- or -NR ^8a -; R ^{8 is} selected from H, C _{1 -6} alkyl, -(CH ₂ ) _m C _3-6 carbocyclic ring, -(CH ₂ ) _m 3 to 6 membered heterocyclic ring, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p O ( CH ₂ ) _p R ^8c , —(CH ₂ ) _p O(C=O)R ^8d or —(CH ₂ ) _p O(C=O)OR ^8d , the alkyl group, carbocyclic ring or heterocyclic ring optionally further Substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl or C _1-4 alkoxy; the heterocyclic ring contains 1 to 3 a hetero atom selected from N, O or S; preferably, R ^{8 is} selected from substituted or unsubstituted H, methyl, ethyl, isopropyl, propyl, phenyl, acridinyl, pyridazinyl, morpholinyl, azacyclopentyl, oxolyl, oxacyclohexyl, -( CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p OR ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , when When substituted, optionally further 1 to 4 are selected from the group consisting of H, F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy Or substituted with a substituent of a propoxy group; R ^8a and R ^8b are each independently selected from H or C _1-6 alkyl, and the alkyl group is optionally further further selected from 0 to 6 selected from H, F, Cl, Br Substituted with a substituent of I, OH, carboxyl, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl; preferably, R ^8a and R ^8b are each independently selected from the group consisting of Or unsubstituted H, methyl, ethyl, isopropyl or propyl, when substituted, optionally further from 1 to 6 selected from H, F, Cl, Br, I, OH, methyl, B Substituted by a substituent of isopropyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy or C _3-6 cycloalkyl; optionally, R ^8a and R ^8b Connected atoms together a 3 to 6 membered ring containing 1 to 3 heteroatoms selected from N, O or S, optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH Substituted with a substituent of a C _1-4 alkyl group or a C _1-4 alkoxy group; preferably, optionally, R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring, said ring Containing 1 to 3 heteroatoms selected from N, O or S, optionally further 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C ₁ Substituted by a substituent of _-4 alkoxy; R ^8c , R ^{8d are} selected from H, C _1-6 alkyl, C _3-6 carbocyclic or 3 to 6 membered heterocyclic ring, said alkyl group, carbocyclic or heterocyclic The ring is optionally further substituted with from 0 to 6 substituents selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl or C _1-4 alkoxy, said heterocycle containing 1 to 3 hetero atoms selected from N, O or S; preferably, R ^8c , R ^{8d are} selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, phenyl, fluorene Pyridyl, pyridazinyl, morpholinyl, azacyclopentyl or oxolyl, when substituted, optionally further from 1 to 6 selected from H, F, Cl, Br, I, OH, Carboxyl group Substituted with a substituent of ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy; m, p are each independently selected from 0, 1, 2 or 3; Selected from 1, 2, 3, 4 or 5.

The present invention provides Selected from isopropoxymethyl, N,N-dimethylaminomethyl, ethoxymethyl, propyl, morpholinylmethyl, oxindolecyclopentyloxymethyl, hydroxymethyl, methoxy Methyl or phenoxymethyl, preferably hydroxymethyl, methoxymethyl or phenoxymethyl; R ¹ or R ² are each independently selected from H, methyl, 2-methylisopropyl a radical, isopropyl or ethoxymethyloxy; optionally R ¹ , R ² together with the atom to which they are attached form a cyclopropyl or cyclobutyl; R ^{5 is} independently selected from H or methyl; optionally , R ¹ , R ⁵ together with the atom to which they are attached form an azetidinyl or azacyclopentyl group; R ^{3 is} selected from a substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl, ring a propyl group, a cyclopropylmethylene group, a phenyl group or a benzyl group, when substituted, optionally further 1 to 4 selected from the group consisting of F, Cl, Br, I, OH, carboxyl, 1-cyclopropylethyl Substituted by a substituent of methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, OC(=O)OR ^3a or OC(=O)R ^3a ; R ^{3a is} selected from substituted or unsubstituted Substituted methyl, ethyl, isopropyl or propyl, when substituted, optionally further from 1 to 4 Substituted with a substituent selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R _{3 is} preferably methyl, ethyl, isopropyl, Benzyl, 2,2,2-trifluoroethyl, 2,2-dimethylpropoxymethyl, methoxyethyl, isopropoxycarbonyloxymethyl, butan-2-yl, 2 -methylpropyl, 2,6-diisopropylphenyl, 2-isopropyl-6-(1-cyclopropylethyl)phenyl, 2,6-di(1-cyclopropylethyl Phenyl, isopropoxycarbonyloxymethyl, 2-methylbutyl, pent-3-yl, 1-cyclopropylethyl or cyclopropyl; M _{2 is} selected from R ^M , H, L- Halogen or L-OH; R ^{M is} selected from Cl, Br, I or OH; L is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC ( =O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(= O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy Substituted by a substituent.

The present invention provides a compound of the formula (Z) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the compound of the formula (Z-2) or a pharmaceutically acceptable salt thereof or Stereoisomers, where:

Y is selected from O or S; R ^{8 is} selected from H or C _1-4 alkyl.

The present invention provides a compound of the formula (Z-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ^{8 is} selected from H or methyl.

The present invention provides a compound of the formula (Z-2) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: n is selected from 1.

The present invention provides a formula (Z-2) shown in a compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: M ² is selected from R ^M, H, L- halogen or L-OH; R ^M is selected from From F, Cl, Br, I or OH; L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N ( C _1-6 alkyl)-, -C(=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _{1 -6} alkyl) -; W is selected from optionally substituted 0-10 W ^a phenyl group, the C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group ^a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, 0 to 10 carbon atoms of the alkylene, alkenylene or alkynylene group optionally substituted by 0 to 10 W ^a Substituting S, N or (C=O), the divalent group formed above is optionally further substituted by 0 to 10 W ^a . The heterocyclic ring contains 0 to 4 impurities selected from O, S or N. An atom; W ^{a is} selected from a C _1-6 alkyl group, a halogen-substituted C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen-substituted C _1-6 alkoxy group, a C _3-6 cycloalkyl group, -OC(=O)C _1-6 alkyl, -(=O)OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl , C _1-6 alkylthio, azido, cyano, nitro, halogen, amino, hydroxy, (=O), carboxyl, C _3-10 carbocyclic, 3 to 10 membered heterocyclic ring, -OC _3-10 carbon substituted cycloalkyl or -O-3 to 10-membered heterocyclic group is substituted, the heterocycle containing from 0 to 4 heteroatoms selected from O, S or N heteroatoms; W ^a selective two atoms can be connected thereto Forming a 3 to 6 membered ring together, said ring comprising a carbocyclic or heterocyclic ring, and optionally further from 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C Substituted by a substituent of _1-4 alkoxy group, the ring contains 0 to 4 hetero atoms selected from O, S or N; the present invention provides a compound of the formula (Z-2) and a pharmaceutically acceptable thereof An acceptable salt or stereoisomer wherein the compound is selected from the group consisting of compounds of the formula (Z-2-1) or (Z`-2-1), wherein:

L is selected from a bond or L ₁ -W; L _{1 is} selected from -O- or -S-; W is selected from phenyl or C _1-10 alkylene groups, and 0 to 10 carbons in said alkylene group The atom is optionally substituted with a substituted or unsubstituted phenyl, O, S, N or (C=O), and the divalent group formed above or the phenyl group is optionally further selected from 0 to 5 From F, Cl, Br, I, azido, cyano, nitro, amino, hydroxy, (=O), carboxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyl Substituted by an oxy or cyclopropyl substituent.

The present invention provides a compound of the formula (Z-2-1) or (Z`-2-1) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: M ^{2 is} selected from the group consisting of H, L-halogen Or L-OH; L is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH _{3 2} -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O) OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, NH2, (C≡N Substituted with a substituent of NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy.

The present invention provides a compound of the formula (Z-2-1) or (Z'-2-1), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ¹ and R ² are each independently Selected from H, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _1-10 alkyl or amino acid side chain, when said amino acid side chain When a hydroxyl group, a mercapto group or a carboxyl group is contained, the hydroxyl group, the mercapto group or the carboxyl group is selectively esterified, and the CH ₂ , alkyl group, carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 3 selected from F, Cl, Br. Substituted with a substituent of I, hydroxy, thiol, carboxy, amino, thiol or ester group containing from 1 to 6 heteroatoms selected from N, O or S; optionally, R ¹ and R ⁵ together with the atom to which it is attached form a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S, said ring optionally further being from 0 to 4 selected from H, F, Substituted by a substituent of Cl, Br, I, OH, amino, carboxyl, C _1-4 alkyl or C _1-4 alkoxy; said amino acid is selected from the group consisting of lysine, methionine, isoleucine, guanidine Amino acid, threonine, tryptophan, serine, cysteine, tyrosine, day Amino acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine, and the amino acid is D-form or L-type; optionally, R ¹ and R ² may form a C _3-6 cycloalkyl group together with the atom to which they are attached, said cycloalkyl group optionally further being from 0 to 3 selected from the group consisting of F, Cl, Br, I. Substituted by a substituent of a hydroxyl group, a carboxyl group or an amino group.

The present invention provides a compound of the formula (Z-2-1) or (Z'-2-1), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ¹ and R ² are each independently selected from H a side chain of a methyl group, an ethyl group, an isopropyl group or an amino acid, which is selectively esterified when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group; optionally, R ¹ and R ⁵ An azacyclopropyl, azetidinyl or azacyclopentyl group may be formed together with the atom to which it is attached, said azacyclopropyl, azetidinyl or azacyclopentyl optionally further Substituting to four substituents selected from the group consisting of F, Cl, Br, I, hydroxy, methyl, ethyl, methoxy, ethoxy, carboxy or amino; the amino acid is selected from the group consisting of lysine, methionine, Isoleucine, valine, threonine, tryptophan, serine, cysteine, tyrosine, aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine Acid, leucine, phenylalanine, aspartame or arginine, and the amino acid is D-form or L-form; optionally, R ¹ and R ² may be together with the atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group, optionally further substituted by 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, carboxy or amino groups Substituted by the base.

The present invention provides a compound of the formula (Z-2-1) or (Z'-2-1), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ¹ and R ² are each independently selected from H a side chain of a methyl group, an ethyl group, an isopropyl group or an amino acid. When the side chain of the amino acid contains a mercapto group, a hydroxyl group or a carboxyl group, the mercapto group, the hydroxyl group or the carboxyl group is selectively esterified; the amino acid is selected from the group consisting of glycine and C. Alkyl, leucine, isoleucine, serine, valine or phenylalanine, and the amino acid is D-form or L-form; optionally, R ¹ and R ² may be attached thereto The atoms together form a cyclopropyl or cyclobutyl group; alternatively, R ¹ and R ⁵ may, together with the atom to which they are attached, form azacyclopropyl, azetidinyl or azacyclopentyl.

The present invention provides a compound of the formula (Z), (Z'-2), (Z-2), (Z'-2-1) or (Z'-2-1) and pharmaceutically acceptable salts thereof or a stereoisomer wherein: R ^{3 is} selected from substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl, - (CH ₂ ) _m -O-methyl or -(CH ₂ ) _m -O-ethyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br, I, OH, Carboxyl, amino, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, OC(=O)OR ^3a or Substituted by a substituent of OC(=O)R ^3a ; R ^{3a is} selected from a substituted or unsubstituted methyl, ethyl, isopropyl or propyl group, and when substituted, optionally further selected from 1 to 4 Substituted by a substituent of H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R ^{5 is} selected from H, methyl, ethyl, isopropyl or C R ⁶ and R ⁷ are each independently selected from H, methyl, ethyl, isopropyl or propyl; optionally, R ⁶ and R ⁷ together with the atom to which they are attached form a cyclopropyl, cyclobutyl or Cyclopentyl , the cyclopropyl, cyclobutyl or cyclopentyl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, methyl, ethyl, isopropyl, propyl, A Substituted by a substituent of an oxy group, an ethoxy group, an isopropoxy group or a propoxy group.

The present invention provides a compound of the formula (Z), (Z`-2), (Z-2), (Z`-2-1) or (Z`-2-1) and a pharmaceutically acceptable compound thereof a salt or stereoisomer wherein: n is selected from 1; R ⁶ and R ⁷ are each independently selected from H.

The present invention provides a compound of the formula (Z), (Z`-2), (Z-2), (Z`-2-1) or (Z`-2-1) and a pharmaceutically acceptable salt thereof Or a stereoisomer wherein: R ¹ and R ² are each independently selected from the side chain of H, methyl, ethyl, isopropyl or amino acid; said amino acid is selected from the group consisting of glycine, alanine, leucine Isoleucine, serine, proline or phenylalanine, and the amino acid is D-form or L-form; optionally, R ¹ and R ² may form a cyclopropane together with the atom to which they are attached R ^{3 is} selected from substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl, -(CH ₂ ) _m -O-methyl or -(CH ₂ ) _m -O-ethyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, 1-cyclopropylethyl, methyl, Substituted with a substituent of ethyl, isopropyl, propyl, OC(=O)OR ^3a or OC(=O)R ^3a ; R ^{3a is} selected from substituted or unsubstituted methyl, ethyl or isopropyl; R ^{M is} selected from F, Cl, Br, I or OH; and R ^{5 is} selected from H.

R ^{8 is} selected from substituted or unsubstituted H, methyl, ethyl, isopropyl, propyl, phenyl, acridine, pyridazinyl, morpholinyl, azacyclopentyl, oxetanyl , oxacyclohexyl, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p OR ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O( C=O)OR ^8d , when substituted, optionally further from 1 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy Substituted by a substituent of ethoxy, isopropoxy or propoxy; R ^8a , R ^8b are each independently selected from substituted or unsubstituted H, methyl, ethyl, isopropyl or propyl, when When substituted, optionally further from 1 to 6 selected from the group consisting of H, F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy Substituted by a substituent of a propyl or a C _3-6 cycloalkyl group; optionally, R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 From a hetero atom of N, O or S, the ring is optionally further from 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy Substituent Substituted; R ^8c , R ^{8d are} selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, phenyl, acridine, pyridazinyl, morpholinyl, azacyclopentyl Or oxacyclopentyl, when substituted, optionally further from 1 to 6 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, propyl, A Substituted by a substituent of an oxy group, an ethoxy group, an isopropoxy group or a propoxy group.

The present invention provides a compound of the formula (Z), (Z`-2), (Z-2), (Z`-2-1) or (Z`-2-1) and a pharmaceutically acceptable salt thereof Or stereoisomers, of which: Selected from one of the following structures:

M _{2 is} selected from R ^M , H, L-halogen or L-OH; R ^{M is} selected from Cl, Br, I or OH; L is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O- Phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH (CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further 0 to 4 are selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, iso Substituted by a substituent of a propoxy group, a propyl group or a propoxy group.

The present invention provides a compound of the formula (Z-5), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

G is selected from any group; M _{1 is} selected from OH or a leaving group; M _{1 is} preferably OH, F, Cl, Br or I; R ^{8 is} selected from H, C _1-6 alkyl, -(CH _{2 m} C _3-6 carbocyclic ring, -(CH ₂ ) _m 3 to 6 membered heterocyclic ring, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p O(CH ₂ ) _p R ^8c , -( CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , the alkyl group, carbocyclic ring or heterocyclic ring optionally further from 0 to 4 selected from H, Substituted with a substituent of F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; said heterocyclic ring containing from 1 to 3 heteroatoms selected from N, O or S; R ^8a and R ^8b are each independently selected from H or C _1-6 alkyl, and the alkyl group is optionally further further selected from 0 to 6 selected from H, F, Cl, Br, I, OH, C _1-4 alkane. Substituted by a substituent of a C _1-4 alkoxy group or a C _3-6 cycloalkyl group; optionally, R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring, said ring containing 1 Up to 3 heteroatoms selected from N, O or S, optionally further 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 Substituted by a substituent of an alkoxy group; R ^8c , R ^{8d are} selected from H, C _1-6 alkyl, C _3-6 carbocyclic or 3 to 6 membered heterocyclic ring, said alkyl group, The carbocyclic or heterocyclic ring is optionally further substituted with from 0 to 6 substituents selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl or C _1-4 alkoxy, The heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S; m, p are each independently selected from 0, 1, 2 or 3; n is selected from 1, 2 or 3; s is selected from 1, 2 , 3, 4, 5 or 6; the definition of R ⁶ , R ⁷ , L, X and the general formula (Z), (Z`-2), (Z-2), (Z`-2-1) Or the definitions are the same as (Z`-2-1).

In the present invention, the condition is that LG is not a C _1-10 alkoxy group, a halogenated C _1-6 alkoxy group, a 1-tert-butoxycarbonylmethylhexyloxy group, a benzyloxy group or a phenoxy group. 2-isopropyl-5-methylcyclohexyloxy, allyloxy, 3-methylcyclopentyloxy, phenylamino, alkyl-substituted amino, N,N-dipropenylamino, or Or when When selected from an alkyl group or a substituted benzyl group, L is not S.

The present invention provides a compound of the formula (Z-5) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ⁶ and R ⁷ are each independently selected from the group consisting of H, methyl, ethyl, and isopropyl. Or a propyl group; optionally, R ⁶ and R ⁷ together with the atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group, said cyclopropyl, cyclobutyl or cyclopentyl optionally further 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, amino, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy Substituted; X is selected from the group consisting of -O-, -S- or -NR ^8a -; M _{1 is} selected from OH, F, Cl, Br or I; R ^{8 is} selected from substituted or unsubstituted H, methyl, Ethyl, isopropyl, propyl, phenyl, acridine, pyridazinyl, morpholinyl, azacyclopentyl, oxetanyl, -(CH ₂ ) _m NR ^8a R ^8b , -( CH ₂ ) _p OR ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , when substituted, optionally further 1 to 4 Substituted from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy Substituted; R ^8a, R ^8b are independently selected from a substituted or unsubstituted H, methyl, ethyl, propyl or isopropyl group, when substituted, optionally further having 1 to 6 selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy or C _3-6 cycloalkyl Substituted by a substituent; optionally, R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S, said ring Further selected by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; R ^8c , R ^{8d are} selected from substitution or Unsubstituted H, methyl, ethyl, propyl, isopropyl, phenyl, acridine, pyridazinyl, morpholinyl, azacyclopentyl or oxolyl, when substituted, Optionally further from 1 to 6 selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or Substituted by a substituent of a propoxy group; m, p are each independently selected from 0, 1, 2 or 3; n is selected from 1, 2, 3 4 or 5, preferably 1, 2 or 3; s is selected from 1,2,3,4,5 or 6.

The present invention provides a compound of the formula (Z-5) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: G is selected from any group containing at least one functional group selected from the group consisting of Through this functional group, it is linked to Q or LQ (Q definition is described below. The functional group of G is covalently bonded to Q or LQ to form a prodrug), and the functional group is selected from a carboxyl group, a hydroxyl group, a nitrogenoxy group, and an oxygen nitrogen. Base, mercapto, amino, amine, sulfhydryl, decyl, decyl, decyl, ureido, amine or sulfhydryl.

The present invention provides a compound of the formula (Z-5) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: G contains at least one group selected from the group consisting of a functional group and L Connected, the functional group is selected from the group consisting of a carboxyl group, a hydroxyl group, a nitrogenoxy group, a oxynitride group, a thiol group, an amino group, an amine group, a fluorenyl group, a fluorenyl group, an anthranyl group, a fluorenyl group, a ureido group, an amine group or a hydrazine group. Wherein: the carboxyl group-containing compound is selected from the group consisting of carboxylic acid compounds and derivatives thereof; the hydroxyl group-containing compound is selected from the group consisting of phenol compounds, naphthol compounds, and heterocyclic phenol compounds , primary alcohol compounds, secondary alcohol compounds, enol compounds, amino alcohol compounds and derivatives thereof; nitrogen oxide functional group-containing compounds are selected from nitrogen oxides or oxygen nitrogen compounds and their derivatives The guanidine-functional compound is selected from the group consisting of anthraquinone compounds and derivatives thereof; the amino group-containing compound is selected from the group consisting of ammonia compounds and derivatives thereof; and the amine group-containing compound is selected from the group consisting of fatty amine compounds and cyclic amines. a compound, an aromatic amine compound, a hydroxylamine compound, and a derivative thereof; the thiol group-containing compound is selected from the group consisting of an anthracene compound, a sulfonium compound, and a derivative thereof; and the thiol group-containing compound is selected from the group consisting of a quinone compound And derivatives thereof; biological activities containing a guanamine functional group and selected from the group consisting of a chain amide compound, an intrinsic amine compound, a sulfonamide compound, and derivatives thereof; the thiol group-containing compound is selected from the group consisting of ruthenium Class of compounds and derivatives thereof; compounds containing a ureido group are selected from the group consisting of urea compounds and derivatives thereof; carbonaceous An amine compound selected from the carbonate functional group is an amine compound and derivatives thereof; sulfhydryl-containing compounds selected from mercaptans functional group compound, sulfur, phenolic compounds and derivatives thereof.

The present invention provides a compound of the above formula (Z-5), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the corresponding compound of the formula (GH) containing the functional group is selected from Table 1. One of the structures:

A compound of the formula (I) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein

L is selected from a bond or a linking group; Q is selected from or ; R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, n, s are as defined by the formula (Z), (Z-1) or (Z ' -1) The definition is consistent; the definition of G is consistent with the definition of the general formula (Z-5); preferably, G contains at least one group selected from the following functional groups, and is linked to L through the functional group, and the functional group is selected From: carboxy, hydroxy, nitrooxy, oxynitro, sulfhydryl, amino, amine, sulfhydryl, fluorenyl, decyl, fluorenyl, ureido, amine or sulfhydryl; wherein: carboxy-functional compound It is selected from the group consisting of carboxylic acid compounds and derivatives thereof; the hydroxyl group-containing compound is selected from the group consisting of phenol compounds, naphthol compounds, heterocyclic phenol compounds, primary alcohol compounds, secondary alcohol compounds, enol compounds, amines a base alcohol compound and a derivative thereof; the nitrogen oxide functional group-containing compound is selected from the group consisting of nitrogen oxides or oxygen nitrogen compounds and derivatives thereof; the phosphonium functional group-containing compound is selected from the group consisting of anthraquinone compounds and derivatives thereof; The compound of the amino group is selected from the group consisting of ammonia compounds and derivatives thereof; The amine functional group compound is selected from the group consisting of a fatty amine compound, a cyclic amine compound, an aromatic amine compound, a hydroxylamine compound, and a derivative thereof; the thiol group-containing compound is selected from the group consisting of an anthracene compound, a sulfonium compound, and the like. a derivative; the thiol-containing functional group-containing compound is selected from the group consisting of an anthraquinone compound and a derivative thereof; a biological activity of a guanamine-containing functional group and a compound selected from the group consisting of a chain amide compound, an intrinsic amine compound, a sulfonamide compound, and Their derivatives; the thiol-containing functional group-containing compound is selected from the group consisting of hydrazine compounds and derivatives thereof; the ureido-functional group-containing compound is selected from the group consisting of urea compounds and derivatives thereof; and the amine carbonate-functional compound is selected from the group consisting of amine carbonates The compounds and their derivatives; the thiol-containing functional group-containing compound is selected from the group consisting of thiol compounds, thiophenol compounds, and derivatives thereof.

The present invention provides a compound of the formula (I) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is selected from a bond or a linking group; preferably, L is selected from a bond or all can be dissociated a linking group for G; preferably, L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N ( C _1-6 alkyl)-, -C(=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _{1 -6} alkyl)-; further preferably, L is selected from a bond or L ₁ -W; L _{1 is} selected from -O- or -S-; more preferably, L is a bond, O-phenyl-CH _2- OC(=O), O-phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group is further further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropoxy, isopropoxy, propoxy group, or propyl substituents; W is selected from optionally substituted 0-10 W ^a is Group, C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group, said alkylene, alkenylene, or alkynylene of 0-10 carbons The atom is optionally substituted by 0 to 10 W ^a substituted C _3-6 carbocyclic ring, 3 to 10 membered heterocyclic ring, O, S, N or (C=O), and the divalent group formed above is optional. Further substituted by 0 to 10 W ^a , the heterocyclic ring containing 0 to 4 hetero atoms selected from O, S or N; W ^{a is} selected from C _1-6 alkyl, halogen substituted C _1-6 alkane , C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, —OC(=O)C _1-6 alkyl, —(=O)OC _{1- 6} alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _1-6 alkylthio, azido, cyano, nitro, halogen, Substituted with a substituent of an amino group, a hydroxyl group, (=O), a carboxyl group, a C _3-10 carbocyclic ring, a 3 to 10 membered heterocyclic ring, a -OC _3-10 carbocyclic ring or a -O-3 to 10 membered heterocyclic ring, heterocycle containing from 0 to 4 heteroatoms selected from O, S or N heteroatoms; form 3-6 ring atoms, W ^a selective two together can be connected thereto, said ring comprising a carbocyclic or a heterocyclic ring, And optionally further from 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C ₁ Substituted by a substituent of _-4 alkoxy, said ring containing 0 to 4 heteroatoms selected from O, S or N; preferably, W is selected from phenyl or C _1-10 alkylene, 0 to 10 carbon atoms in the alkylene group are optionally substituted by a substituted or unsubstituted phenyl group, O, S, N or (C=O), and the divalent group or the above formed The phenyl group optionally further selected from 0 to 5 is selected from the group consisting of F, Cl, Br, I, azido, cyano, nitro, amino, hydroxy, (=O), carboxy, methyl, ethyl, iso Substituted by a substituent of a propyl group, a methoxy group, an ethoxy group, an isopropoxy group or a cyclopropyl group; the present invention provides a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof And wherein R ¹ and R ² are each independently selected from H, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _1-10 alkyl group Or an amino acid side chain, when the amino acid side chain contains a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group is selectively esterified, and the CH ₂ , alkyl group, carbocyclic ring or heterocyclic ring is optionally further From 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxyl, sulfhydryl, carboxyl, amino, fluorenyl Group substituted by an ester group substituted with a heterocyclic ring containing from 1 to 6 selected from N, O, or S heteroatom; a selective, R ¹ and R ⁵ form together with the atoms to which they are attached a 3-6 ring The ring contains 1 to 3 heteroatoms selected from N, O or S, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, amino, carboxyl, C Substituted by a substituent of _1-4 alkyl or C _1-4 alkoxy; said amino acid is selected from the group consisting of lysine, methionine, isoleucine, valine, threonine, tryptophan, serine, Cysteine, tyrosine, aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine And the amino acid is D-form or L-form; optionally, R ¹ and R ² may form a C _3-6 cycloalkyl group together with the atom to which they are attached, the cycloalkyl group optionally further being 0 Substituted to three substituents selected from the group consisting of F, Cl, Br, I, a hydroxyl group, a carboxyl group or an amino group.

The present invention provides a compound of the formula (I), wherein R ¹ and R ² are each independently selected from H, methyl, ethyl, isopropyl, and a pharmaceutically acceptable salt or stereoisomer thereof. Or a side chain of an amino acid, when the amino acid side chain contains a mercapto group, a hydroxyl group or a carboxyl group, the mercapto group, the hydroxyl group or the carboxyl group is selectively esterified; optionally, R ¹ and R ⁵ may form an aza together with the atom to which they are attached a cyclopropyl, azetidinyl or azacyclopentyl group, optionally further from 0 to 4 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, hydroxy, methyl, ethyl, methoxy, ethoxy, carboxy or amino; said amino acid is selected from the group consisting of lysine, methionine, isoleucine, valine, sul Amino acid, tryptophan, serine, cysteine, tyrosine, aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine , asparagine or arginine, and the amino acid is D- or L- type type; form a ring together selectivity, R ¹ and R ² may be connected with their atomic a cyclopropyl, cyclobutyl or cyclopentyl group, optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, carboxy or amino Replace.

The present invention provides a compound of the formula (I), wherein R ¹ and R ² are each independently selected from H, methyl, ethyl, isopropyl, and a pharmaceutically acceptable salt or stereoisomer thereof. Or a side chain of an amino acid, when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, the thiol group, the hydroxyl group or the carboxyl group is selectively esterified; the amino acid is selected from the group consisting of glycine, alanine, leucine, and isoleucine Acid, serine or valine, and said amino acid is D-form or L-form; optionally, R ¹ and R ² may form a cyclopropyl or cyclobutyl group together with the atom to which they are attached; And R ¹ and R ⁵ may form an azacyclopropyl, azetidinyl or azacyclopentyl group together with the atom to which they are attached.

The present invention provides a compound of the formula (I) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of the formula (II), (II'), (III) or ( Compounds shown in III`): Wherein L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N(C _1-6 alkyl)-, -C(=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl)-; optionally from 0 to 10 W ^a is substituted phenyl, C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group, the alkylene group, ^a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, O, S, N or (C=O) of 0 to 10 carbon atoms in the alkenyl or alkynylene group, optionally substituted by 0 to 10 W ^a Alternatively, the divalent group formed above is optionally further substituted by 0 to 10 W ^a , the heterocyclic ring containing 0 to 4 hetero atoms selected from O, S or N; W ^{a is} selected from C _{1 -6} alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, -OC(=O)C _{1 -6} alkyl, -(=O)OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _1-6 alkylthio , azido, cyano, nitro, halogen, amino, hydroxy, (=O), carboxy, C _3-10 carbocyclic, 3 to 10 membered heterocyclic ring, -OC _3-10 carbocyclic ring or -O-3 To 10 members of the heterocyclic ring Group is substituted, the heterocycle containing from 0 to 4 heteroatoms selected from O, S or N heteroatoms; 3-6 ring formed together with two atoms of W ^a can be selectively connected thereto, said ring comprising Carbocyclic or heterocyclic, and optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy, The ring described contains from 0 to 4 heteroatoms selected from O, S or N.

The present invention provides a compound of the formula (I) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of the formula (IV), (IV-1), (IV) ' ) or the compound shown by (IV ' -1):

The present invention provides a compound of the formula (II), (II'), (III), (III'), (IV), (IV ' ), (IV-1) or (IV ' -1) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC(=O) , O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group is further further selected from 0 to 4 selected from H, F, Cl, Br, Substituents for I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy Replace. The present invention provides a compound of the formula (II), (II'), (III), (III'), (IV), (IV ' ), (IV-1) or (IV ' -1) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ¹ and R ² are each independently selected from the side chain of H, methyl, ethyl, isopropyl or amino acid, and when the amino acid side chain contains a thiol group or a hydroxyl group Or a carboxyl group, the thiol group, the hydroxyl group or the carboxyl group is selectively esterified; the amino acid is selected from the group consisting of glycine, alanine, leucine, isoleucine, serine or valine, and the amino acid is D-form or L-form; optionally, R ¹ and R ² may form a cyclopropyl or cyclobutyl group together with the atom to which they are attached.

The present invention provides a compound of the formula (II), (II'), (III), (III'), (IV), (IV ' ), (IV-1) or (IV ' -1) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ^{8 is} selected from H, phenyl or C _1-4 alkyl.

The present invention provides a compound of the formula (II), (II'), (III), (III'), (IV), (IV ' ), (IV-1) or (IV ' -1) and A pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ^{8 is} selected from H or methyl, and s is preferably 1 or 2.

The present invention provides a compound of the formula (IV-1-1) or (IV ' -1-1), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein

L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N(C _1-6 alkyl)-, -C (=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S (=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl)-; is selected from 0-10 W ^a substituted phenyl group, the C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group, the alkylene group, alkenylene group Or ^a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, an O, S, N or (C=O) substituted with 0 to 10 carbon atoms in the alkynylene group, optionally substituted with 0 to 10 W ^a The divalent group formed above is optionally further substituted by 0 to 10 W ^a , the heterocyclic ring containing 0 to 4 hetero atoms selected from O, S or N; W ^{a is} selected from C _1-6 Alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, -OC(=O)C _1-6 Alkyl, -(=O)OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _1-6 alkylthio, stack Nitro, cyano, nitro, halogen, amino, hydroxy, (=O), carboxy, C _3-10 carbocyclic, 3 to 10 membered heterocyclic ring, -OC _3-10 carbocyclic ring or -O-3 to 10 Substituent of heterocyclic ring Generation membered heterocyclic ring containing 0-4 selected from O, S or N heteroatoms; 3-6 ring formed together with two atoms of W ^a can be selectively connected thereto, the carbocyclic ring comprises Or a heterocyclic ring, and optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy, said The ring contains 0 to 4 hetero atoms selected from O, S or N; the present invention provides a compound of the formula (IV-1-1) or (IV ' -1) and a pharmaceutically acceptable salt thereof Or a stereoisomer wherein L is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C (CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC( =O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, NH2 ( Substituted by a substituent of C≡N), NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy.

The present invention provides a compound of the formula (IV-1-1) or (IV ' -1) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² are each independently selected From H, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _1-10 alkyl or amino acid side chain, when said amino acid side chain contains In the case of a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, the mercapto group or the carboxyl group is selectively esterified, and the CH ₂ , alkyl group, carbocyclic ring or heterocyclic ring is optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, Substituted by a substituent of a hydroxyl group, a thiol group, a carboxyl group, an amino group, a thiol group or an ester group containing from 1 to 6 hetero atoms selected from N, O or S; optionally, R ¹ and R ⁵ A 3 to 6 membered ring is formed together with the atom to which it is attached, said ring containing 1 to 3 heteroatoms selected from N, O or S, said ring optionally further being 0 to 4 selected from H, F, Cl Substituted with a substituent of Br, I, OH, amino, carboxyl, C _1-4 alkyl or C _1-4 alkoxy; said amino acid is selected from the group consisting of lysine, methionine, isoleucine, guanidine Acid, threonine, tryptophan, serine, cysteine, tyrosine, Aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine, and the amino acid is D-form Or L-form; optionally, R ¹ and R ² may form a C _3-6 cycloalkyl group together with the atom to which they are attached, said cycloalkyl group optionally further being from 0 to 3 selected from the group consisting of F, Cl, Br Substituted by a substituent of I, a hydroxyl group, a carboxyl group or an amino group.

The present invention provides a compound of the formula (IV-1-1) or (IV ' -1) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² are each independently selected From the side chain of H, methyl, ethyl, isopropyl or amino acid, when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, the thiol group, hydroxyl group or carboxyl group is selectively esterified; optionally, R ¹ and R ⁵ may form an azacyclopropyl, azetidinyl or azacyclopentyl group together with the atom to which it is attached, optionally a further further azacyclopropyl, azetidinyl or azacyclopentyl Substituted by 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, methyl, ethyl, methoxy, ethoxy, carboxy or amino; the amino acid is selected from the group consisting of lysine, Methionine, isoleucine, valine, threonine, tryptophan, serine, cysteine, tyrosine, aspartic acid, histidine, glutamic acid, glutamine, glycine, Alanine, leucine, phenylalanine, aspartame or arginine, and the amino acid is D-form or L-form; optionally, R ¹ and R ² may be attached thereto original Forming a cyclopropyl, cyclobutyl or cyclopentyl group together, the cyclopropyl, cyclobutyl or cyclopentyl group optionally further being from 0 to 3 selected from F, Cl, Br, I, hydroxy, carboxy or amino groups Substituted by a substituent.

The present invention provides a compound of the formula (IV-1-1) or (IV ' -1) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² are each independently selected From the side chain of H, methyl, ethyl, isopropyl or amino acid, when the amino acid side chain contains a mercapto group, a hydroxyl group or a carboxyl group, the mercapto group, the hydroxyl group or the carboxyl group is selectively esterified; the amino acid is selected from the group consisting of glycine Alanine, leucine, isoleucine, serine or valine, and the amino acid is D-form or L-form; optionally, R ¹ and R ² may be together with the atom to which they are attached Forming a cyclopropyl or cyclobutyl group; alternatively, R ¹ and R ⁵ may, together with the atom to which they are attached, form azacyclopropyl, azetidinyl or azacyclopentyl.

The present invention provides a compound of the formula (I), (II), (II'), (III), (III'), (IV) or (IV ' ), and a pharmaceutically acceptable salt thereof or a stereoisomeric thereof a structure, wherein G is selected from any group containing at least one functional group selected from the group consisting of a functional group selected from a carboxyl group, a hydroxyl group, a nitrogenoxy group, and an oxygen nitrogen. a base, a mercapto group, an amino group, an amine group, a fluorenyl group, a fluorenyl group, a decyl group, a fluorenyl group, a ureido group, a thiol group, an amine carbonate or a thiophenol group, wherein: the carboxyl group-containing compound is selected from the group consisting of a carboxylic acid compound and a derivative thereof; a hydroxyl functional group-containing compound is selected from the group consisting of a phenol compound, a naphthol compound, a heterocyclic phenol compound, a primary alcohol compound, a secondary alcohol compound, an enol compound, an amino alcohol compound, and the like a derivative; the oxy-functional group-containing compound is selected from the group consisting of nitrogen oxides or oxygen-nitrogen compounds and derivatives thereof; the ruthenium-functional compound is selected from the group consisting of anthraquinones and derivatives thereof; From ammonia compounds and their derivatives The amino group-containing functional group-containing compound is selected from the group consisting of a fatty amine compound, a cyclic amine compound, an aromatic amine compound, a hydroxylamine compound, and a derivative thereof; and the thiol group-containing compound is selected from the group consisting of an anthracene compound and a sulfonium compound. And derivatives thereof; the thiol-containing functional group-containing compound is selected from the group consisting of anthraquinone compounds and derivatives thereof; biological activity of a guanamine-containing functional group and a chain-like amide compound, an intrinsic amine compound, a sulfonamide a compound of the formula and a derivative thereof; the compound containing a mercapto group is selected from the group consisting of an anthracene compound and a derivative thereof; the compound containing a urea group functional group is selected from the group consisting of a urea compound and a derivative thereof; and the compound containing an amine carbonate functional group is selected from the group consisting of The amine carbonate-based compound and the derivative thereof; the thiol-functional group-containing compound is selected from the group consisting of a thiol compound, a thiophenol compound, and a derivative thereof; and a compound containing the above functional group is bonded to the L phase through the functional group.

The present invention provides a compound of the formula (I), (II), (II'), (III), (III'), (IV) or (IV ' ), and a pharmaceutically acceptable salt thereof or a stereoisomeric thereof A construct in which GH is identical to the definition of GH as described for the compound of formula (Z-5).

The present invention provides a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound comprises a compound of the formula (VIII) or (VIII ' ) and a pharmaceutically acceptable compound thereof Salt or stereoisomer,

L is selected from a bond, L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N(C _1-6 alkyl)-, -C (=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S (=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl)-; is selected from 0-10 W ^a substituted phenyl group, the C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group, the alkylene group, alkenylene group Or ^a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, an O, S, N or (C=O) substituted with 0 to 10 carbon atoms in the alkynylene group, optionally substituted with 0 to 10 W ^a The divalent group formed above is optionally further substituted by 0 to 10 W ^a wherein the heterocyclic ring contains 0 to 4 hetero atoms selected from O, S or N; W ^{a is} selected from C _1-6 alkane , halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, -OC(=O)C _1-6 alkane , -(=O)OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _1-6 alkylthio, azide Base, cyano, nitro, halogen, amino, hydroxy, (=O), carboxyl, C _3-10 carbocyclic, 3 to 10 membered heterocyclic ring, -OC _3-10 carbocyclic ring or -O-3 to 10 member Heterocyclic substituent The heterocycle containing from 0 to 4 heteroatoms selected from O, S or N heteroatoms; 3-6 ring formed together with two atoms of W ^a can be selectively connected thereto, said ring or ring comprising carbon a heterocyclic ring, and optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy, said ring Containing 0 to 4 hetero atoms selected from O, S or N; L is preferably a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC (= O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O ), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group is optionally further selected from 0 to 4 selected from H, F, Cl, Substitution of Br, I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy Substituted; L is more preferably OCH(CH ₃ ), OC(CH ₃ ) ₂ or OCH ₂ ; R ¹ and R ² are each independently selected from H, a side chain of a natural or pharmaceutically acceptable amino acid or C _1-4 An alkyl group, wherein the amino acid side chain contains a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group Optional be esterified; selectively, R ¹ and R ² form a C _3-6 cycloalkyl group together with the carbon atom to which they are attached; said alkyl, cycloalkyl optionally further substituted with 0 to 3 substituents selected from Substituted by a substituent of F, Cl, Br, I, hydroxy or amino; R ^{3 is} selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m- C _3-10 carbocyclic ring, -(CH ₂ ) _m -O -(CH ₂ ) _m -3 to 10 membered heterocyclic ring or -(CH ₂ ) _m -OC _1-4 alkyl group, said CH ₂ , alkenyl group, alkynyl group, alkyl group, carbocyclic ring or heterocyclic ring optionally further From 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, C _1-4 alkyl, C _1-4 alkoxy, OC (=O Substituted by a substituent of OR ^3a or OC(=O)R ^3a containing from 1 to 6 heteroatoms selected from N, O or S; R ^{3a is} selected from C _1-4 alkyl, C _{3 a -10} carbocyclic ring or a 3 to 10 membered heterocyclic ring, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-4 Substituted by a substituent of an alkyl group, a C _1-4 alkoxy group, a C _3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring containing from 1 to 6 selected from N, a hetero atom of O or S; R ^{4 is} selected from , , or ; A is selected from F, Cl, Br, I, -OR ^4b or ; B is selected from ; T is selected from H, F, OH or carboxyl; R is selected from H, -C(=O)OC _1-4 alkyl, -C(=O)O-(3-8 membered carbocyclyl), -C (=O)O-(5-8 membered heterocyclic group) or ; R ^4a1 , R ^4a2 , R ^4a3 , R ^4a4 are each independently selected from H, F, Cl, Br, I, C _1-4 alkoxy or C _1-4 alkyl, C _3-5 carbocyclyl or - C _1-4 alkyl-C _3-5 carbocyclic group, said alkyl group, alkoxy group, carbocyclic group may be further further selected from 0 to 5 selected from OH, F, Cl, Br, I, C Substituted by a substituent of _1-4 alkyl, C _1-4 alkoxy, -C(=O)OC _1-4 alkyl or C _3-5 carbocyclyl; R ^{4a5 is} selected from H, F, Cl, Br, I or C _1-4 alkyl, said alkyl optionally further substituted by 1 to 5 substituents selected from OH, F, Cl, Br, I or -C(=O)OC _1-4 alkyl Substituted; R ^4b1 and R ^4b2 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, C _1-4 alkyl, C _1-4 alkoxy, 3 to 5 membered carbocyclyl Or a 3 to 5 membered heterocyclic group, the alkyl group, alkoxy group, carbocyclic group or heterocyclic group optionally further selected from 0 to 5 selected from the group consisting of a hydroxyl group, a C _1-4 alkyl group, and a C _1-4 alkane group. Substituted by a substituent of an oxy group, a 3 to 5 membered carbocyclyl group or a 3 to 5 membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O or S; optionally, R ^4b1 and R ^4b2 and form a 3-5 ring, said ring may be 3-5 3-5 0-2 ring containing from N, O or S heteroatom, and optionally may be further formed with 0 to 4 substituents selected from F, Cl, Br, hydroxy, C _1-4 alkyl, Substituted by a substituent of a C _1-4 alkoxy group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S R ^{4b5 is} selected from H or a hydroxyl group; R ^4b3 , R ^4b4 , R ^4b6 and R ^4b7 are each independently selected from H, F, Cl, Br, I, hydroxy, C _1-4 alkyl or C _1-4 alkoxy R ^4b8 , R ^4b9 and R ^4b10 are each independently selected from H, F, Cl, Br, I, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, 3 to 5 membered carbocyclyl or 3 To a 5-membered heterocyclic group, the alkyl, alkoxy, carbocyclic or heterocyclic group is further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, C _1-4 alkyl Substituted by a substituent of a C _1-4 alkoxy group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, O or S Atom; optionally, R ^4b8 and R ^4b9 , R ^4b9 and R ^4b10 or any of R ^4b8 and R ^4b10 form a 3 to 5 membered ring, and the 3 to 5 membered ring contains 0 to 2 selected from N , a hetero atom of O or S, and the formed 3 to 5 membered ring is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, 3 to Substituted by a 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O or S; R ^4c1 and R ^4c2 are each independently selected from H, hydroxy, C _1-4 alkyl, cyano, azido, C _1-4 alkoxy or 3 to 5 membered carbocyclyl, said alkyl, alkoxy or carbocyclic group may be optionally Further substituted by 0 to 3 substituents selected from a C _1-4 alkyl group or a C _1-4 alkoxy group.

R ^4c3 , R ^4c4 and R ^4c5 are each independently selected from H or C _1-4 alkyl, wherein at least one of R ^4c3 , R ^4c4 and R ^4c5 is H; R ^4d1 , R ^4d2 , R ^4d3 , R ^4d4 , R ^4d5 , R ^4d6 , R ^4d7 , R ^4d8 are each independently selected from H, F, Cl, Br, I, C _1-4 alkoxy or C _1-4 alkyl, C _3-5 carbocyclyl or -C _1-4 alkyl-C _3-5 carbocyclyl, said alkyl, alkoxy, carbocyclic group may optionally be further from 0 to 5 selected from OH, F, Cl, Br, I, C ₁ Substituted by a substituent of _-4 alkyl, C _1-4 alkoxy, -C(=O)OC _1-4 alkyl or C _3-5 carbocyclyl; R ^{5 is} selected from H or C _1-4 alkane R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl; R ^{8 is} selected from H, C _1-6 alkyl, -(CH ₂ ) _m C _3-6 carbocyclic, -(CH _{2 m} 3 to 6 member heterocycle, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p O(CH ₂ ) _p R ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , the alkyl, carbocyclic or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C Substituted by a substituent of _1-4 alkyl or C _1-4 alkoxy; said heterocyclic ring containing 1 to 3 hetero atoms selected from N, O or S; R ^8a and R ^8b are each independently selected from H Or a C _1-6 alkyl group, the alkyl group optionally further from 0 to 6 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl, C _1-4 alkoxy Or a substituent of a C _3-6 cycloalkyl group; optionally, R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 selected from N, O or a hetero atom of S, which ring is optionally further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; R ^8c , R ^{8d are} selected from H, C _1-6 alkyl, C _3-6 carbocyclic or 3 to 6 membered heterocyclic ring, and the alkyl, carbocyclic or heterocyclic ring is optionally further selected from 0 to 6 Substituted by a substituent of H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl or C _1-4 alkoxy containing from 1 to 3 selected from N, O or S a hetero atom; X is selected from the group consisting of -O-, -S- or -NR ⁹ -; R ^{9 is} selected from H or C _1-4 alkyl; optionally, R ⁸ and R ⁹ are formed with the attached nitrogen a heterocyclic ring of 3 to 6 members, which is optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, hydroxy, amino, C _1-4 alkyl or -OC _1-4 alkyl, The heterocyclic ring contains 1 to 3 impurities selected from N, O or S Sub; Q is selected from 1, 2 or 3; m is selected from 2 or 3; n is selected from 3, 4 or 5.

The present invention provides a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound comprises a compound of the formula (VIII) or (VIII ' ) and a pharmaceutically acceptable compound thereof Salt or stereoisomer, wherein R ¹ and R ² are each independently selected from H, a side chain of a natural or pharmaceutically acceptable amino acid or a C _1-4 alkyl group, the amino acid side chain containing a hydroxyl group, a thiol group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group is selectively esterified; optionally, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group; the alkyl group, cycloalkyl group Further selected to be substituted by 0 to 3 substituents selected from F, Cl, Br, I, hydroxy or amino; R ^{3 is} selected from substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl , cyclopropyl, cyclopropylmethylene, phenyl, benzyl, -(CH ₂ ) _m -O-methyl or -(CH ₂ ) _m -O-ethyl, when substituted, optionally further 1 to 4 are selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy Base, isopropoxy, propoxy, OC (= O) substituted with a substituent of OR ^3a or OC(=O)R ^3a ; R ^{3a is} selected from a substituted or unsubstituted methyl, ethyl, isopropyl or propyl group, and when substituted, optionally further Substituted to 4 substituents selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R ^{4 is} selected from , , , , , ,

or R ^{5 is} selected from H or C _1-4 alkyl; R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl; R ^{8 is} selected from C _1-4 alkyl, -(CH ₂ ) _m - OC _1-4 alkyl, -(CH ₂ ) _m -C _3-8 carbocyclic ring, -(CH ₂ ) _m -C _3-8 heterocyclic ring, -(CH ₂ ) _m -C(=O)-C _{3 -8} carbocycle, -(CH ₂ ) _m -C(=O)-C _3-8 heterocycle or -(CH ₂ ) _m -NR ^8a R ^8b , said CH ₂ , alkyl, carbocyclic or hetero The ring is optionally further substituted with from 0 to 5 substituents selected from the group consisting of F, Cl, hydroxy, amino, C _1-4 alkyl or -OC _1-4 alkyl, said heterocycle containing from 1 to 3 a hetero atom from N, O or S; R ^8a and R ^8b are each independently selected from H or C _1-4 alkyl; X is selected from the group consisting of absent, -O-, -S- or -NR ⁹ -; R ^{9 is} selected From H or C _1-4 alkyl; optionally, R ⁸ and R ⁹ form a 3 to 6 membered heterocyclic ring with the attached nitrogen, optionally further 0 to 5 selected from F, Cl, Substituted by a substituent of a hydroxy group, an amino group, a C _1-4 alkyl group or an -OC _1-4 alkyl group, the heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S.

The present invention provides that m is selected from 0, 1, 2 or 3; n is selected from 1, 2, 3, 4 or 5.

The present invention provides a compound of the formula (VIII) or the formula (VIII'), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² are each independently selected from H, -(CH _{2 ) m} - C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _1-10 alkyl or amino acid side chain, preferably H, -(CH ₂ ) _m -C _{3- a 6} carbocyclic ring, a -(CH ₂ ) _m -3 to 6 membered heterocyclic ring, a C _1-6 alkyl group or an amino acid side chain, when the amino acid side chain contains a hydroxyl group, a thiol group or a carboxyl group, the hydroxyl group, a thiol group or a carboxyl group Optionally esterified, the CH ₂ , alkyl, carbocyclic or heterocyclic ring optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, thiol, carboxyl, amino, thiol or Substituted by a substituent of an ester group containing from 1 to 6 heteroatoms selected from N, O or S; optionally, R ¹ and R ² together with the atom to which they are attached may form a 3 to 6 membered ring The ring is optionally further substituted with from 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, carboxy or amino, said ring containing from 0 to 6 selected from N, O or S. a hetero atom; the alkyl group, cycloalkyl group, optionally further from 0 to 3, selected from the group consisting of F, Cl, Br, Substituting a substituent of I, hydroxy or amino; R ^{3 is} selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -(CH ₂ ) _m -C _3-10 carbocyclic, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m a 3- to 10-membered heterocyclic ring or a -(CH ₂ ) _m -OC _1-4 alkyl group, the CH ₂ , alkenyl, alkynyl, alkyl, carbocyclic or heterocyclic ring optionally further selected from 0 to 4 From H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, C _1-4 alkyl, C _1-4 alkoxy, OC(=O)OR ^3a or OC ( Substituted by a substituent of R ^3a which contains from 1 to 6 heteroatoms selected from N, O or S; R ^{3a is} selected from C _1-4 alkyl, C _3-10 carbocyclic or Up to 10 membered heterocyclic ring, the alkyl group, carbocyclic ring or heterocyclic ring optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl, C _1- Substituted by a substituent of a ₄ alkoxy group, a C _3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring containing 1 to 6 hetero atoms selected from N, O or S; R ^{3 is} preferably substituted Or unsubstituted methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl or benzyl, when substituted, Further 1 to 4 are selected from the group consisting of F, Cl, Br, I, OH, carboxyl, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, OC (=O) substituted with a substituent of OR ^3a or OC(=O)R ^3a ; R ^{3a is} selected from a substituted or unsubstituted methyl, ethyl, isopropyl or propyl group, when substituted, optionally further Substituted by 1 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R _{3 is} further preferably methyl or Base, isopropyl, benzyl, 2,2,2-trifluoroethyl, 2,2-dimethylpropoxymethyl, methoxyethyl, isopropoxycarbonyloxymethyl, But-2-yl, 2-methylpropyl, 2,6-diisopropylphenyl, 2-isopropyl-6-(1-cyclopropylethyl)phenyl, 2,6-di ( 1-cyclopropylethyl)phenyl, isopropoxycarbonyloxymethyl, 2-methylbutyl, pent-3-yl, 1-cyclopropylethyl or cyclopropyl; B is selected from ;R is selected from , preferably R ^4d5 , R ^4d6 , R ^4d7 , R ^4d8 are each independently selected from H, methyl, ethyl or cyclopropyl; L is preferably a bond, O-phenyl-CH ₂ -OC(=O), O-benzene -CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , OC(CH ₃ ) ₂ OC(=O ), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group is optionally further selected from 0 to 4 selected from H, F, Cl, Substitution of Br, I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy Substituted; R ^{5 is} selected from H or C _1-4 alkyl; optionally, R ¹ and R ⁵ together with the atom to which they are attached form azetidinyl or azacyclopentyl; R ⁶ and R ⁷ Each independently selected from H, C _1-4 alkyl or R ⁶ and R ⁷ together with the atom to which they are attached form a 3 to 6 membered ring containing 0 to 3 heteroatoms selected from N, O or S, The ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; R ^{8 is} selected from H , C _1-4 alkyl, -(CH ₂ ) _m -OC _1-4 alkyl, -(CH ₂ ) _m -C _3-8 carbocyclic, -(CH ₂ ) _m -C _3-8 Ring, -(CH ₂ ) _m -C(=O)-C _3-8 carbocyclic ring, -(CH ₂ ) _m -C(=O)-C _3-8 heterocyclic ring or -(CH ₂ ) _m -NR ^8a R ^8b , wherein the CH ₂ , alkyl, carbocyclic or heterocyclic ring is further optionally 0 to 5 selected from the group consisting of F, Cl, hydroxy, amino, C _1-4 alkyl or —OC _1-4 alkyl Substituted by a substituent containing 1 to 3 heteroatoms selected from N, O or S

R ^8a and R ^8b are each independently selected from H or C _1-4 alkyl; X is selected from the group consisting of absent, -O-, -S- or -NR ⁹ -, preferably O; R ^{9 is} selected from H or C _{1 -4} alkyl; Alternatively, R ⁸ and R ⁹ form a 3 to 6 membered heterocyclic ring with the attached nitrogen, and the heterocyclic ring is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, hydroxy, amino, C Substituted by a substituent of _1-4 alkyl or -OC _1-4 alkyl, the heterocyclic ring containing from 1 to 3 heteroatoms selected from N, O or S.

The present invention provides that m is selected from 0, 1, 2 or 3; n is selected from 1, 2, 3, 4 or 5.

The present invention provides a compound of the formula (A) or the formula (A1), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² are each independently selected from H, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _1-10 alkyl group or amino acid side chain, preferably H, -(CH ₂ ) _m -C _3-6 Carbocyclic, -(CH ₂ ) _m -3 to 6-membered heterocyclic ring, C _1-6 alkyl or amino acid side chain, when the amino acid side chain contains a hydroxyl group, a thiol group or a carboxyl group, the hydroxyl group, a thiol group or a carboxyl group is selected Optionally esterified, the CH ₂ , alkyl, carbocyclic or heterocyclic ring optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, thiol, carboxyl, amino, thiol or ester Substituted by a substituent having from 1 to 6 heteroatoms selected from N, O or S; optionally, R ¹ and R ² together with the atom to which they are attached may form a 3 to 6 membered ring, Preferred is cyclopropyl, cyclobutyl or cyclopentyl, and the ring, cyclopropyl, cyclobutyl or cyclopentyl is optionally further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, Substituted by a substituent of a carboxyl group or an amino group, the ring containing 0 to 6 heterogeneous selected from N, O or S ; Said alkyl, cycloalkyl optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, hydroxy or amino substituents; R ³ is selected from C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, -(CH ₂ ) _m -C _3-10 carbocyclic, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m- C _3-10 carbocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m -3 to 10 membered heterocyclic ring or -(CH ₂ ) _m -OC _1-4 alkyl group, said CH ₂ , alkenyl, alkynyl, alkyl, carbocyclic or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, Substituted by a substituent of C _1-4 alkyl, C _1-4 alkoxy, OC(=O)OR ^3a or OC(=O)R ^3a containing from 1 to 6 selected from N, O Or a hetero atom of S; R ^{3a is} selected from C _1-4 alkyl, C _3-10 carbocyclic or 3 to 10 membered heterocyclic ring, and the alkyl, carbocyclic or heterocyclic ring is optionally further selected from 0 to 4 Substituted from a substituent of H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbocyclic or 3 to 10 membered heterocyclic ring, said heterocyclic ring containing 1-6 heteroatoms selected from N, O or S; R ³ is preferably a substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl Cyclopropyl, cyclopropylmethylene, phenyl or benzyl, when substituted, optionally further from 1 to 4 selected from the group consisting of F, Cl, Br, I, OH, carboxyl, 1-cyclopropyl Substituted by a substituent of a methyl group, a methyl group, an ethyl group, an isopropyl group, a propyl group, a methoxy group, an ethoxy group, an OC(=O)OR ^3a or an OC(=O)R ^3a ; R ^{3a is} selected from a substituent or Unsubstituted methyl, ethyl, isopropyl or propyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl Substituted by a methoxy or ethoxy substituent; R _{3 is} further preferably methyl, ethyl, isopropyl, benzyl, 2,2,2-trifluoroethyl, 2,2-dimethyl Propyl methoxymethyl, methoxyethyl, isopropoxycarbonyloxymethyl, butan-2-yl, 2-methylpropyl, 2,6-diisopropylphenyl, 2- Isopropyl-6-(1-cyclopropylethyl)phenyl, 2,6-bis(1-cyclopropylethyl)phenyl, isopropoxycarbonyloxymethyl, 2-methylbutyl , pent-3-yl, 1-cyclopropylethyl or cyclopropyl; R ^{4 is} selected from R ^{B is} selected from ;R is selected from , preferably R ^4d5 , R ^4d6 , R ^4d7 , R ^4d8 are each independently selected from H, methyl, ethyl or cyclopropyl; L is preferably a self-bond, O-phenyl-CH ₂ -OC(=O), O- Phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH (CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further 0 to 4 are selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, iso Substituted by a substituent of a propoxy, propyl or propoxy group; R ^{5 is} selected from H or C _1-4 alkyl; optionally, R ¹ and R ⁵ together with the atom to which they are attached may form azelotidine Or azacyclopentyl, R ⁶ and R ⁷ are each independently selected from H, C _1-4 alkyl or R ⁶ and R ⁷ together with the atom to which they are attached form a 3 to 6 membered ring containing 0 to 3 heteroatoms selected from N, O or S, optionally further 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkane Substituted by a substituent of an oxy group; R ^{8 is} selected from H, C _1-4 alkyl, -(CH ₂ ) _m -OC _1-4 alkyl, -(CH ₂ ) _m -C _{3- 8} carbocyclic ring, -(CH ₂ ) _m -C _3-8 heterocyclic ring, -(CH ₂ ) _m -C(=O)-C _3-8 carbocyclic ring, -(CH ₂ ) _m -C(=O) a -C _3-8 heterocyclic ring or -(CH ₂ ) _m -NR ^8a R ^8b , wherein the CH ₂ , alkyl group, carbocyclic ring or heterocyclic ring is further further selected from 0 to 5 selected from the group consisting of F, Cl, hydroxyl, Substituted by a substituent of amino, C _1-4 alkyl or -OC _1-4 alkyl, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S; R ^8a and R ^8b are each independently Selected from H or C _1-4 alkyl; X is selected from the group consisting of -O-, -S- or -NR ⁹ -, preferably O; R ^{9 is} selected from H or C _1-4 alkyl; And R ⁸ and R ⁹ form a 3 to 6 membered heterocyclic ring with the attached nitrogen, and the heterocyclic ring is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, hydroxy, amino, C _1-4 alkyl or Substituted by a substituent of OC _1-4 alkyl, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S; m being selected from 0, 1, 2 or 3; n being selected from 1 or 2 .

The present invention provides a compound of the formula (A) or the formula (A1), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² are each independently selected from the group consisting of an ethyl group and a lysine side. Chain, methionine side chain, isoleucine side chain, proline side chain, threonine side chain, tryptophan side chain, serine side chain, cysteine side chain, tyrosine side chain, aspart Side chain, histidine side chain, glutamic acid side chain, glutamine side chain, glycine side chain, alanine side chain, leucine side chain, phenylalanine side chain, aspartame a side chain of an amine side chain or arginine which, when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, is selectively esterified; optionally, R ¹ and R ^{2 are} bonded to the atom Together, a cyclopropyl, cyclobutyl or cyclopentyl group can be formed, and R ^{3 is} selected from a substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene group. , phenyl or benzyl, when substituted, optionally further from 1 to 4 selected from the group consisting of F, Cl, Br, I, OH, carboxyl, 1-cyclopropylethyl, methyl, ethyl, isopropyl Base, propyl, methoxy Substituted by a substituent of ethoxy, OC(=O)OR ^3a or OC(=O)R ^3a ; R ^{3a is} selected from substituted or unsubstituted methyl, ethyl, isopropyl or propyl groups when When substituted, it is optionally further substituted with from 1 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R _{3 is} preferably Is methyl, ethyl, isopropyl, benzyl, 2,2,2-trifluoroethyl, 2,2-dimethylpropoxymethyl, methoxyethyl, isopropoxycarbonyl Oxymethyl, butan-2-yl, 2-methylpropyl, 2,6-diisopropylphenyl, 2-isopropyl-6-(1-cyclopropylethyl)phenyl, 2 ,6-bis(1-cyclopropylethyl)phenyl, isopropoxycarbonyloxymethyl, 2-methylbutyl, pent-3-yl, 1-cyclopropylethyl or cyclopropyl R ^{5 is} selected from H or methyl; as an alternative, R ¹ and R ⁵ together with the atom to which they are attached may form azeticyclic or azacyclopentyl, and R ⁶ and R ⁷ are each independently selected from H, Methyl, ethyl or R ⁶ and R ⁷ together with the atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group; R ^{8 is} selected from H, methyl, ethyl, propyl, isopropyl, butyl Base, 2-butyl , tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, , , , , , Preferably, H, methyl; X is selected from the absence, -O- or NR ⁹ -, preferably O; R ^{9 is} selected from H or methyl; optionally, R ⁸ and R ⁹ are attached to the nitrogen Atomic formation , .

The present invention provides a compound of the formula (A) or formula (A1), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² are each independently selected from H, methyl, 2 Methylpropyl, isopropyl or ethoxymethyloxy; optionally, R ¹ and R ² together with the carbon atom to which they are attached form a cyclopropyl group; R _{3 is} selected from methyl, ethyl, isopropyl Base, benzyl, 2,2,2-trifluoroethyl, 2,2-dimethylpropoxymethyl, methoxyethyl, isopropoxycarbonyloxymethyl, but-2- Base, 2-methylpropyl, 2,6-diisopropylphenyl, 2-isopropyl-6-(1-cyclopropylethyl)phenyl, 2,6-di(1-cyclopropane Ethyl ethyl) phenyl, isopropoxycarbonyloxymethyl, 2-methylbutyl, pent-3-yl, 1-cyclopropylethyl or cyclopropyl; R ^{4 is} selected from , , or ; R ^4d5 , R ^4d6 , R ^4d7 , R ^4d8 are each independently selected from H, methyl, ethyl or cyclopropyl; L is preferably a bond, O-phenyl-CH ₂ -OC(=O), O- Phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , OC(CH ₃ ) ₂ OC(= O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further from 0 to 4 selected from H, F, Cl , Br, I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy Substituted by a substituent; R ⁵ , R ⁶ and R ^{7 are} selected from H; alternatively, R ¹ and R ⁵ together with the atom to which they are attached may form azeticyclic or azacyclopentyl, and R ^{8 is} selected from H, methyl, ethyl, propyl, isopropyl, , , , or Preferably, H or methyl; X is selected from -O-, -NR ⁹ - or is absent, preferably O

R ^{9 is} selected from H or methyl; optionally, R ⁸ and R ⁹ are formed with a linked nitrogen atom , .

The present invention provides a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound comprises a compound of the formula (B), a pharmaceutically acceptable salt thereof or a stereoisomeric Structure, B ₁ and B ₂ are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, (C _{1 -6} alkyl) _t1 NHC _1-6 alkyl or (C _1-6 alkyl) _t1 N(C _1-6 alkyl) ₂ , t1 is selected from 0 or 1; nb, mb are each independently selected from 0, 1, 2, 3 or 5.

The present invention provides a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound comprises a compound of the formula (C), a pharmaceutically acceptable salt thereof or a stereoisomeric Structure, where:

"-----" represents a single bond or a double bond; C _{1 is} independently selected from H, F, Cl, Br, I, OH, C _1-6 alkyl or C _1-6 alkoxy, The alkyl or alkoxy group is optionally further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-6 alkyl or C _1-6 alkoxy; C ₂ , C ₃ , C ₄ are each independently selected from the group consisting of H, F, Cl, Br, I, =0, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, OC(=O)(C _1-6 alkyl) or OC(=O)(C _1-6 alkoxy), optionally alkyl, alkenyl, alkynyl or alkoxy Further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, C _1-6 alkyl, C _1-6 alkoxy or a 3 to 6 membered ring, The ring contains 0 to 4 heteroatoms selected from N, O or S; nc, mc, pc, qc are each independently selected from 0, 1, 2, 3 or 5.

The present invention provides a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound comprises a compound of the formula (D), a pharmaceutically acceptable salt thereof or a stereoisomer Structure, where:

D _{1 is} independently selected from the group consisting of H, F, Cl, Br, I, OH, ureido, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy , S(=O) ₂ NR ^1D1 R ^1D2 or (C _1-6 alkyl) _0-1 -3 to 6 membered ring, said alkyl, alkenyl, alkynyl, alkoxy or ring optionally further Substituted by 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, OH, =O, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered ring, The ring contains 0 to 4 heteroatoms selected from N, O or S; D _{2 is} independently selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-6 alkyl, C _1-6 Alkoxy, (C _1-6 alkyl) _0-1 -3 to 6 membered ring, (C _1-6 alkyl) _0-1 C(=O)R ^2D1 or (C _1-6 alkyl) _{0 -1} C(=O)NR ^2D1 R ^2D2 , the alkyl group, alkoxy group or ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C(=O)R ^2d1 R ^2d2 , C(=O)NR ^2d1 R ^2d2 , (C _1-6 alkyl) _0-1 NR ^2d1 R ^2d2 Substituted by a substituent, the ring contains 0 to 4 heteroatoms selected from N, O or S; optionally, two D ₂ may form a 3 to 8 membered ring together with the atoms to which they are attached, said ring Optional one 0-4 is selected from H, F, Cl, Br, I, OH, amino, carboxy, C _1-6 alkyl, (C _{1-6 ^{alkyl) 0-1 NR 2D1 R 2D2, C}} 1-6 Substituted by alkoxy or a substituent of C(=O)R ^2d1 , which is optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, amino, Substituted by a carboxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group or a substituent of a 3 to 6 membered ring containing 0 to 4 hetero atoms selected from N, O or S; R ^1D1 , R ^1D2 , R ^2D1 , R ^2D2 , R ^2d1 , and R ^2d2 are each independently selected from the group consisting of H, OH, C _1-6 alkyl, C _1-6 alkoxy, (C _1-6 alkyl) _0-1 N(C _1-6 alkyl) ₂ or 3 to 6 membered ring, said alkyl, alkoxy or ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, Substituted by a substituent of =O, NR ^2D1 R ^2D2 , C _1-6 alkyl, C _1-6 alkoxy or a 3 to 6 membered ring, the ring containing 0 to 4 selected from N, O or S Heteroatoms; nd or md are each independently selected from 0, 1, 2, 3 or 5.

The present invention provides a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound comprises a compound of the formula (E) or (E ' ) and a pharmaceutically acceptable compound thereof Salt or stereoisomer, of which: or

Each of E _{1 is} independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, N ₃ , C _1-6 alkyl or C _1-6 alkoxy, said OH, NH ₂ , The alkyl or alkoxy group is further optionally from 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy or C (= O) substituted by a R ^1E1 substituent; E _{1 is} preferably H, F or OH; alternatively, two E ₁ may form a 3 to 6 membered ring together with the atom to which they are attached, optionally further to 0 to Substituted by four substituents selected from H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy, said ring containing 0 to 4 From N, O or S heteroatoms; E ₂ , E ₃ are each independently selected from H, OH or C(=O)R ^1E1 ; E ₂ , E _{3 are} preferably H; V is selected from CH ₂ or S; V _{2 is} selected from C or N; R ^{1E1 is} each independently selected from H or C _1-20 alkyl, and the alkyl group is optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, Substituted with a substituent of NH ₂ , C _1-6 alkyl, C _1-6 alkoxy or C _3-6 carbocyclic ring; E _{4 is} independently selected from H, F, Cl, Br or I, preferably H or F; E _{5 is} selected from H or C(=O)R ^1E1 ; me or ne are each independently selected from 0, 1 , 2, 3 or 5.

The present invention provides a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound comprises a compound of the formula (F), a pharmaceutically acceptable salt thereof or a stereoisomeric Structure, where:

"-----" represents a single bond or a double bond; F _{1 is} selected from C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl; the alkyl, alkenyl, alkynyl or The alkoxy group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, C _1-6 alkyl, C _1-6 alkoxy or a 3 to 6 membered ring. Substituted, the ring contains 0 to 4 heteroatoms selected from N, O or S; F1 is preferably methyl, ethyl, isopropyl, propenyl, -CH ₂ -cyclopropyl or - CH ₂ -cyclobutyl; F _{2 is} selected from H, OH, C _1-6 alkyl or C _1-6 alkoxy, optionally further from 0 to 4 selected from H, Substituted by a substituent of F, Cl, Br, I, OH, =O, C _1-6 alkyl, C _1-6 alkoxy or a 3 to 6 membered ring, said ring containing 0 to 4 selected from a hetero atom of N, O or S; F2 is preferably H, OH, methoxy, ethoxy or -O-(CH ₂ )3-phenyl; F _{3 is} independently selected from H, hydroxy or (C) =O)NH ₂ ; F _{4 is} selected from H or C _1-6 alkyl, preferably H or methyl; F ₅ and F ₆ are each independently selected from H, OH, NH(CH ₂ ) _1-3 COOH , O(CH ₂ CH ₂ O) _0-10 CH ₃ , Alternatively, F5 and F6 can form = or =O.

The definitions of L and Q are the general formula (I), general formula (LO-1), general formula (LS-1), general formula (GO-1), general formula (GS-1), general formula (II), The definitions described in the general formula (II ' ), the general formula (III), the general formula (III'), the general formula (IV) or the general formula (IV ' ) are identical.

The present invention provides a compound of the formula (B), (C), (D), (E) or (F) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N(C _1-6 alkyl)-, -C(=O)-, - OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O) ₂ N( C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl)-; W is selected from 0 to 10 W, optionally ^a substituted phenyl group, a C _1-25 alkylene group, a C _2-25 alkenylene group or a C _2-25 alkynylene group, 0 of said alkylene, alkenylene or alkynylene group Substituting a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, O, S, N or (C=O), optionally substituted with 0 to 10 W ^a to 10 carbon atoms, The group is optionally further substituted by 0 to 10 W ^a wherein the heterocyclic ring contains 0 to 4 heteroatoms selected from O, S or N; W ^{a is} selected from C _1-6 alkyl, halogen substituted C _{1 -6} alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, -OC(=O)C _1-6 alkyl, -(=O) OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _1-6 alkylthio, azide, cyano, nitro ,halogen Amino, hydroxy, (= O), carboxy, C _3-10 carbocyclyl, 3-10 heterocycle, -OC _3-10 carbon ring or 3-10 -O-heterocycle substituents, the heterocycle containing from 0 to 4 heteroatoms selected from O, S or N heteroatoms; form 3-6 ring atoms, W ^a selective two together can be connected thereto, said ring comprising a carbocyclic or a heterocyclic ring, And optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy, said ring containing 0 to 4 heteroatoms selected from O, S or N; L is preferably a bond or L ₁ -W; L _{1 is} selected from -O- or -S-; W is selected from phenyl, C _1-10 alkylene a C _2-12 alkenylene group or a C _2-12 alkynylene group, preferably a phenyl group or a C _1-10 alkylene group, in the alkylene group, alkenylene group or alkynylene group 0 to 10 carbon atoms are optionally substituted with a substituted or unsubstituted phenyl, O, S, N or (C=O), and the divalent group formed above or the phenyl group optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, azido, cyano, nitro, halogen, amino, hydroxy, (=O), carboxyl, methyl, ethyl, isopropyl, methoxy Ethoxygen , Isopropoxy or cyclopropyl substituent; L more preferably is a bond, O- phenyl _{-CH 2 -OC (= O),} O- phenyl _{-CH (CH 3) -OC (=} O ), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH3), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ , optionally further 0 to 4 selected from H, F, Cl, Br, Substituents for I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy Substituted; R ¹ and R ² are each independently selected from H, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _1-10 alkyl group or amino acid a side chain, preferably H, -(CH ₂ ) _m -C _3-6 carbocyclic, -(CH ₂ ) _m -3 to 6 membered heterocyclic, C _1-6 alkyl or amino acid side chain, as described When the amino acid side chain contains a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group is selectively esterified, and the CH ₂ , alkyl group, carbocyclic ring or heterocyclic ring is further further selected from 0 to 3 selected from F Substituted by a substituent of Cl, Br, I, a hydroxyl group, a thiol group, a carboxyl group, an amino group, a thiol group or an ester group, the hetero Containing 1 to 6 hetero atoms selected from N, O or S; preferably: the amino acid is selected from the group consisting of lysine, methionine, isoleucine, valine, threonine, tryptophan, serine , cysteine, tyrosine, aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or refined ammonia Acid; preferably lysine, methionine, isoleucine, valine, threonine, tryptophan, valine, serine, cysteine, tyrosine, aspartic acid, histamine Acid, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine; further preferably glycine, alanine, leucine, different Leucine, serine, proline or phenylalanine; said amino acids include D-form and L-form; optionally, R ¹ and R ² may form a 3 to 6-membered ring together with the atom to which they are attached Preferred is cyclopropyl, cyclobutyl or cyclopentyl, further preferably cyclopropyl or cyclobutyl; said cyclopropyl, cyclobutyl or cyclopentyl, cycloalkyl optionally further Up to 3 from F, Substituted by a substituent of Cl, Br, I, a hydroxyl group or an amino group, the ring contains 0 to 6 hetero atoms selected from N, O or S; R ^{3 is} selected from C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, -(CH ₂ ) _m -C _3-10 carbocyclic, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, -(CH ₂ ) _m -O-(CH _{2 m-} C _3-10 carbocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m -3 to 10 membered heterocyclic ring or -(CH ₂ ) _m -OC _1-4 alkyl group, said CH ₂ Or alkenyl, alkynyl, alkyl, carbocyclic or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, C Substituted by a substituent of _1-4 alkyl, C _1-4 alkoxy, OC(=O)OR ^3a or OC(=O)R ^3a containing from 1 to 6 selected from N, O or a hetero atom of S; R ^{3 is} preferably a substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl, -( CH ₂ ) _m -O-methyl or -(CH ₂ ) _m -O-ethyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br, I, OH, carboxyl , amino, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy OC (= O) OR ^3a, or OC (= O) R ^3a group substituted with a substituent; R ^3a is selected from C _1-4 alkyl, C _3-10 carbon ring or 3-10 heterocyclyl, said alkyl , carbocyclic or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbon Substituted by a ring or a substituent of a 3 to 10 membered heterocyclic ring containing from 1 to 6 heteroatoms selected from N, O or S; R ^{3a is} preferably a substituted or unsubstituted methyl, ethyl, Isopropyl or propyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy Substituted by a substituent; R ^{3 is} preferably a substituted or unsubstituted methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl or benzyl group, when When substituted, optionally further 1 to 4 are selected from the group consisting of F, Cl, Br, I, OH, carboxyl, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl, methoxy, Substituted by a substituent of ethoxy, OC(=O)OR ^3a or OC(=O)R ^3a ; R ^{3a is} selected from substituted or unsubstituted methyl, ethyl, isopropyl or propyl groups when substituted Time Optionally further substituted with 1 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxy, methyl, ethyl, methoxy or ethoxy substituent; R ₃ is preferably A further Base, ethyl, isopropyl, benzyl, 2,2,2-trifluoroethyl, 2,2-dimethylpropoxymethyl, methoxyethyl, isopropoxycarbonyloxy Methyl, butan-2-yl, 2-methylpropyl, 2,6-diisopropylphenyl, 2-isopropyl-6-(1-cyclopropylethyl)phenyl, 2,6 - bis(1-cyclopropylethyl)phenyl, isopropoxycarbonyloxymethyl, 2-methylbutyl, pent-3-yl, 1-cyclopropylethyl or cyclopropyl; R ^{5 is} selected from H or C _1-10 alkyl, preferably H or C _1-4 alkyl, further preferably H; optionally, R ¹ and R ⁵ together with the atom to which they are attached form 3 to 6 members a ring, preferably azacyclopropyl, azetidinyl, azacyclopentyl, said ring containing 1 to 3 heteroatoms selected from N, O or S, said ring, azacyclopropane Further, the azetidinyl group, the azacyclopentyl group are further further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, amino, carboxyl, C _1-4 alkyl or C _1-4 alkoxy substituents; R ⁶ R ⁷ is independently selected from H or C _1-10 alkyl, preferably H or C _1-4 alkyl, more preferably H, methyl, ethyl, propyl or isopropyl group, more preferably H Optionally, R ⁶ and R ⁷ together with the atom to which they are attached form a 3 to 6 membered ring, preferably cyclopropyl, cyclobutyl, cyclopentyl, said ring containing 0 to 3 selected from N, a hetero atom of O or S, the ring, cyclopropyl, cyclobutyl, cyclopentyl optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, C _1-4 alkyl Or a substituent of a C _1-4 alkoxy group; preferably the cyclopropyl, cyclobutyl or cyclopentyl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, Substituted by a substituent of amino, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy; X is selected from the absence, -O-, -S- Or -NR ^8a -, preferably O, S or NH, further preferably O; R ^{8 is} selected from H, C _1-6 alkyl, -(CH ₂ ) _m C _3-6 carbocyclic, -(CH ₂ ) _m 3 to 6 member heterocyclic ring, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p O(CH ₂ ) _p R ^8c , -(CH ₂ ) _p O(C=O)R ^8d or _{- (CH 2) p O (} C = O) oR 8d, said alkyl, carbocycle, heteroaryl Optionally further substituted with 0-4 selected from H, F, Cl, Br, I, OH, carboxy, C _1-4 alkyl or C _1-4 alkoxy substituent; a heterocyclic ring containing 1 Up to 3 heteroatoms selected from N, O or S; preferably R ^{8 is} selected from substituted or unsubstituted H, methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopentane Base, cyclobutyl, oxopropyl, oxetanyl, oxetanyl, oxacyclohexyl, azacyclopropyl, azacyclopentyl, azetidinyl, nitrogen heterocycle Hexyl, pyridazinyl, morpholinyl, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p OR ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , when substituted, optionally further from 1 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, C Substituted by a substituent of a methoxy group, a methoxy group, an isopropoxy group or a propoxy group; R ^8a and R ^8b are each independently selected from H, C _1-6 alkyl, and the alkyl group optionally further Substituted by 0 to 6 substituents selected from H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl; Jia is R ^8a and R ^8b are independent H, methyl, ethyl, isopropyl or propyl selected from substituted or unsubstituted, when substituted, optionally further from 1 to 6 selected from H, F, Cl, Br, I, OH, Substituted by a substituent of carboxy, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, C _3-6 cycloalkyl; optionally, R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring, preferably a cyclopropyl, cyclobutyl or cyclopentyl group, said ring containing 1 to 3 heteroatoms selected from N, O or S. The ring, cyclopropyl, cyclobutyl or cyclopentyl is optionally further further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkane Substituted by a substituent of an oxy group; R ^8c , R ^{8d are} selected from H, C _1-6 alkyl, C _3-6 carbocyclic or 3 to 6 membered heterocyclic ring, optionally alkyl, carbocyclic or heterocyclic Further substituted by 0 to 6 substituents selected from H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl or C _1-4 alkoxy, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S heteroatom; and preferably R ^8c, R ^8d is selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, phenyl, quack a group, a pyridazinyl group, a morpholinyl group, a nitrogen heterocyclopentyl group or an oxolyl group, when substituted, optionally further 1 to 6 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl Substituted by a substituent of a methyl group, an ethyl group, an isopropyl group, a propyl group, a methoxy group, an ethoxy group, an isopropoxy group or a propoxy group.

The present invention provides a compound of the formula (B), (C), (D) or (E) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the formula (B-1) a compound represented by (C-1), (D-1) or (E-1), wherein

The present invention provides a compound represented by the formula (B-1), (C-1), (D-1) or (E-1) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L Selected from a bond or L ₁ -W; L _{1 is} selected from -O- or -S-; W is selected from phenyl, C _1-10 alkylene, C _2-12 alkenylene or C _2-12 An alkynylene group, preferably a C _1-10 alkylene group, optionally substituted or unsubstituted phenyl group of 0 to 10 carbon atoms in the alkylene, alkenylene or alkynylene group O, S, N or (C=O) is substituted, and the divalent group or the phenyl group formed above is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, azide, Substituted by a substituent of cyano, nitro, halogen, amino, hydroxy, (=O), carboxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl ; L is preferably a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ - OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC (=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, N a bond substituted with a substituent of O ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy; each of R ¹ and R ² Independently selected from H, a side chain of an amino acid or a C _1-4 alkyl group, preferably a side chain of H, methyl, ethyl, isopropyl, or amino acid; when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, The thiol group, hydroxyl group or carboxyl group is selectively esterified; the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, hydroxy or amino groups; Lysine, methionine, isoleucine, valine, threonine, tryptophan, valine, serine, cysteine, tyrosine, aspartic acid, histidine, glutamic acid , glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine; preferably lysine, methionine, isoleucine, valine, threonine Acid, tryptophan, valine, serine, cysteine, tyrosine, aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, benzene Alanine, Amides winter or arginine; more preferred is glycine, alanine, leucine, isoleucine, valine or phenylalanine; selective, R ¹ and R ² may be connected to it The atoms together form a C _3-6 cycloalkyl group, preferably a cyclopropyl group, a cyclobutyl group or a cyclopentyl group, further preferably a cyclopropyl group or a cyclobutyl group; the cyclopropyl group, cyclobutyl group or ring The pentyl group and the cycloalkyl group are optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, a hydroxyl group or an amino group; and R ^{3 is} selected from a substituted or unsubstituted methyl group, an ethyl group, and an isopropyl group. Base, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl, -(CH ₂ ) _m -O-methyl or -(CH ₂ ) _m -O-ethyl, when When substituted, optionally further 1 to 4 are selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl Substituted by a substituent of methoxy, ethoxy, isopropoxy, propoxy, OC(=O)OR ^3a or OC(=O)R ^3a ; R ^{3a is} selected from substituted or unsubstituted methyl , ethyl, isopropyl or propyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br Substituted with a substituent of I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R _{3 is} preferably methyl, ethyl, isopropyl, benzyl, 2,2,2- Trifluoroethyl, 2,2-dimethylpropoxymethyl, methoxyethyl, isopropoxycarbonyloxymethyl, butan-2-yl, 2-methylpropyl, 2,6 -diisopropylphenyl, 2-isopropyl-6-(1-cyclopropylethyl)phenyl, 2,6-di(1-cyclopropylethyl)phenyl, isopropoxycarbonyl Oxymethyl, 2-methylbutyl, pent-3-yl, 1-cyclopropylethyl or cyclopropyl; R ^{5 is} selected from H, methyl, ethyl, isopropyl or propyl; R ⁶ And R ⁷ are each independently selected from H, methyl, ethyl, isopropyl or propyl; optionally, R ⁶ and R ⁷ together with the atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group, The cyclopropyl, cyclobutyl or cyclopentyl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, methyl, ethyl, isopropyl, propyl, methoxy Substituted by a substituent of a ethoxy group, an isopropoxy group or a propoxy group; X is selected from the group consisting of -O-, -S- or -NR ^8a -; R ^{8 is} selected from substituted or unsubstituted H, Methyl, ethyl Isopropyl, propyl, phenyl, piperidinyl, piperazinyl, morpholinyl, aza-cyclopentyl group, oxolanyl _{group, - (CH 2) m NR} 8a R 8b, - (CH 2) _p OR ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , when substituted, optionally further from 1 to 4 selected from H Substituted with a substituent of F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy; R ^8a , R ^{8b is} independently selected from substituted or unsubstituted H, methyl, ethyl, isopropyl or propyl, and when substituted, optionally further from 1 to 6 selected from H, F, Cl, Br, I Substituted by a substituent of OH, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, C _3-6 cycloalkyl; R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring containing 1 to 3 heteroatoms selected from N, O or S, optionally further 0 to 4 is selected from H, F, Cl, Br, I, OH, carboxy, C _1-4 alkyl or C _1-4 alkoxy substituents; R ^8c, R ^8d is selected from substituted or unsubstituted H Methyl, ethyl, propyl, isopropyl, phenyl, acridine, pyridazinyl, morpholinyl, azacyclopentyl or oxolyl, when substituted, optionally further Up to 6 substituents selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy Substituted; m, p are each independently selected from 0, 1, 2 or 3; n is selected from 1, 2 or 3.

The present invention provides a formula (Z-5), (I), formula (II), formula (II'), formula (III), formula (III'), formula (IV) or formula (IV ') pharmaceutically acceptable salts of said compounds and or stereoisomer thereof, provided wherein: G is any group, preferably _{G x -O-, G x -S-,} G x -NH- , (G _x -) ₂ N-, G _x = N-, Or a compound G _y containing a lone pair of electrons; G _x and G _y are each independently selected from the group consisting of C _1-50 alkyl, C _2-50 alkenyl, C _2-50 alkynyl, 3 to 40 membered ring, said alkane The base, alkenyl or alkynyl group is optionally further substituted by from 0 to 20 R ^G2 which contains from 0 to 10 heteroatoms selected from N, O or S, said alkyl, alkenyl, alkynyl or R The atom on ^G2 is optionally further substituted by R ^G1 ; the two R ^{G2 moieties} together with the atom to which they are attached may form a 3 to 40 membered ring, optionally further 0 to 20 selected from H, F, Cl , Br, I, =O, nitro, amino, OH, carboxyl, cyano, azido, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkenyl, C _1-10 Substituted by alkynyl, 3 to 10 membered ring substituents containing from 0 to 10 heteroatoms selected from N, O or S, the atoms of the ring or ring substituent optionally further being R ^G1 And R ^G1 are each independently selected from the group consisting of CO, C=S, C=N, O, S, SO, SO2, N, NO or a 3 to 50 membered ring, optionally further selected from 0 to 10 H, F, Cl, Br, I, =O, hydroxy, nitro, amino, carboxyl, cyano, azide, C _1-10 alkyl, C _1-10 alkoxy Substituted by a substituent of a C _1-10 alkenyl group, a C _1-10 alkynyl group, a 3 to 50 membered ring containing 0 to 10 hetero atoms selected from N, O or S; R ^G2 are each independently Selected from H, F, Cl, Br, I, =O, hydroxy, amino, nitro, carboxy, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkenyl, C _{1- 10} alkynyl or 3 to 10 membered ring, optionally further selected from 0 to 20 selected from the group consisting of H, F, Cl, Br, I, =O, nitro, amino, OH, carboxyl, cyano, azide Substituted by a substituent of a C _1-10 alkyl group, a C _1-10 alkoxy group, a C _1-10 alkenyl group, a C _1-10 alkynyl group or a 3 to 10 membered ring, the ring containing 0 to 10 A hetero atom selected from N, O or S.

The present invention provides a general formula (I), a general formula (II), a general formula (II'), a general formula (III), a general formula (III'), a general formula (IV), a general formula (IV ' ), and a pass. Formula (VIII), Formula (VIII ' ), Formula (A), Formula (A1), Formula (B), Formula (B-1), Formula (C), Formula (C-1) ), general formula (D), general formula (D-1), general formula (E), general formula (E ' ), general formula (E-1), general formula (E ' -1) or formula (F) a compound, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from, but not limited to, one of the structures shown in Table 2:

The present invention provides a pharmaceutical composition comprising: an effective amount of the general formula (I), formula (II), formula (II'), formula (III), formula (III) of the present invention. ), general formula (IV), general formula (IV ' ), general formula (VIII), general formula (VIII ' ), general formula (A), general formula (A1), general formula (B), general formula (B) -1), general formula (C), general formula (C-1), general formula (D), general formula (D-1), general formula (E), general formula (E ' ), general formula (E- 1) a compound of the formula (E ' -1) or formula (F), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from, but not limited to, one of the following structures: The compound, and pharmaceutically acceptable salts or stereoisomers thereof, or further comprise one or more additional therapeutic agents, and a pharmaceutically acceptable carrier or excipient.

The invention provides an improvement of oral bioavailability, prolonging the pharmacodynamic half-life of the parent drug, avoiding drug tolerance, improving solubility, improving stability, reducing the dosage and frequency of administration, improving patient compliance, and improving the effect of the drug on the target site. a method of reducing the effects of food, reducing the effects of drugs on gastrointestinal tract irritation, reducing toxic side effects, improving safety, prolonging half-life, and prolonging the duration of action, by administering to the animal an effective dose of the general formula (I) of the present invention, General formula (II), general formula (II'), general formula (III), general formula (III'), general formula (IV), general formula (IV ' ), general formula (VIII), general formula (VIII ' ), general formula (A), general formula (A1), general formula (B), general formula (B-1), general formula (C), general formula (C-1), general formula (D), general formula a compound of the formula (D-1), the formula (E), the formula (E ' ), the formula (E-1), the formula (E ' -1) or the formula (F) and a pharmaceutically acceptable compound thereof Accepted salt or stereoisomer.

The present invention provides the general formula (I), the general formula (II), the general formula (II'), the general formula (III), the general formula (III'), the general formula (IV), the general formula (IV ' ), General formula (VIII), general formula (VIII ' ), general formula (A), general formula (A1), general formula (B), general formula (B-1), general formula (C), general formula (C- 1), general formula (D), general formula (D-1), general formula (E), general formula (E ' ), general formula (E-1), general formula (E ' -1) or formula ( F) a compound, and a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition of the invention, prepared for use in improving oral bioavailability, prolonging the pharmacodynamic half-life of the parent drug, avoiding drug tolerance, Improve solubility, improve stability, reduce dosage and frequency of administration, improve patient compliance, increase the specificity of drugs on target sites, reduce food effects, reduce gastrointestinal irritation, reduce toxic side effects, improve safety, and prolong Mid-life of drugs with half-life and prolonged duration of action.

The present invention provides the general formula (Z), (Z-1), (Z-2), (Z-1-1), (Z`-1-1), (Z-2-1), (Z Use of a compound represented by `-2-1), (Z-3), (Z-4) or (Z-5) or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a prodrug.

The present invention also provides a pharmaceutical composition comprising: an effective amount of the general formula (I), formula (II), formula (II'), formula (III), formula (III) `), general formula (IV), general formula (IV ' ), general formula (VIII), general formula (VIII ' ), general formula (A), general formula (A1), general formula (B), general formula ( B-1), general formula (C), general formula (C-1), general formula (D), general formula (D-1), general formula (E), general formula (E ' ), general formula (E) a compound of the formula (E ' -1) or (F), and a pharmaceutically acceptable salt or stereoisomer thereof, or further comprising one or more other therapeutic agents, and pharmaceutically acceptable Carrier or excipient.

The present invention also provides a pharmaceutical composition comprising: an effective amount of a compound of the formula (A) or formula (A1) or a pharmaceutically acceptable salt or stereoisomer thereof, or further comprising One or more additional therapeutic agents and a pharmaceutically acceptable carrier or excipient.

The present invention also provides a method of increasing oral bioavailability, prolonging the pharmacodynamic half-life of a parent drug, reducing the dosage and frequency of administration, increasing patient compliance, or prolonging half-life by administering to a subject an effective dose. The above compound or a pharmaceutically acceptable salt or stereoisomer thereof.

The present invention also provides a general formula (I), a general formula (II), a general formula (II'), a general formula (III), a general formula (III'), a general formula (IV), a general formula (IV ' ), General formula (VIII), general formula (VIII ' ), general formula (A), general formula (A1), general formula (B), general formula (B-1), general formula (C), general formula (C- 1), general formula (D), general formula (D-1), general formula (E), general formula (E ' ), general formula (E-1), general formula (E ' -1) or formula ( F) a compound, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition as described above, for use in improving oral bioavailability, prolonging the pharmacodynamic half-life of the parent drug, and reducing The use of a dose and frequency, or a drug that extends half-life.

The present invention also provides a general formula (I), a general formula (II), a general formula (II'), a general formula (III), a general formula (III'), a general formula (IV), a general formula (IV ' ), General formula (VIII), general formula (VIII ' ), general formula (A), general formula (A1), general formula (B), general formula (B-1), general formula (C), general formula (C- 1), general formula (D), general formula (D-1), general formula (E), general formula (E ' ), general formula (E-1), general formula (E ' -1) or formula ( F) the compound or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a therapeutic respiratory disease, a digestive system disease, a circulatory disease, a urinary system disease, a blood system disease, an endocrine and metabolic system disease, a cardiovascular Application in diseases such as systemic diseases, lymphatic diseases, neuropsychiatric diseases, gynecological diseases, pediatric diseases, otolaryngology diseases, eye diseases, oral diseases, bone diseases, tumor diseases, and the like.

The present invention also provides a general formula (I), a general formula (II), a general formula (II'), a general formula (III), a general formula (III'), a general formula (IV), a general formula (IV ' ), General formula (VIII), general formula (VIII ' ), general formula (A), general formula (A1), general formula (B), general formula (B-1), general formula (C), general formula (C- 1), general formula (D), general formula (D-1), general formula (E), general formula (E ' ), general formula (E-1), general formula (E ' -1) or formula ( F) use of the compound or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a medicament comprising: pneumonia, lung cancer, pulmonary thromboembolism, tuberculosis, bronchitis, chronic obstructive pulmonary disease and Chronic pulmonary heart disease, bronchial asthma, pulmonary thromboembolism, pneumonia, bronchiectasis, lung abscess, tuberculosis, primary bronchogenic carcinoma, diffuse interstitial lung disease, pleural disease, sleep apnea syndrome, Respiratory failure, irritable bowel syndrome, gastritis, gastric ulcer, stomach cancer, hepatitis, liver cancer, liver cirrhosis, hepatic encephalopathy, pancreatitis, pancreatic cancer, colorectal cancer, angina pectoris, myocardial infarction, premature heart beat, heart failure, thrombosis , high blood pressure, coronary heart disease Primary glomerular disease, secondary glomerular disease, tubulointerstitial nephritis, urinary tract infection, renal tubular disease, renal vascular disease, acute renal failure, chronic renal failure, lupus nephritis, myeloproliferative Abnormal syndrome, allergic purpura, secondary thrombocytopenic purpura, primary thrombocytopenic purpura, aplastic anemia, immunological hemolytic anemia, hemolytic anemia, thalassemia, iron deficiency anemia, giant Young cell anemia, neutropenia and neutropenia, myelodysplastic syndrome, leukemia, lymphoma, plasma cell disease, myeloproliferative disease, hypersplenism, hemorrhagic disease, vascular purpura, idiopathic platelets Reduced purpura, thrombotic thrombocytopenic purpura, coagulopathy, disseminated intravascular coagulation, blood transfusion and transfusion reactions, thrombophilia and hypercoagulable state, menopausal syndrome, pituitary adenoma, hypothalamic disease, pituitary tumor , pituitary hypofunction, diabetes insipidus, inappropriate secretion of vasopressin, non-toxic goiter, Graves disease, thyroid Hypothyroidism, thyroiditis, thyroid neoplasms, cortisol, aldosteronism, adrenal insufficiency, congenital adrenal hyperplasia, pheochromocytoma, primary hyperparathyroidism, thyroid Parathyroidism, multiple endocrine neoplasia syndrome, autoimmune multiple endocrine adenosis syndrome, ectopic hormone secretion syndrome, diabetes, hypoglycemia, metabolic syndrome, dyslipidemia, primary osteoporosis Symptoms, gout, protein-thermal malnutrition, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, Obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension, heart failure, arrhythmia, sudden cardiac death, syncope, essential hypertension, coronary atherosclerosis Heart disease, valvular heart disease, infective endocarditis, cardiomyopathy, pericardial disease, adult congenital heart disease, blood vessels Disease, venous disease, peripheral arterial disease, arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, cerebral arterial thrombosis, arterial embolism, coronary thrombosis, pulmonary embolism, renal embolism, cerebral embolism, atherosclerosis Sclerotherapy, acute coronary syndrome, unstable angina pectoris, acute coronary syndrome, myocardial infarction, atherosclerosis, sudden ischemic attack, transient ischemia, external obstructive arterial disease, stroke or cerebrovascular disease, Rheumatoid arthritis, systemic lupus erythematosus, seronegative spondyloarthropathy, systemic vasculitis, polymyositis and dermatomyositis, Sjogren's syndrome, multiple organ dysfunction syndrome, skin or soft tissue surgery, surgical infection, trauma And weapon injuries, burns and frostbite, increased intracranial pressure and cerebral palsy, craniocerebral injury, intracranial tumors, intraspinal tumors, intracranial and intraspinal vascular diseases, congenital malformations of the brain and spinal cord, neck disease , breast disease, chest damage, chest wall pleural disease, lung disease, esophageal disease, mediastinal disease, heart disease, Aortic aneurysm, abdominal hernia, abdominal injury, acute suppurative peritonitis, gastroduodenal diseases, small bowel disease, appendic disease, colorectal and anal canal diseases, liver disease, portal hypertension, biliary tract disease, pancreatic disease, surgical jaundice, Spleen disease, acute abdomen, abdominal mass, upper gastrointestinal bleeding, pediatric abdominal surgery, vascular surgery, genitourinary malformation, urinary system injury, urinary, male reproductive system infection, urinary, male reproductive system tuberculosis, urinary system obstruction , urolithiasis, urology, male reproductive system tumors, urinary, other diseases of the male reproductive system, adrenal diseases, male birth control, infertility and sexual dysfunction, upper limb fractures, hand trauma, lower limb fractures and joint injuries, spinal cord injury and Pelvic fracture, joint dislocation, peripheral nerve injury, limb replantation, chronic injury of the motor system, cervical and lumbar degenerative diseases, bone and joint purulent infection, bone and joint tuberculosis, non-suppurative arthritis, arthritis , motor system malformations, brain and spinal cord disease sequelae, bone tumors, viral infections, Hypophyseal, bacterial infection, fungal infection, spirochete infection, protozoal infection, peripheral neuropathy, spinal cord disease, cerebrovascular disease, central nervous system infectious disease, central nervous system demyelinating disease, dyskinesia, epilepsy, headache , nervous system deformed diseases, nervous system hereditary diseases, nervous system dysplastic diseases, neuromuscular joints and muscle diseases, paraneoplastic syndromes, autonomic nervous system diseases, mental disorders associated with nervous system diseases, common nervous system diseases Critical illness, brain organic mental disorder, mental disorder caused by physical illness, mental disorder caused by psychoactive substances, schizophrenia and other psychotic disorders, mood disorder, neurosis and hysteria, psychological factors related to physiological disorders, stress related Disorders, personality disorders and sexual psychological disorders, suicidal behavior and crisis intervention, childhood and mental disorders, eyelid disease, ocular surface disease, lacrimal disease, conjunctival disease, corneal disease, sclera, lens disease, vitreous disease, glaucoma, grapes Membrane disease, retinopathy, neuro-ophthalmology, eye Optics, strabismus and amblyopia, eyelid disease, ocular trauma, cervical congenital disease, neck trauma, cervical inflammatory disease, cervical and cervical disease, lateral skull base tumor, cerebellar pons tumor, HIV, HBV, HCV , MCV, HSV, HPV, brain tumor, non-small cell lung cancer, squamous cell, bladder cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, colorectal cancer, kidney cancer , esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin's lymphoma, liver cancer, lung cancer, skin cancer, thyroid cancer, head and neck cancer, prostate cancer, glioma and nasopharyngeal cancer.

The present invention also provides a general formula (I), a general formula (II), a general formula (II'), a general formula (III), a general formula (III'), a general formula (IV), a general formula (IV ' ), General formula (VIII), general formula (VIII ' ), general formula (A), general formula (A1), general formula (B), general formula (B-1), general formula (C), general formula (C- 1), general formula (D), general formula (D-1), general formula (E), general formula (E ' ), general formula (E-1), general formula (E ' -1) or formula ( F) use of a compound or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a medicament comprising: inducing and maintaining anesthesia, brain protection, or promoting sedation and hypnosis of an animal or human in an animal or human Use in the treatment, and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy drugs, preferably in the preparation of anesthetic agents for inducing and maintaining animals or humans.

The present invention provides a method for improving drug absorption, which comprises: forming a prodrug by directly or via a linking group L with one or more groups of the formula (Q), wherein: Q is as defined above the same.

The present invention provides a method for improving oral bioavailability of a medicament, the method comprising: forming the prodrug by directly or via a linking group L with one or more groups of the formula (Q), wherein: the definition of Q Same as the previous definition.

The present invention provides a method for extending the half-life of a parent drug, the method comprising: forming the prodrug by directly or via a linking group L with one or more groups of the formula (Q), wherein: Q is defined The foregoing definitions are the same.

The present invention provides a method as described above, which comprises: hydrolyzing a prodrug in vivo to release a prodrug. Specifically, the prodrug may be administered to a subject; preferably, the subject is administered by oral administration to hydrolyze the prodrug to release the original drug.

a prodrug of the present invention, which has a compound represented by the formula (LO-1) or (LS-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein

The definitions of G, L, Q, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, n, s are consistent with the definitions of formula (I); The following is not limited to the hydrolysis to release the original drug: the ester, thioester in the compound can be hydrolyzed to release the compound of the formula (LO-2), and the carboxylic acid can be used as a warhead group to attack the phosphorus atom. An intermediate state with a linking group is released which is further hydrolyzed to give a compound of the formula (GH), while the prodrug fragment of the formula (LO-3) can be further metabolized and excreted:

a prodrug of the present invention, which has a compound represented by the formula (GO-1) or (GS-1), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein

The definitions of G, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, n, s are consistent with the definitions of formula (I);

The drug is hydrolyzed by the following formula, but is not limited to the following: the compound represented by the formula (GO-1) or (GS-1) and the pharmaceutically acceptable salt or stereoisomer thereof, ester, sulfur The ester can be hydrolyzed to release a compound of the formula (GO-2), the carboxylic acid can be used as a warhead group, attacking the phosphorus atom, releasing the compound of the general formula (GH), and the prodrug fragment formula (LO-3) The compound can be further metabolized and excreted.

Terms used in the specification and the scope of the patent application have the following meanings unless stated to the contrary.

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I mentioned in the groups and compounds of the present invention include their isotopic conditions, and the groups and compounds mentioned in the present invention The carbon, hydrogen, oxygen, sulfur or nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, and the hydrogen isotopes include helium (H), helium ( D, also known as heavy hydrogen), 氚 (T, also known as super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotope Including ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" means a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms. Further, it is preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and Various branched isomers; the alkyl group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, thiol, -SR ^18a , nitro, cyano, amino, Alkylamino, amidino, alkenyl, alkynyl, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, 3 to 8 membered carbocyclyl, 3 to 8 membered Substituted by a substituent of a cyclic group, a 3 to 8 membered carbocyclyloxy group, a 3 to 8 membered heterocyclyloxy group, a carboxyl group or a carboxylate group, wherein R ^{18a is} selected from C _1-6 alkyl groups, 3 to 8 A carbocyclyl or a 3 to 8 membered heterocyclic group, the alkyl group appearing herein, is as defined in this definition.

"Alkoxy" means an -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, Cyclopropoxy and cyclobutoxy. The alkyl group may be further optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, decyl, -SR ^18a , nitro, cyano, amino, alkylamino, decylamino. Substituted by a substituent of an alkenyl group, an alkynyl group, an alkyl group, a hydroxyalkyl group, an alkoxy group, a carbocyclic group, a heterocyclic group, a carbocyclic oxy group, a heterocyclic oxy group, a carboxy group or a carboxylate group, Wherein R ^{18a is} as defined above. The alkoxy groups present herein are defined in accordance with this definition.

"Alkylamino" means an amino group having one or two alkyl substituents.

The "carboxylate group" means -COOR ^19a wherein R ^19a is a C _1-6 alkyl group.

"=O" is a commonly used practice in the art and refers to an oxygen atom connected by a double bond, such as a double bond oxygen atom attached to a carbon atom in a carbonyl group.

The "hydroxyalkyl group" is an alkyl group substituted by 1, 2 or 3 hydroxyl groups, and the alkyl group is preferably a C _1-4 alkyl group. Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl.

"Alkenyl" means an alkyl group having from 1 to 3 carbon-carbon double bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms. More preferably, it is an alkenyl group of 2 to 8 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hex-2-yl, Hexene-3,hepten-2-yl,hepten-3-yl,hepten-4-yl,oct-3-yl,nonen-3-yl,nonen-4-yl and eleven Alk-3-yl. The alkenyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of a mercaptoamine, a carbocyclic group or a heterocyclic group.

"Alkynyl" means an alkynyl group having from 1 to 3 carbon-carbon triple bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms. More preferably, it is an alkynyl group of 2 to 8 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyrynyl-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyne-4- Base, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of a mercaptoamine, a carbocyclic group or a heterocyclic group.

"Carbocycle" means a saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring may be a single ring of 3 to 8 members, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system. The group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, and rings. Hexene, , , , . The carbocyclic group may be further optionally further selected from 0 to 8 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, decyl, -SR ^18a , nitro, cyano, amino, alkylamino, decylamine. Substituted by a base, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate group, wherein R ^{18a is} as defined above. The definition of carbocyclic groups appearing herein is consistent with this definition.

"Cycloalkyl" means a saturated or unsaturated monocyclic cyclic hydrocarbon group which may be substituted or unsubstituted, and the ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl , cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl, and the like. When substituted, the substituent may be from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyanide , isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cyclyl, hydroxyalkyl, =0, carbonyl, aldehyde, carboxylic acid, formate, -(CH ₂ ) _m -C(=O)-R ^a , -O-(CH ₂ ) _m -C(=O)-R ^a , -(CH ₂ ) _m -C(=O)-NR ^b R ^c ,- (CH ₂ ) _m S(=O) _n R ^a , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (where m and n are 0, a group such as 1 or 2), arylthio, thiocarbonyl, decyl or -NR ^b R ^c wherein R ^b and R ^{c are} independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy , cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, optionally, R ^b and R ^c may form a five or six membered cycloalkyl or heterocyclic group. R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, a heterocyclic group, a carbonyl group, an ester group, a cycloalkyl group bridged, and spiro ring group or a cycloalkyl group.

"Heterocyclic" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring may be a single ring of 3 to 8 members, a 4 to 12 membered double ring or 10 to 15 members. a tricyclic system comprising 1 to 3 hetero atoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group may be oxidized to various Oxidation state. The heterocyclic group may be attached to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include epoxyethyl, azacyclopropyl, oxetanyl, aza. Cyclobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxohexyl, azepanyl, pyridyl, furyl, thienyl, pyridyl Meryl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, acridinyl, fluorenyl, morpholinyl, thiomorpholinyl, 1,3-dithia, Dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl , pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]decyl, oxatricyclo[5.3.1.1] Alkyl, azaadamantyl and oxaspiro[3.3]heptanyl. The heterocyclic group may be further optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, decyl, -SR ^18a , nitro, cyano, amino, alkylamino, decylamine. Substituted by a substituent of a base, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate group Wherein R ^{18a is} as defined above. The heterocyclic groups appearing herein are defined in accordance with this definition.

"Amino acid": The basic skeleton of a protein molecule is an amino acid sequence, and there are 20 basic amino acids constituting a protein. These 20 basic amino acids are the basis for biological late modification of the protein. In addition, based on these basic amino acids, the organism also synthesizes The types of amino acids derived from hydroxyproline, hydroxylysine, etc., which are biosynthetic amino acids are collectively referred to as "natural amino acids"; artificially synthesized are "unnatural amino acids". "Pharmaceutically acceptable amino acid" means a pharmaceutically acceptable natural or unnatural amino acid. Amino acids include all amino acids, both natural and non-natural.

"A side chain of an amino acid" means an amino acid formula The group represented by R, such as the side chain of lysine, refers to -(CH ₂ ) ₄ NH ₂ , the side chain of methionine refers to -CH ₂ CH ₂ SCH ₃ , and the side chain of amino acid includes both natural and non-natural. The side chain of the amino acid.

"Ester group" means -C(=O)OR or -OC(=O)R, and R includes, but is not limited to, substituted or unsubstituted alkyl, alkenyl, alkynyl, heterocycloalkyl or carbocycloalkyl. And the substituent may be selected from the group consisting of halogen, hydroxy, thiol, CN, carboxyl, nitro, alkyl, alkoxy, alkenyl, alkynyl and the like.

"Mercapto" means -COR, and R includes, but is not limited to, substituted or unsubstituted alkyl, alkenyl, alkynyl, heterocycloalkyl or carbocycloalkyl, and the substituent may be selected from halogen, hydroxy, Mercapto group, CN, carboxyl group, nitro group, alkyl group, alkoxy group, alkenyl group, alkynyl group and the like.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or organic A base obtained by reacting the free base with a non-toxic inorganic or organic acid.

"Pharmaceutical composition" means a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein "other chemical components" means pharmaceutically acceptable A carrier, excipient, and/or one or more additional therapeutic agents.

"Carrier" means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.

"Excipient" means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders And disintegration Agent.

"Prodrug" means a compound of the invention which can be metabolized by the body to be biologically active. Prodrugs of the invention are prepared by modifying a phenolic group in a compound of the invention, which modification can be removed by routine manipulation or in vivo to provide the parent compound.

"eutectic" refers to a crystal in which an active pharmaceutical ingredient (API) and a eutectic former (CCF) are combined by hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF is at room temperature. It is a solid and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate.

"Animal" means including mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.

"Stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

"Optional" or "optional" or "optional" or "optionally" means that the subsequently described event or condition may, but does not necessarily, occur, including where the event or condition occurred and What happened. For example, "heterocyclic group optionally substituted by an alkyl group" means that the alkyl group may be, but not necessarily, the description includes the case where the heterocyclic group is substituted by an alkyl group, and the heterocyclic group thereof is not substituted with an alkyl group. Happening.

As used herein, "as a selection" refers to a juxtaposed existence relationship, such as "R _a and R _b are each independently selected from an alkyl group, an alkoxy group; alternatively, R _a and R _b form an aromatic ring", and R _{a is} represented. relationship form an aromatic ring and R _a and R _b each independently selected from alkyl or alkoxy with in parallel a R _b, defined by each other is not limited.

Anesthesia induction time and anesthesia maintenance time: start timing after administration, and closely observe the general symptoms of the animal and the local and respiratory changes. If a normal animal pushes it down or is lying on its back, it can be turned over immediately. This reflection is judged as a normal reflection. On the contrary, it is regarded as the disappearance of the righting reflection, and the reflection disappearance time is recorded. When the animal reappears the righting reflection, the reflection recovery time is recorded. The time from the end of administration to the righting reflex was recorded as the anesthesia onset time, and the disappearance of the righting reflex to the reflex recovery time was recorded as the anesthesia maintenance time.

Method for synthesizing the compound of the present invention

Preparation method one:

Wherein M _{1 is} selected from F, Cl, Br or I; M _{2 is} selected from R ^M , H, L-halogen or L-OH; R ^{M is} selected from F, Cl, Br, I or OH; R ¹ , R ² And R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , L, X, G, n, s, Q are as defined in the definition of the compound of formula (I);

First step: A compound of the formula (Z-3) is reacted with a compound of the formula (Z-2) in the presence of a base to give a compound of the formula (Z-1).

The second step: a compound of the formula (Z-1) is reacted with a compound of the formula (Z-4) in the presence of a base to give a compound of the formula (I).

Alternatively, the compound of the formula (Z-3) is reacted with a compound of the formula (Z-2) in the presence of a base, and then a compound of the formula (Z-4) is directly added to obtain a compound of the formula (I);

Preparation method two:

Wherein M _{1 is} selected from OH, F, Cl, Br or I; M _{2 is} selected from R ^M , H, L-halogen or L-OH; R ^{M is} selected from F, Cl, Br, I or OH; R ¹ , The definitions of R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , L, X, G, n, s, Q are identical to those defined for the compound of formula (I);

First step: A compound of the formula (Z-3) is reacted with a compound of the formula (Z-4) in the presence of a base to give a compound of the formula (Z-5).

The second step: a compound of the formula (Z-5) is reacted with a compound of the formula (Z-2) in the presence of a base to give a compound of the formula (1).

Alternatively, a compound of the formula (Z-3) is reacted with a compound of the formula (Z-4) in the presence of a base, and then a compound of the formula (Z-2) is directly added to obtain a compound of the formula (I).

Preparation method three:

M _{1 is} selected from F, Cl, Br or I; R ^{M is} selected from F, Cl, Br, I or OH; R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , L, X The definitions of G, n, s, Q are consistent with the definitions of the compounds of formula (I);

First step: a compound of the formula (Z-3-1) is reacted with a compound of the formula (Z-2) in the presence of a base to obtain A compound of the formula (Z-6).

The second step: a compound of the formula (Z-6) is reacted with a compound of the formula (Z-7) in the presence of a base to give a compound of the formula (1).

Preparation method four:

M _{1 is} selected from F, Cl, Br or I; M _{2 is} selected from L-halogen or L-OH; R ^{M is} selected from F, Cl, Br, I or OH; L is selected from a linking group

The definitions of R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, G, n, s, Q are identical to those defined for the compound of formula (I); (Z-3-1) The compound is reacted with a compound of the formula (Z-2) in the presence of a base to obtain a compound of the formula (Z-1-1); the second step: a compound of the formula (Z-1-1) is The compound of the formula (Z-1) is reacted with a compound of the formula (Z-8) in the presence of a base; the third step: a compound of the formula (Z-1) in the presence of a base and a compound of the formula (Z-4) The reaction gives a compound of the formula (1).

The preparation methods of the general formula (Z'-1), the general formula (II') and the general formula (III') can be prepared by referring to the methods one to four.

The bases described in the first method, the second method, the third method and the fourth method are selected from the group consisting of triethylamine, N,N-diisopropylethylamine, tri-n-butylamine, trimethylamine, N,N,N',N' -tetramethylethylenediamine, N-methylmorpholine, N-methylacridine, 2,2,6,6-tetramethylacridine, 1,1,3,3-tetramethylguanidine, three Butylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, carbonic acid Bismuth, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium hydroxide, talonine, n-butyl lithium, Isopropyl lithium, second butyl lithium, phenyl lithium, lithium diisopropylamide, lithium 2,2,6,6-tetramethyl acridine, lithium bis(trimethyldecyl)amide, double (trimethyldecyl)amino sodium, bis(trimethylsulfonyl)amino potassium, isopropyl magnesium chloride, isopropyl magnesium bromide, third butyl magnesium chloride, third butyl magnesium bromide, Potassium tributolate, sodium butoxide, magnesium butoxide, lithium hydride, sodium ethoxide, sodium trimethylaluminum, triethylaluminum, diethylzinc, pyridine, 2-methylpyridine, 2 , 4-dimethyl Pyridine, 2,6-lutidine, 4-dimethylaminopyridine, quinoline, isoquinoline, imidazole, potassium hydride, calcium hydride, lithium hydride or sodium hydride; if formula (Z-1), Z-1-1), (Z-3-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7) Or (Z-8) containing other groups which affect the reaction such as amino group, aldehyde group, amine group or hydroxyl group, etc., may be selected to be protected with a protecting group before the reaction, and then the protection is removed; wherein the protecting group includes It is not limited to a mercapto group, an ether, an ester or an acetal ketal, and the like, preferably a third butoxycarbonyl group, a benzyloxycarbonyl group, a fluorenylmethoxycarbonyl group, an allyloxycarbonyl group or a trichloroethoxy group. Carbonyl, trimethylsulfonylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2-biphenyl-2-propoxycarbonyl, tert-butoxy, phthalic acid, p-toluenesulfonyl, O-nitrophenylsulfonyl, p-nitrophenylsulfonyl, tert-amyl, carbenyl, trifluoroethenyl, benzhydryl, benzyl, trityl, p-methoxybenzyl Or 2,4-dimethoxybenzyl, further preferably H or a third butoxycarbonyl group.

The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is ^reported in units of 10 ^-6 (ppm). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, and the solvent was deuterated dimethyl hydrazine (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD _{3 ).} OD), the internal standard is tetramethyl decane (TMS). The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)). The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatography (Zorbax SB-C18 100 x 4.6 mm). The thin layer chromatography tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet, and the specification of the tantalum sheet used by thin layer chromatography (TLC) is 0.15mm~0.20mm. Unless otherwise specified, the detection wave separated by supercritical fluid chromatography is UV. Pipe column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh silicone as carrier. The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies. The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L. The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume. The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times. Unless otherwise stated in the examples, the solution means an aqueous solution. There is no particular description in the examples, and the reaction temperature is room temperature. The room temperature is 20 ° C ~ 30 ° C. Brief description of the group: iPr: isopropyl; Et: ethyl; Ms: methylsulfonyl; Min: minute.

Intermediate 1

(2S)-ethyl 2-((chloro(methoxymethyl)phosphonium)amino)propionate; (2S)-ethyl 2-((chloro(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphonium dichloride (0.23 g, 1.41 mmol) was dissolved in dichloromethane (5 mL) and EtOAc (0.16 g, 1.37 mmol) A solution of a mixture of triethylamine (0.3 g, 2.97 mmol) in dichloromethane (1.5 mL). After stirring at this temperature for 10 min, the solvent was evaporated under reduced pressure to give crude Intermediate .

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.62-4.03 (m, 3H), 4.03-3.60 (m, 2H), 3.58-3.38 (m, 3H), 1.40-1.37 (m, 3H), 1.37-1.23 ( m, 3H). LC-MS m/z = 226.1.

Intermediate 2

(2S)-isopropyl 2-((chloro(methoxymethyl)phosphonium)amino)propionate; (2S)-isopropyl 2-((chloro(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphine dichloride (0.23 g, 1.41 mmol) was dissolved in dichloromethane (5 mL), and isopropyl L-alanine (0.18 g, 1.37) was slowly added dropwise at -30 °C. A solution of a mixture of mmol) and triethylamine (0.3 g, 2.97 mmol) in dichloromethane (1.5 mL). After stirring at this temperature for 10 min, the solvent was evaporated under reduced pressure to give crude Intermediate .

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.16-4.97 (m, 1H), 4.50-3.74 (m, 3H), 3.60-3.43 (m, 3H), 1.39 (d, 3H), 1.34-1.20 (m, 6H). LC-MS m/z = 240.2.

Intermediate 3

2-[Chloro(methoxymethyl)phosphonium]oxy-1,3-diisopropyl-benzene

2-[chloro(methoxymethyl)phosphoryl]oxy-1,3-diisopropyl-benzene

(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonic acid

(2,6-diisopropylphenoxy)-(methoxymethyl)phosphinic acid

(Methoxymethyl)phosphine dichloride (5.0 g, 30.69 mmol) was dissolved in dichloromethane (50 mL), and propofol (8.0 g, 4.87 mmol) was added dropwise at -10 ° C under nitrogen. A solution of triethylamine (12.4 g, 122.74 mmol) in dichloromethane (50 mL) was evaporated. And 50 mL of water was added at this temperature. The reaction was carried out for 2 hours at room temperature. Liquid separation, the aqueous phase was adjusted to PH 2 with concentrated hydrochloric acid, and the aqueous was extracted with ethyl acetate (50mL) phase was separated, dried over anhydrous sodium sulfate, and concentrated to give an intermediate. 3A, as a yellow solid (2.0 g of, yield 22.76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 7.19-6.93 (m, 3H), 3.81 (d, 2H), 3.56-3.27 (m, 5H), 1.14 (m, 12H). LCMS m/z = 287.2 [M + 1].

2-[Chloro(methoxymethyl)phosphonium]oxy-1,3-diisopropyl-benzene

2-[chloro(methoxymethyl)phosphoryl]oxy-1,3-diisopropyl-benzene

Intermediate 3A (0.70 g, 2.4 mmol) was dissolved in dichloromethane (20 mL). After the addition was completed, the mixture was heated under reflux for 3 hours. Concentration gave Intermediate 3 as a yellow oil (0.8 g, yield: 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22-7.07 (m, 3H), 4.41-4.01 (m, 2H), 3.58-3.33 (m, 5H), 1.26-1.20 (m, 12H).

Intermediate 4

Isopropyl (2S)-2-[[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphoryl]amino-]propanoate

(Methoxymethyl)phosphine dichloride dichloride (3.00 g, 18.4 mmol) was dissolved in 100 mL of dry dichloromethane, and then filtered with nitrogen, and triethylamine (7.45 g, 73.6 mmol) was added dropwise at -30 ° C, L- A mixture of alanine isopropyl ester hydrochloride (3.09 g, 18.4 mmol) was reacted for 30 minutes after the dropwise addition, and 4-(hydroxymethyl)phenol (3.43 g, 27.6 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Add 50 mL of water, extract with dichloromethane (100 mL×2), wash once with saturated aqueous sodium dihydrogen phosphate solution (50 mL), and wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, Chromatographic separation and purification (purification of methanol: dichloromethane (v / v) = 0: 100 ~ 1: 50), the above compound isopropyl (2S)-2-[[[4-(hydroxymethyl) Phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Intermediate 4 ), light yellow oil (3.60 g, yield 56.6%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.34 (d, 2H), 7.25-7.19 (m, 2H), 4.99 (m, 1H), 4.56 (d, 2H), 4.17-4.04 (m, 1H), 3.87 -3.72 (m, 2H), 3.53 (t, 1H), 3.46 (m, 3H), 1.60 (d, 1H), 1.32 (d, 3H), 1.26-1.19 (m, 6H). LC-MS m/ z=346.1[M+1].

Intermediate 5

N-[(1S)-2-Ethoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphoric acid

N-[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphonamidic acid

Ethyl (2S)-2-[[benzyloxy(methoxymethyl)phosphonium]amino]propionate

Ethyl(2S)-2-[[benzyloxy(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (20 g, 122.7 mmol) was dissolved in dichloromethane (250 mL) and EtOAc (12.92 g, 110.43 mmol) A solution of a mixture of triethylamine (49.66 g, 490.8 mmol) in dichloromethane (150 mL). After warming to room temperature and stirring for 30 minutes, benzyl alcohol 5A (13.25 g, 122.7 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Washed with a saturated solution of sodium dihydrogen phosphate (250 mL × 1) and saturated sodium chloride solution (250 mL × 1), dried over anhydrous sodium sulfate, and then filtered and evaporated. Purification (petroleum ether / ethyl acetate = (v / v) 8:1 ~ 0:1), the above compound ethyl (2S)-2-[[benzyloxy(methoxymethyl)phosphonium]amino] Propionate ( Intermediate 5B ) pale yellow liquid (12.1 g, yield 31.30%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.42-7.27 (m, 5H), 5.18-4.95 (m, 2H), 4.26-4.03 (m, 3H), 3.73-3.68 (m, 2H), 3.41 (dd, 3H), 3.31 (m, 1H), 1.36 (dd, 3H), 1.26 (m, 3H). LCMS m/z = 316.1 [M+1].

N-[(1S)-2-Ethoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphorine ( Intermediate 5 )

N-[(1S)-2-ethoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphonamidic acid

Ethyl (2S)-2-[[benzyloxy(methoxymethyl)phosphonium]amino]propionate (Intermediate 5B ) (1 g, 3.17 mmol) was dissolved in methanol (15 mL) and palladium carbon was added. (1 g, 100% by weight), triethylamine (0.32 g, 3.17 mmol), and the reaction system was replaced with hydrogen, and then reacted at room temperature for 3 hours under a hydrogen atmosphere under normal pressure. The catalyst was removed by filtration through celite, and the filter cake was washed with methanol (15 mL × 2), and the filtrate was concentrated under reduced pressure to give the compound Intermediate 5 as a colorless liquid (0.44 g, yield 61.62%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 4.05 (m, 2H), 3.82-3.68 (m, 1H), 3.29-3.24 (m, 1H), 3.23 (s, 2H), 3.17 (s, 3H) , 1.39-1.05 (m, 6H). LCMS m / z = 226.1 [M + 1].

Intermediate 6

N-[(1S)-2-Isopropoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphorine (Intermediate 6)

N-[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphonamidic acid

Isopropyl (2S)-2-[[benzyloxy(methoxymethyl)phosphonium]amino]propionate ( Intermediate 6A )

Isopropyl(2S)-2-[[benzyloxy(methoxymethyl)phosphoryl]amino]propanoate

1C (23.0 g, 141.2 mmol) was dissolved in dichloromethane (400 mL). Under a nitrogen atmosphere, a solution of L-alanine isopropyl ester (18.5 g, 141.2 mmol) and triethylamine (57.1 g, 564.6 mmol) in dichloromethane (200 mL) was added dropwise at -30 ° C and stirred for 1 hour. At this temperature, benzyl alcohol (15.2 g, 141.2 mmol) was added, allowed to naturally return to room temperature, and stirred for 1 hour. Add a saturated aqueous solution of sodium dihydrogen phosphate (300 mL), and extract with dichloromethane (500 mL×2). Ether = (v/v) 1/20 to 1/1) gave a yellow oil ( Intermediate 6A ) (15.0 g, yield 32.7%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.39-7.36 (m, 5H), 5.11-4.99 (m, 3H), 4.03-.4.0 (m, 1H), 3.69 (t, 2H), 3.43-3.34 (m , 4H), 1.39-1.32 (m, 3H), 1.26-1.22 (m, 6H)

N-[(1S)-2-Isopropoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphorine ( Intermediate 6 )

N-[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]-(methoxymethyl)phosphonamidic acid

(2S)-Isopropyl 2-(((phenoxy)(methoxymethyl)phosphonium)amino)propionate ( Intermediate 6A ) (600 mg, 1.82 mmol) was dissolved in methanol (10 mL) Triethylamine (202 mg, 1.99 mmol) and palladium on carbon (600 mg, 10%) were added in that order. Stir under hydrogen (1 atm) for 2 hours. Filtration and concentration gave a white solid intermediate 6 (650 mg).

LCMS m/z = 240.2 [M + 1].

Intermediate 7

Isopropyl (2S)-2-[[[4-(hydroxymethyl)-2-methoxy-phenoxy]-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[4-(hydroxymethyl)-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (3.258 g, 20.00 mmol) was dissolved in 30 mL of dry dichloromethane, nitrogen-protected, and isopropyl ester of L-alanine (5.246 g, 40.00) was added dropwise at -30 °C. Methylene chloride solution (15 mL), 1 h after the dropwise addition, triethylamine (8.093 g, 80.00 mmol) and 3-hydroxymethyl-4-hydroxy-benzyl alcohol (4.624 g, 30.00 mmol), Raise to room temperature and react for 2 h. Water (40 mL) was added, and the aqueous layer was separated with methylene chloride (40 mL×2). ) = 1:1). The above compound intermediate 7 was obtained as a pale yellow liquid (2.753 g, yield 36.7%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.27 (dd, 1H), 7.00 (d, 1H), 6.87-6.83 (m, 1H), 5.04-4.91 (m, 1H), 4.64 (d, 2H), 4.16 -3.99(m,1H),3.93-3.85(m,5H),3.71-3.64(m,1H),3.51-3.48(m,3H),1.98(s,1H),1.32-1.19(m,9H) .LC-MS(m/z)=376.2[M+1].

Intermediate 8

Isopropyl (2S)-2-[[[4-(hydroxymethyl)-2,6-bis(methoxy)-phenoxy]-(methoxymethyl)phosphine oxime] propionate

Isopropyl(2S)-2-[[[4-(hydroxymethyl)-2,6-dimethoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride ( 1C ) (3.258 g, 20.00 mmol) was dissolved in dry dichloromethane (30 mL), nitrogen-protected, and isopropyl ester of L-alanine was added dropwise at -30 °C. (5.246 g, 40.00 mmol) in dichloromethane (15 mL), 1 h after the dropwise addition, triethylamine (8.093 g, 80.00 mmol) and 3,5-di(hydroxymethyl)-4-hydroxy-benzyl Alcohol (3.683 g, 20.00 mmol) was naturally allowed to react to room temperature for 2 h. Water (40 mL) was added, and the aqueous layer was separated with methylene chloride (40 mL×2). ) = 1: 2). The aforementioned compound Intermediate 8 was obtained as a pale yellow liquid (3.468 g, yield: 38.0%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.59 (d, 2H), 5.07-4.96 (m, 1H), 4.61 (d, 2H), 4.26-4.15 (m, 1H), 4.02-3.88 (m, 2H) , 3.86 (s, 3H), 3.84 (s, 3H), 3.52-3.51 (m, 3H), 1.96 (s, 1H), 1.43-1.32 (m, 3H), 1.26-1.22 (m, 6H). -MS(m/z)=406.2[M+1].

Example 1

Methyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropylphenoxy]-(methoxymethyl)phosphonio]amino] Propionate ( Compound 1 )

Methyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

First step: diethyl (methoxymethyl) phosphonate ( 1B )

Diethyl(methoxymethyl)phosphonate

Sodium hydride (8.5 g, 0.35 mol) was dissolved in 500 mL of tetrahydrofuran, and diethyl hydroxymethylphosphonate 1A (50 g, 0.29 mol) was added dropwise at 0 ° C under a nitrogen atmosphere, and reacted at this temperature for 30 minutes. A solution of methyl iodide (50.7 g, 0.35 mol) in tetrahydrofuran (100 mL) was added dropwise. After the dropwise addition, the reaction was carried out for 2 hours at room temperature. Saturated ammonium chloride solution (50 mL) and water (500 mL) were added dropwise, ethyl acetate (500 mL×3), and the organic phase was dried over anhydrous sodium sulfate and evaporated. Purification (petroleum ether: ethyl acetate (v/v) = 10:1 to 1:1) gave Compound 1B as a yellow liquid (25.0 g, yield 46.2%).

LC-MS (m/z) = 183.2 [M+1].

The second step: (methoxymethyl) phosphine dichloride ( 1C )

(methoxymethyl)phosphonic dichloride

Compound 1B (0.5 g, 2.7 mmol) was dissolved in acetonitrile (5 mL), and trimethylbromohexane (1.26 g, 8.2 mmol) was added at room temperature, and the reaction was heated at 50 ° C for 2 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane (10 mL), and two portions of N,N-dimethylformamide and oxalyl chloride (1.03) were added dropwise to the reaction mixture under ice-water bath and nitrogen. g, 8.2 mmol), and allowed to react at room temperature overnight. The reaction mixture was concentrated to give Compound 1C (yield:

The third step: methyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropylphenoxy]-(methoxymethyl)phosphonium Amino]propionate ( compound 1 )

Methyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Compound 1C (7.5 g, 46 mmol) was dissolved in dichloromethane (100 mL), and (R)-2-(1-cyclopropylethyl)-6-isopropyl was added dropwise at -10 °C under nitrogen. A solution of phenol (9.3 g, 46 mmol) and triethylamine (18.5 g, 0.184 mol) dissolved in dichloromethane (100 mL) was added dropwise, and reacted at room temperature for 1 hour. At this temperature, L-alanine was added. A solution of the methyl ester (9.4 g, 0.092 mol) in dichloromethane (100 mL) was then allowed to react at room temperature for two hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. ) = 10:1 to 1:1) Compound 1 was obtained as a yellow oil (8.0 g, yield 43.9%).

LC-MS (m/z) = 398.3 [M+1].

Compound 1 was isolated by supercritical fluid chromatography to give two optical isomer compounds 1-a (2.25 g, pale yellow oil, retention time 0.676 min, ee% = 100%), compound 1-b (2.622) g, residence time 1.00 min, light yellow oil, ee% = 100%). Preparation conditions: instrument: SFC-80 (Thar, Waters); chromatography column: CHIRLPAK AD (30 * 250mm 5μm) (Daicel); column temperature: 35 ° C; mobile phase: phase A is carbon dioxide, phase B is methanol; gradient : B 20%; back pressure: 100 bar; total flow rate: 45 g/min; period: 5.0 min; detection wavelength: 215 nm.

Compound 1-a :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.26-7.22 (m, 1H), 7.17-7.10 (m, 2H), 4.14-4.08 (m, 1H), 3.89-3.84 (m, 1H), 3.76 (dd, 1H), 3.62 (s, 3H), 3.54-3.47 (m, 1H), 3.46 (s, 1H), 3.44 (d, 3H), 2.78-2.71 (m, 1H), 1.35 (d, 3H), 1.28 (d, 3H), 1.22 ( dd, 6H), 0.99-0.78 (m, 1H), 0.56-0.53 (m, 1H), 0.39-0.27 (m, 1H), 0.28-0.15 (m, 2H). 31 P NMR (162 MHz, CDCl ₃ ) δ 22.49.

Compound 1-b :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.26-7.22 (m, 1H), 7.17-7.10 (m, 2H), 4.11 (m, 1H), 3.89-3.84 (m, 1H), 3.76 (dd, 1H) , 3.62 (s, 3H), 3.54-3.47 (m, 1H), 3.46 (s, 1H), 3.44 (d, 3H), 2.74 (m, 1H), 1.35 (d, 3H), 1.28 (d, 3H) ), 1.22 (dd, 6H), 0.99-0.78 (m, 1H), 0.56-0.51 (m, 1H), 0.39-0.27 (m, 1H), 0.28-0.15 (m, 2H). ³¹ P NMR (162 MHz) , CDCl ₃ ) δ 21.30.

Example 2

Isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphonium] Amino]propionate ( compound 2 )

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Compound 1C (7.5 g, 46 mmol) was dissolved in dichloromethane (100 mL), and (R)-2-(1-cyclopropylethyl)-6-isopropyl was added dropwise at -10 °C under nitrogen. A solution of phenol (9.3 g, 46 mmol) and triethylamine (18.5 g, 0.184 mol) in dichloromethane (100 mL) was then evaporated. A solution of L-alanine isopropyl ester (12.0 g, 0.092 mol) in dichloromethane (100 mL) was added at room temperature and the reaction was continued for two hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. ) = 10:1 to 1:1) Compound 2 was obtained as a yellow oil (7.0 g, yield: 35.8%).

LC-MS (m/z) = 426.4 [M+1].

Compound 2 was isolated by supercritical fluid chromatography to give two optical isomer compounds 2-a (2.738 g, retention time 0.653 min, pale yellow oil, ee% = 100%), compound 2-b ( 3.5 g, residence time 0.996 min, light yellow oil, ee% = 100%). Preparation conditions: instrument: SFC-80 (Thar, Waters); chromatography column: CHIRLPAK AD (30 * 250mm 5μm) (Daicel); column temperature: 35 ° C; mobile phase: phase A is carbon dioxide, phase B is methanol; gradient : B 20%; back pressure: 100 bar; total flow rate: 45 g/min; detection wavelength: 215 nm; period: 4.6 min.

Compound 2-a :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.29-7.22 (m, 1H), 7.14-7.11 (m, 2H), 5.04-4.97 (m, 1H), 4.13-3.97 (m, 1H), 3.91-3.73 ( m, 2H), 3.57-3.43 (m, 4H), 3.44-3.27 (m, 1H), 2.86-2.65 (m, 1H), 1.33-1.17 (m, 15H), 1.11 (dd, 3H), 0.97- 0.90 (m, 1H), 0.63-0.48 (m, 1H), 0.42-0.31 (m, 1H), 0.32-0.13 (m, 2H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.47.

Compound 2-b :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.25-7.22 (m, 1H), 7.16-7.11 (m, 2H), 4.98-4.92 (m, 1H), 4.07-4.01 (m, 1H), 3.86-3.74 ( m, 2H), 3.56-3.48 (m, 2H), 3.44 (d, 3H), 2.80-2.72 (m, 1H), 1.33 (d, 3H), 1.28 (d, 3H), 1.22-1.17 (m , 12H), 0.94-0.88 (m, 1H), 0.56-0.50 (m, 1H), 0.36-0.30 (m, 1H), 0.25-0.19 (m, 2H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.35.

Example 3

Methyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy](isopropoxymethyl)phosphonium]amino Propionate ( compound 3 )

Methyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(isopropoxymethyl)phosphoryl]amino]propanoate

First step: diethyl (isopropoxymethyl) phosphonate ( 3B )

Diethyl(isopropoxymethyl)phosphonate

Triethyl phosphite 3A (20.0 g, 0.12 mol) and chloromethyl isopropyl ether (14.3 g, 0.13 mol) were dissolved in a 500 mL single-mouth flask, heated to 130 ° C, and reacted for 4 hours. The reaction solution was cooled to room temperature, concentrated, and purified by silica gel column chromatography ( petroleum ether: ethyl acetate (v/v) = 10:1 to 1:1) to obtain compound 3B , colorless liquid (20.0 g, yield 80%).

LC-MS (m/z) = 211.2 [M+1].

Second step: (isopropoxymethyl)phosphonium dichloride ( 3C )

(isopropoxymethyl)phosphonic dichloride

Compound 3B (15 g, 71.42 mmol) was dissolved in acetonitrile (200 mL), and trimethylbromohexane (32.78 g, 210 mmol) was added at room temperature, and the mixture was heated to 50 ° C for 2 hours. The reaction solution was concentrated, and the residue was evaporated mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 210 mmol), the reaction was continued overnight at room temperature. The reaction solution was concentrated to give Compound 3C (yield: 13.0 g, yield 95%).

Step 3: Methyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy](isopropoxymethyl)phosphine Mercapto]amino]propionate ( compound 3 )

Methyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(isopropoxymethyl)phosphoryl]amino]propanoate

Compound 3C (6.8 g, 35.7 mmol) was dissolved in dichloromethane (60 mL), and (R)-2-(1-cyclopropylethyl)-6-iso was added dropwise at -10 °C under nitrogen. A solution of propyl phenol (7.2 g, 35.7 mmol) and triethylamine (14.4 g, 0.14 mol) in dichloromethane (100 mL) was evaporated. A solution of L-alanine methyl ester (7.2 g, 0.071 mol) in dichloromethane (100 mL) was added at room temperature and the reaction was continued for 2 hr. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and the mixture was evaporated, evaporated, evaporated, evaporated. v/v) = 10:1 to 1:1) gave Compound 3 as a yellow oil (5.0 g, yield 33%).

LC-MS (m/z) = 426.3 [M+1].

Compound 3 was isolated by supercritical fluid chromatography to give two optical isomer compounds 3-a (1.724 g, retention time 0.667 min, white solid, ee% = 100%), compound 3-b (0.6 g, Retention time 1.07 min, white solid, ee% = 100%). Preparation conditions: instrument: SFC-80 (Thar, Waters); chromatography column: CHIRLPAK AD (30 * 250 mm 5 μm) (Daicel); column temperature: 35 ° C; mobile phase: A is carbon dioxide, phase B is methanol; B 20%; back pressure: 100 bar; total flow rate: 45 g/min; period: 5.4 min; detection wavelength: 215 nm.

Compound 3-a :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.33-7.20 (m, 1H), 7.16-7.12 (m, 2H), 4.18-4.02 (m, 1H), 3.92 (dd, 1H), 3.77 (dd, 1H) , 3.73-3.53(m,5H), 3.43(t,1H),2.87-2.79(m,1H),1.36-1.14(m,15H),1.08(d,3H),1.00-0.85(m,1H) , 0.64-0.46 (m, 1H), 0.42-0.31 (m, 1H), 0.31 - 0.25 (m, 1H), 0.21 - 0.15 (m, 1H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 26.75.

Compound 3-b :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.26-7.20 (m, 1H), 7.17-7.06 (m, 2H), 4.16-4.02 (m, 1H), 3.92 (dd, 1H), 3.75 (dd, 1H) , 3.70-3.53 (m, 5H), 3.49-3.37 (m, 1H), 2.90-2.82 (m, 1H), 1.29 (dd, 6H), 1.20 (dd, 12H), 1.00-0.78 (m, 1H) , 0.62-0.41 (m, 1H), 0.40-0.16 (m, 3H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.45.

Example 4

Isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(isopropoxymethyl)phosphonium Amino]propionate ( compound 4 )

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(isopropoxymethyl)phosphoryl]amino]propanoate

Compound 3C (6.8 g, 35.7 mmol) was dissolved in dichloromethane (60 mL), and (R)-2-(1-cyclopropylethyl)-6-iso was added dropwise at -10 ° C under nitrogen. A solution of propyl phenol (7.2 g, 35.7 mmol) and triethylamine (14.4 g, 0.14 mol) in dichloromethane (100 mL) was evaporated. A solution of isopropyl L-alanine (9.4 g, 0.071 mol) in dichloromethane (100 mL) was added at room temperature and the reaction was continued for two hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. ) = 10:1 to 1:1) Compound 4 was obtained as a yellow oil (5.0 g, yield 31%).

LC-MS (m/z) = 454.4 [M+1].

Compound 4 was isolated by supercritical fluid chromatography to give two optical isomer compounds 4-a (2.171 g, retention time 0.651 min, pale yellow oil, ee% = 100%), compound 4-b (2.61) g, residence time 0.929 min, light yellow oil, ee% = 100%). Preparation conditions: instrument: SFC-80 (Thar, Waters); chromatography column: CHIRLPAK AD (30 * 250mm 5μm) (Daicel); column temperature: 35 ° C; mobile phase: phase A is carbon dioxide, phase B is methanol; gradient : B 20%; detection wavelength: 215 nm; period: 4.0 min; back pressure: 100 bar; total flow rate: 45 g/min.

Compound 4-a :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.35-7.19 (m, 1H), 7.18-7.05 (m, 2H), 4.99 (m, 1H), 4.11-3.97 (m, 1H), 3.92 (dd, 1H) , 3.83-3.53 (m, 3H), 3.51-3.42 (m, 1H), 2.87-2.80 (m, 1H), 1.29-1.18 (m, 21H), 1.04 (d, 3H), 0.98-0.84 (m, 1H), 0.63-0.45 (m, 1H), 0.45-0.11 (m, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 26.76.

Compound 4-b :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.23 (t, 1H), 7.12 (d, 2H), 4.93 (m, 1H), 4.10-3.97 (m, 1H), 3.91 (dd, 1H), 3.75 (dd , 1H), 3.70-3.54 (m, 2H), 3.52 (d, 1H), 2.88-2.84 (m, 1H), 1.29 (dd, 6H), 1.23-1.15 (m, 18H), 0.97-0.81 (m , 1H), 0.58-0.43 (m, 1H), 0.38-0.13 (m, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 22.57.

Example 5

Isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 5 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

Compound 1C (1.0 g, 6.1 mmol) was dissolved in dichloromethane (10 mL), and propofol (1.09 g, 6.1 mmol) and triethylamine (2.4 g, 34.4) were added dropwise at -10 ° C under nitrogen. A solution of methylene chloride (10 mL) was added dropwise and then reacted at -10 ° C for 1 hour. A solution of L-alanine isopropyl ester (2.05 g, 12.2 mmol) in dichloromethane (20 mL) was added at -10. After the addition was completed, the reaction was continued for two hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (50 mL), and then evaporated. = 10:1~1:1) gave compound 5 as a yellow oil (1.0 g, yield 40.9%).

LC-MS (m/z) = 400.3 [M+1].

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12 (d, 3H), 5.18 - 4.76 (m, 1H), 4.12-4.06 (m, 1H), 4.00 - 3.71 (m, 2H), 3.65 - 3.35 (m, 6H), 1.41-1.09 (m, 21H).

Compound 5 (13.0 g) was isolated by supercritical fluid chromatography to give two optical isomer compounds 5-a (4.8 g, retention time 0.637 min, pale yellow oil, ee% = 100%), Compound 5 -b (5.2 g, residence time 0.892 min, pale yellow oil, ee% = 100%). Preparation conditions: instrument: SFC-80 (Thar, Waters); chromatography column: CHIRLPAK AD (30 * 250mm 5μm) (Daicel); column temperature: 35 ° C; mobile phase: phase A is carbon dioxide, phase B is methanol; gradient : B 15%; back pressure: 100 bar; detection wavelength: 210 nm; period: 4.6 min; total flow rate: 45 g/min.

Compound 5-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.06-4.96 (m, 1H), 4.14-4.04 (m, 1H), 3.94-3.84 (m, 2H), 3.55-3.41 (m, 6H), 1.25-1.14 (m, 21H). LC-MS (m/z) = 400.3 [M+1]. ³¹ P NMR (162MHz, CDCl ₃ ) δ 22.58.

Compound 5-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.99-4.92 (m, 1H), 4.11-4.06 (m, 1H), 3.92-3.79 (m, 2H), 3.59-3.46 (m, 6H), 1.36-1.11 (m, 21H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.57. LC-MS (m/z) = 400.3 [M+1].

Example 6

Isopropyl (2S)-2-[[[2,6-bis[(1R)-1-cyclopropylethyl]phenoxy]-(methoxymethyl)phosphonium]amino]propionic acid Ester ( compound 6 )

Isopropyl(2S)-2-[[[2,6-bis[(1R)-1-cyclopropylethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Compound 1C (4.0 g, 25 mmol) was dissolved in dichloromethane (50 mL), cooled to 0 ° C, and 2,6-di((R)-1-cyclopropylethyl)phenol was added dropwise under nitrogen. (5.6 g, 25 mmol) and a solution of triethylamine (9.9 g, 98 mmol) in dichloromethane (50 mL), EtOAc EtOAc EtOAc The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. Compound 1 was obtained as a yellow oil (3.0 g, yield: 27.0%).

LC-MS (m/z) = 452.2 [M+1].

Compound 6 (3.0 g) was isolated by supercritical fluid chromatography to give two optical isomer compounds 6-a (1.59 g, retention time 3.19 min, colorless oil, ee% = 99.11%), compound 6- b (1.36 g, retention time 6.17 min, colorless oil, ee% = 99.91%). Preparation conditions: Instrument: Thar 200 preparative SFC (SFC-7); chromatography column: ChiralPak AS, 300 × 50 mm ID, 10 μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; B 45%; back pressure: 100 bar; period: 7 min; detection wavelength: 220 nm; flow rate: 200 mL/min.

Compound 6-a :

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.28 (d, 2H), 7.15 (t, 1H), 5.03-4.97 (m, 1H), 4.22-3.92 (m, 1H), 3.91-3.65 (m, 2H ), 3.45 (d, 3H), 3.31 (t, 1H), 2.80-2.72 (m, 2H), 1.37-1.15 (m, 12H), 1.11 (d, 3H), 0.96-0.91 (m, 2H), 0.64-0.46 (m, 2H), 0.47-0.06 (m, 6H). 31 P NMR (162MHz, CDCl 3) δ 22.34.LC-MS (m / z) = 452.2 [m + 1].

Compound 6-b:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.27 (d, 2H), 7.15 (t, 1H), 4.97-4.91 (m, 1H), 4.03-3.98 (m, 1H), 3.85-3.82 (m, 1H ), 3.74-3.69 (m, 1H), 3.48-3.43 (m, 4H), 2.81-2.74 (m, 2H), 1.32-1.27 (m, 9H), 1.19-1.16 (m, 6H), 0.96-0.88 (m, 2H), 0.57-0.51 (m, 2H), 0.47-0.15 (m, 6H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.17. LC-MS (m/z) = 452.2 [M+1 ].

Example 7

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 7 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

Compound 1C (3.5 g, 21 mmol) was dissolved in dichloromethane <RTI ID=0.0>(50 </RTI><RTIID=0.0></RTI></RTI><RTIgt; A solution of dichloromethane (50 mL) was added dropwise and allowed to react at room temperature for 1 hour. L-Alanine ethyl ester hydrochloride (6.5 g, 43 mmol) was added and the reaction was continued at room temperature for two hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. :1~1:1) gave compound 7 as a yellow oil (2.5 g, yield 30.0%).

LC-MS (m/z) = 386.3 [M+1].

Compound 7 (2.5 g) was isolated by supercritical fluid chromatography to give two optical isomer compounds 7-a (1.09 g, retention time 2.54 min, pale yellow oil, ee% = 100%), Compound 7 -b (1.25 g, residence time 3.9 min, white solid, ee% = 99.85%). Preparation conditions: instrument: Sepiatec pre100 SFC (SFC-12); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; gradient: B 20%; back pressure: 100 bar; period: 3 min; detection wavelength: 220 nm; flow rate: 60 mL/min.

Compound 7-a:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.12 (s, 3H), 4.33-4.02 (m, 3H), 3.91-3.88 (m, 2H), 3.69-3.17 (m, 6H), 1.39-0.94 (m ^{, 18H). 31 P NMR (} 162MHz, CDCl 3) δ 22.62.LC-MS (m / z) = 386.3 [m + 1].

Compound 7-b:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.11 (s, 3H), 4.19-3.98 (m, 3H), 3.93-3.79 (m, 2H), 3.66-3.33 (m, 6H), 1.37 (d, 3H ), 1.300-1.06 (m, 15H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.49. LC-MS (m/z) = 386.4 [M+1].

Example 8

Ethyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphonium]amino Propionate ( compound 8 )

Ethyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Compound 1C (3.5 g, 21 mmol) was dissolved in dichloromethane (50 mL), cooled to -10 ° C, and (R)-2-(1-cyclopropylmethyl)-6- A solution of isopropyl phenol (4.4 g, 21 mmol) and triethylamine (8.7 g, 86 mmol) in dichloromethane (50 mL). 43 mmol), the reaction was continued for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. Compound 1 was obtained as a yellow oil (2.5 g, yield 28.0%).

LC-MS (m/z) = 412.4 [M+1].

Compound 8 (2.5 g of) two optical isomers of the compounds obtained by supercritical fluid chromatography separation 8-a (1.22g, retention time 2.61min, light yellow oil, ee% = 99.81%), Compound 8 -b (1.28 g, residence time 4.25 min, pale yellow oil, ee% = 99.84%). Preparation conditions: instrument: Sepiatec pre100 preparative SFC (SFC-12); chromatography column: ChiralPak AD, 250 × 30mm ID, 5μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; gradient: B 20%; back pressure: 100 bar; period: 3 min; detection wavelength: 220 nm; flow rate: 60 mL/min.

Compound 8-a:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.27-7.25 (m, 1H), 7.17-7.09 (m, 2H), 4.31-3.98 (m, 3H), 3.98-3.69 (m, 2H), 3.61-3.22 (m, 5H), 2.79-2.75 (m, 1H), 1.32-1.18 (m, 12H), 1.15 (d, 3H), 1.00-0.86 (m, 1H), 0.60-0.50 (m, 1H), 0.42 -0.30 (m, 1H), 0.21 - 0.17 (m, 2H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.47. LC-MS (m/z) = 412.3 [M+1].

Compound 8-b:

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.26-7.21 (m, 1H), 7.19-7.07 (m, 2H), 4.12-4.06 (m, 3H), 3.89-3.74 (m, 2H), 3.64-3.35 (m, 5H), 2.77-2.73 (m, 1H), 1.35 (d, 3H), 1.28 (d, 3H), 1.23-1.06 (m, 9H), 1.03-0.80 (m, 1H), 0.62-0.46 (m, 1H), 0.41 - 0.12 (m, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.34. LC-MS (m/z) = 412.4 [M+1].

Example 9

Methyl 1-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphonium]amino]cyclopropanecarboxylate Acid ester ( compound 9 )

Methyl 1-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-pheuoxy]-(methoxymethyl)phosphoryl]amino]cyclopropanecarboxylate

First step: methyl 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride ( 9B )

Methyl 1-aminocyclopropanecarboxylate hydrochloride

Compound 9A (50.0 g, 494.6 mmol) was dissolved in methanol (500 mL), and dichloromethane (117.68 g, 989.2 mmol) was added dropwise at room temperature, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated to give a white solid was washed with ether, and dried under reduced pressure to give compound 9B, as a white solid (60g, 80.0% yield).

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.18 (s, 3H), 3.71 (s, 3H), 1.54-1.50 (m, 2H), 1.41-1.33 (m, 2H).

Second step: methyl 1-[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphonium]amino] Cyclopropane carboxylate ( compound 9 )

Methyl 1-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]cyclopropanecarboxylate

Compound 1C (5.0 g, 31 mmol) was dissolved in dichloromethane (100 mL), cooled to -10 ° C, and (R)-2-(1-cyclopropylethyl)-6- isopropyl phenol (6.3g, 31mmol) and triethylamine (12.0g, 118mmol) in dichloromethane (50mL) solution, dropwise, at room temperature for 1 hour, compound 9B (7.1g, 61mmol) at room temperature The reaction was continued for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. : 1 to 1:1) gave Compound 9 as a yellow oil (4.0 g, yield: 32.0%).

LC-MS (m/z) = 410.2 [M+1].

Compound 9 (4.0 g) was isolated by supercritical fluid chromatography to give two optical isomers compound 9-a (1.21 g, retention time 2.5 min, pale yellow oil, ee% = 100%), compound 9 -b (1.3 g, residence time 3.61 min, light yellow oil, ee% = 99.72%). Preparation conditions: instrument: Sepiatec pre100 SFC (SFC-12); chromatography column: Celllulose-2, 250 × 30mm ID, 5μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; gradient: B 15 %; back pressure: 100 bar; period: 4 min; detection wavelength: 220 nm; flow rate: 50 mL/min.

Compound 9-a:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.26-7.19 (m, 1H), 7.18-7.07 (m, 2H), 4.01-3.98 (m, 1H), 3.91-3.85 (m, 1H), 3.68-3.51 (m, 5H), 3.49 (d, 3H), 2.74-2.70 (m, 1H), 1.46-1.44 (m, 1H), 1.36-1.13 (m, 10H), 1.06-1.02 (m, 1H), 0.95 -0.80 (m, 2H), 0.55-0.50 (m, 1H), 0.36-0.15 (m, 3H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.53. LC-MS (m/z) = 410.2 [M +1].

Compound 9-b:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.26-7.19 (m, 1H), 7.18-7.07 (m, 2H), 4.01-3.95 (m, 1H), 3.91-3.83 (m, 1H), 3.68-3.51 (m, 4H), 3.50-3.43 (m, 4H), 2.80-2.73 (m, 1H), 1.46-1.42 (m, 1H), 1.36-1.09 (m, 11H), 0.97-0.88 (m, 2H) , 0.57-0.51 (m, 1H), 0.38-0.13 (m, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 23.54. LC-MS (m/z) = 410.2 [M+1].

Example 10

Methyl 2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphonio]amino]-2- Methyl-propionate ( compound 10 )

Methyl 2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]-2-methyl-propanoate

First step: methyl 1-aminocyclopropanecarboxylic acid methyl ester hydrochloride ( 10B )

Methyl 1-aminocyclopropanecarboxylate hydrochloride

Compound 10A (100.0 g, 969.74 mmol) was dissolved in methanol (1000 mL), and dichloromethane (118.97 g, 989.12 mmol) was added dropwise at room temperature, and the mixture was heated to reflux for 4 hours. Concentrated to give a white solid solid was washed with ether, and dried under reduced pressure to give compound 10B, as a white solid (120g, yield 80.55%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.90 (s, 3H), 3.75 (s, 3H), 1.51 (s, 6H).

Second step: methyl 2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphonium]amino ]-2-methyl-propionate (compound 10 )

Methyl 2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]-2-methyl-propanoate

Compound 1C (3.5 g, 21 mmol) was dissolved in dichloromethane (50 mL), cooled to -10 ° C, and (R)-2-(1-cyclopropylethyl)-6- isopropyl phenol (4.4g, 21mmol) and triethylamine (8.7g, 86mmol) in dichloromethane (50mL) solution, dropwise, at room temperature for 1 hour, compound 10B (6.6g, 43mmol), room temperature The reaction was continued for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. The compound 10 was obtained as a yellow oil (3.5 g, yield 40.0%). LC-MS (m/z) = 412.3 [M+1].

Compound 10 (3.5 g) was isolated by supercritical fluid chromatography to give two optical isomer compounds 10-a (1.08 g, retention time 3.37 min, colorless oil, ee% = 99.74%), Compound 10- b (1.02 g, retention time 3.92 min, pale yellow oil, ee% = 99.64%). Preparation conditions: instrument: Thar 200 preparative SFC (SFC-7); chromatography column: Cellulose-4, 300 × 50 mm ID, 10 μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is isopropanol; gradient : B 15%; back pressure: 100 bar; period: 4.2 min; detection wavelength: 220 nm; flow rate: 200 mL/min.

Compound 10-a:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.28-7.18 (m, 1H), 7.14-7.13 (m, 2H), 3.90-3.70 (m, 3H), 3.68 (s, 3H), 3.63-3.59 (m , 1H), 3.45 (d, 3H), 2.81-2.77 (m, 1H), 1.48 (s, 3H), 1.35 (s, 3H), 1.30 (d, 3H), 1.22 (t, 6H), 0.89- 0.84 (m, 1H), 0.59-0.42 (m, 1H), 0.37-0.16 (m, 3H). 31 P NMR (162MHz, CDCl 3) δ 21.13.LC-MS (m / z) = 412.2 [m + 1].

Compound 10-b:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.32-7.21 (m, 1H), 7.19-7.07 (m, 2H), 3.91-3.73 (m, 3H), 3.69 (s, 3H), 3.59-3.54 (m , 1H), 3.45 (d, 3H), 2.85-2.77 (m, 1H), 1.50 (s, 3H), 1.36 (s, 3H), 1.34-1.12 (m, 9H), 0.94-0.87 (m, 1H) ), 0.63-0.44 (m, 1H), 0.46-0.11 (m, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.26. LC-MS (m/z) = 412.2 [M+1].

Example 11

Isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(morpholinylmethyl)phosphonium) Amino) propionate ( compound 11 )

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(morpholinomethyl)phosphoryl]amino]propanoate

First step: (diethoxyphosphonyl) methyl methanesulfonate ( 11A )

(diethoxyphosphoryl)methyl methanesulfonate

Compound 1A (200 g, 1.2 mol) was dissolved in dichloromethane (2000 mL), triethylamine (144.45 g, 1.42 mol) was added under ice-cooling, and methanesulfonium chloride (163.52 g, 1.42) was added dropwise. Mol), added, and reacted at room temperature for 4 hours. The reaction mixture was washed with water (2 L), and the organic layer was evaporated, evaporated, evaporated, evaporated, evaporated Compound 11A was obtained as a yellow oil (150 g, yield 51.21.%).

LC-MS m/z (ESI)=247.2 [M+1].

Second step: (dichlorophosphonium) methyl methanesulfonate (11B)

(dichlorophosphoryl)methyl methanesulfonate

Compound 11A (50 g, 203.25 mmol) was dissolved in acetonitrile (5 mL), trimethylbromodecane (93.26 g, 609.21 mmol) was added at room temperature, added, heated to 50 ° C for 2 hours, concentrated, residue Dissolved in dichloromethane (500 mL). N,N-dimethylformamide (4 mL) and grass chlorohydrin (77.32 g, 609.21 mmol) were added dropwise under ice-cooling and nitrogen atmosphere, and allowed to react overnight at room temperature. The reaction solution was concentrated to give Compound 11B (yield: 47.0 g).

The third step: isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropylphenoxy]-(methylsulfonyl)oxy Methyl)phosphonium]amino]propionate ( 11C )

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(methylsulfonyloxymethyl)phosphoryl]amino]propanoate

Compound 11B (0.8 g, 4 mmol) was dissolved in dichloromethane (20 mL), and (R)-2-(1-cyclopropylethyl)-6-isopropyl was added dropwise at -10 °C under nitrogen. A solution of phenol (1.0 g, 5 mmol) and triethylamine (1 g, 10 mmol) in dichloromethane (10 mL), EtOAc EtOAc EtOAc The reaction was continued at room temperature for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (20 mL), and the mixture was evaporated. EtOAcjjjjjjjjjjjjj Compound 11C was obtained as a yellow oil (0.8 g, yield 50.0%).

LC-MS m/z (ESI) =495.

Fourth step: isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(morpholinylmethyl) Phosphonium)amino)propionate ( compound 11 )

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(morpholinomethyl)phosphoryl]amino]propanoate

Compound 11C (2.6 g, 5.3 mmol) was dissolved in tetrahydrofuran (20 mL), morpholine (1.4 g, 16 mmol) and (2.7 g, 27 mmol) were added and the mixture was heated to 80 ° C for 8 hours. The reaction mixture was concentrated, the residue was purified by column chromatography using silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 1: 1), to give compound 11 as a yellow oil (2.0 g of, yield 78.0%).

LC-MS m/z (ESI) = 481.4 [M+1].

Compound 11 (2.0 g) was isolated by supercritical fluid chromatography to give two optical isomers compound 11-a (0.86 g, retention time 3.22 min, colorless oil, ee% = 100%), compound 11- b (0.91 g, residence time 4.21 min, white solid, ee% = 99.70%). Preparation conditions: instrument: Sepiatec prep SFC 100 preparative SFC (SFC-12); chromatography column: ChiralPak AD, 250 × 30mm ID, 5μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is isopropyl Alcohol; Gradient: B 20%; Back pressure: 100 bar; Period: 4 min; Detection wavelength: 220 nm; Flow rate: 60 mL/min.

Compound 11-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.27-7.24 (m, 1H), 7.14-7.13 (m, 2H), 5.03-4.93 (m, 1H), 4.08-4.06 (m, 1H), 3.71 (br, 4H), 3.60-3.51 (m, 2H), 3.02-2.73 (m, 5H), 2.65 (br, 2H), 1.32-1.16 (m, 15H), 1.04 (d, 3H), 0.94-0.92 (m, 1H), 0.62 - 0.45 (m, 1H), 0.41 - 0.09 (m, 3H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.26. LC-MS m/z (ESI) = 481.4 [M+1].

Compound 11-b:

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.26-7.21 (m, 1H), 7.12 (d, 2H), 4.97-4.92 (m, 1H), 4.05-3.99 (m, 1H), 3.84-3.53 (m , 5H), 3.49-3.42 (m, 1H), 2.88-2.65 (m, 7H), 1.38 (d, 3H), 1.30-1.09 (m, 15H), 0.97-0.90 (m, 1H), 0.56-0.49 (m, 1H), 0.36-0.18 (m, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 24.22. LC-MS m/z (ESI)=481.4 [M+1].

Example 12

Methyl 1-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]cyclopropylcarboxylate ( Compound 12 )

Methyl 1-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]cyclopropanecarboxylate

Compound 1C (5 g, 31 mmol) was dissolved in dichloromethane (100 mL). EtOAc (5 g, &lt;RTI ID=0.0&gt;&gt; A solution of methyl chloride (100 mL) was added dropwise at room temperature for 1 hour, and compound 9B (7.1 g, 61 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. Compound 1 was obtained as a yellow oil (3.8 g, yield: 32.0%).

LC-MS m/z (ESI) = 384.2 [M+1].

Compound 12 (3.8 g) was isolated by supercritical fluid chromatography to give two optical isomer compounds 12-a (1.68 g, retention time 2.46 min, pale yellow oil, ee% = 98.77%), compound 12 -b (1.84 g, residence time 3.14 min, light yellow oil, ee% = 99.18%). Preparation conditions: instrument: Sepiatec pre100 SFC (SFC-12); chromatography column: Celllulose-2, 250 × 30mm ID, 5μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; gradient: B 15 %; back pressure: 100 bar; period: 4 min; detection wavelength: 220 nm; flow rate: 50 mL/min.

Compound 12-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.05-4.0 (m, 1H), 3.94-3.89 (m, 1H), 3.70 (d, 1H), 3.64 (s, 3H), 3.56 -3.43(m,5H), 1.49-1.43(m,1H),1.41-1.28 (m,1H),1.21-1.19(m,12H),1.15-1.11(m,1H),0.98-0.92(m, ^{1H). 31 P NMR (162MHz} , CDCl 3) δ 21.39.LC-MS m / z (ESI) = 384.2 [m + 1].

Compound 12-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.05-4.0 (m, 1H), 3.94-3.89 (m, 1H), 3.70 (d, 1H), 3.65 (s, 3H), 3.58 -3.43(m,5H), 1.49-1.43(m,1H), 1.41-1.28(m,1H),1.21-1.19(m,12H),1.15-1.11(m,1H),0.98-0.92(m, ^{1H). 31 P NMR (162MHz} , CDCl 3) δ 21.41.LC-MS m / z (ESI) = 384.2 [m + 1].

Example 13

Methyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]acetate ( Compound 13 )

Methyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]acetate

Compound 1C (8 g, 49 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI><RTIID=0.0></RTI></RTI><RTIgt; A solution of dichloromethane (100 mL) was added dropwise, and the mixture was reacted at room temperature for 1 hour, and glycine methyl ester hydrochloride (12.3 g, 98 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. :1~1:1), compound 13 was obtained as a yellow oil (5.0 g, yield 28.49%)

LC-MS m/z (ESI) = 358.1 [M+1].

Compound 13 (5.0 g) was isolated by supercritical fluid chromatography to give two optical isomers of compound 13-a (2.24 g, retention time 3.72 min, pale yellow oil, ee% = 100%), compound 13 -b (2.34 g, retention time 6.37 min, light yellow oil, ee% = 100%). Preparation conditions: Instrument: Thar 350 preparative SFC (SFC-6); chromatography column: ChiralPak AS, 300 × 50 mm ID, 10 μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; B 40%; back pressure: 100 bar; period: 8.2 min; detection wavelength: 220 nm; flow rate: 200 mL/min.

Compound 13-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.01-3.84 (m, 3H), 3.80-3.64 (m, 4H), 3.59-3.44 (m, 5H), 3.39 (s, 1H) , 1.23 (d, 12H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.12. LC-MS m/z (ESI)=358.1 [M+1].

Compound 13-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.13 (s, 3H), 4.03-3.84 (m, 3H), 3.83-3.64 (m, 4H), 3.59-3.44 (m, 5H), 3.39 (s, 1H) , 1.22 (d, 12H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.13. LC-MS m/z (ESI)=358.1 [M+1].

Example 14

Isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(dimethylaminomethyl)phosphonium]amino]propionate ( Compound 14 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(dimethylaminomethyl)phosphoryl]amino]propanoate

First step: isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methylsulfonyloxymethyl)phosphonium]amino]propionate ( 14A )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methylsulfonyloxymethyl)phosphoryl]amino]propanoate

Compound 11B (18 g, 79.29 mmol) was dissolved in dichloromethane (400 mL), and propofol (21.20 g, 119.1 mmol) and triethylamine (32.09 g, 317.18 mmol) were added dropwise at -10 °C under nitrogen. A solution of methylene chloride (100 mL) was added dropwise, and the mixture was reacted at room temperature for 1 hour. L-Alanine isopropyl ester hydrochloride (26.48 g, 158.59 mmol) was added and allowed to react at room temperature for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (200 mL), and then evaporated to dryness. ~ 1:1) Compound 14A was obtained as a yellow oil (20 g, yield 54.42%).

LC-MS m/z (ESI) = 464.2 [M+1].

Second step: isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(dimethylaminomethyl)phosphonium]amino]propionate ( Compound 14 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(dimethylaminomethyl)phosphoryl]amino]propanoate

Compound 14A (4.0 g, 8.6 mmol) was dissolved in tetrahydrofuran (20 mL), dimethylamine in tetrahydrofuran (2 mol/L, 2.15 mL, 43.2 mmol) and triethylamine (4.4 g, 43.0 mmol). The tube was sealed at 80 ° C for 8 hours. The reaction mixture was concentrated, the residue was purified by column chromatography using silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 1: 1) to give compound 14 as a yellow oil (3.5g, yield 98.0 %).

LC-MS m/z (ESI) = 413.4 [M+1].

Compound 14 (3.5 g) was isolated by supercritical fluid chromatography to give two optical isomers of compound 14-a (1.40 g, retention time: 1.9 min white solid, ee% = 99.72%), compound 14-b ( 1.35 g, residence time: 3.4 min white solid, ee% = 99.78%). Preparation conditions: instrument: Sepiatec pre100 SFC (SFC-12); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; gradient: B 10%; back pressure: 100 bar; period: 3.5 min; detection wavelength: 220 nm; flow rate: 50 mL/min.

Compound 14-a:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11 (s, 3H), 5.03-4.97 (m, 1H), 4.11-4.05 (m, 1H), 3.62-3.53 (m, 3H), 2.95-2.90 (m, 2H), 2.45 (s, 6H), 1.30-1.13 (m, 18H), 1.07 (d, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 26.28. LC-MS m/z (ESI) = 413.3 [ M+1].

Compound 14-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.10 (s, 3H), 5.07-4.74 (m, 1H), 4.18-3.92 (m, 1H), 3.88-3.64 (m, 1H), 3.52-3.45 (m, 2H), 3.06-2.80 (m, 2H), 2.45 (s, 6H), 1.37 (d, 3H), 1.22-1.17 (m, 18H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 28.23. LC-MS m/z (ESI) = 413.4 [M + 1].

Example 15

Isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(ethoxymethyl)phosphonium]amino]propionate ( Compound 15 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(ethoxymethyl)phosphoryl]amino]propanoate

First step: 1-(diethoxyphosphonium methoxy)ethane ( 15A )

1-(diethoxyphosphorylmethoxy)ethane

Triethyl phosphite compound 3A (5.0 g, 25 mmol) was added to a vial, and chloromethylether (2.8 g, 25 mmol) was added, and the mixture was heated to 130 ° C for 3 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography (purified petroleum ether: ethyl acetate (v/v) = 1:0 to 1:1) to give compound 15A as colorless oil (5.0 g , yield 85%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.22-4.15 (m, 4H), 3.77 (d, 2H), 3.65-3.60 (m, 2H), 1.39-1.33 (m, 6H), 1.22 (t, 3H) .LC-MS m/z (ESI) = 197.2 [M+1].

The second step: (ethoxymethyl) phosphonic acid ( 15B )

(ethoxymethyl)phosphonic acid

Compound 15A (5.0 g, 25 mmol) was dissolved in acetonitrile (20 mL), trimethylbromohexane (12 g, The reaction mixture was concentrated under reduced pressure to give Compound 15B The crude product was a pale yellow oil (3.6 g of), without purification was used directly in the next step.

The third step: (ethoxymethyl) phosphine dichloride ( 15C )

(ethoxymethyl)phosphonic dichloride

Compound 15B (3.6 g, 26 mmol) was dissolved in dry methylene chloride (20 mL), cooled to 0 ° C under nitrogen atmosphere, and then added dropwise chlorobenzene (9.8 g, 78 mmol). The temperature was reacted for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product compound 15C as a pale yellow oil (4.5 g of), without purification was used directly in the next step.

The fourth step: isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(ethoxymethyl)phosphonium]amino]propionate ( compound 15 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(ethoxymethyl)phosphoryl]amino]propanoate

Compound 15C (2.20 g, 12.4 mmol) was dissolved in dry methylene chloride (15 mL), cooled to -20 ° C under nitrogen atmosphere, propofol (2.22 g, 12.4 mmol) was added, and triethylamine (5.03) was slowly added dropwise. g, 49.7 mmol), after completion, the reaction was continued at -20 ° C for 2 hours. L-Alanine isopropyl ester (3.26 g, 24.9 mmol) was added, and after completion, the reaction was allowed to warm to room temperature and the reaction was continued for 3 hours. After adding water (20 mL), ethyl acetate (50 mL), EtOAc (EtOAc m. The obtained crude product was purified by silica gel column chromatography (ethyl ether: ethyl acetate (v/v) = 9:1 to 7:3) to give compound 15 as a pale yellow oil (1.60 g, yield 31.1%) ).

Compound 15 (1.6 g) was isolated by supercritical fluid chromatography to give two optical isomers of compound 15-a (375.37 mg, retention time: 2.67 min, pale yellow oil, ee% = 100%), compound 15-b (363.17 mg, residence time: 3.51 min, pale yellow oil, ee% = 100%). Preparation conditions: instrument: Sepiatec pre100 SFC (SFC-12); chromatography column: Celllulose-2, 250 × 30mm ID, 5μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; gradient: B 15 %; back pressure: 100 bar; period: 4 min; detection wavelength: 220 nn; flow rate: 50 mL/min.

Compound 15-a :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.06-4.95 (m, 1H), 4.11-4.05 (m, 1H), 4.01-3.92 (m, 1H), 3.90-3.84 (m, 1H), 3.68-3.53 (m, 4H), 3.51-3.42 (m, 1H), 1.27-1.18 (m, 21H), 1.10 (d, 3H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.97. -MS m/z (ESI) = 414.4 [M+1].

Compound 15-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.97-4.91 (m, 1H), 4.14-4.03 (m, 1H), 3.96-3.92 (m, 1H), 3.84-3.80 (m, 1H), 3.67-3.50 (m, 5H), 3.48 (s, 1H), 1.34 (d, 3H), 1.25-1.17 (m, 21H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.99. LC-MS m/z (ESI) = 414.4 [M + 1].

Example 16

Isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropylphenoxy]-(ethoxymethyl)phosphonium]amino Propionate ( compound 16 )

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-(ethoxymethyl)phosphoryl]amino]propanoate

Compound 15C (2.20 g, 12.4 mmol) was dissolved in dry dichloromethane (15 mL), cooled to -20 ° C under N.sub.2, and (R)-2-(1-cyclopropylethyl)-6- Propylphenol (2.22 g, 12.4 mmol), triethylamine (5.03 g, 49.7 mmol) was slowly added dropwise, and the mixture was reacted at -20 ° C for 2 hours. L-Alanine isopropyl ester (3.26 g, 24.9 mmol) was added, and after completion, the reaction was allowed to warm to room temperature and the reaction was continued for 3 hours. After adding water (20 mL), ethyl acetate (50 mL), EtOAc (EtOAc m. The obtained crude product was purified by silica gel column chromatography (ethyl ether: ethyl acetate (v/v) = 9:1 to 7:3) to give compound 16 as pale yellow oil (1.80 g, yield 32.9%) ).

Compound 16 (1.8 g) was isolated by supercritical fluid chromatography to give two optical isomers of compound 16-a (662.34 mg, retention time: 2.17 min, colorless oil, ee% = 100%), Compound 16 -b (803.11 mg, residence time: 3.73 min, colorless oil, ee% = 100%). Preparation conditions: instrument: Sepiatec pre100 SFC (SFC-12); chromatography column: Celllulose-2, 250 × 30mm ID, 5μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is ethanol; gradient: B 15 %; back pressure: 100 bar; period: 4 min; detection wavelength: 220 nm; flow rate: 50 mL/min.

Compound 16-a :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.29-7.22 (m, 1H), 7.13 (d, 2H), 5.05-4.95 (m, 1H), 4.10-3.99 (m, 1H), 3.95-3.89 (m, 1H), 3.85-3.80 (m, 1H), 3.67-3.52 (m, 3H), 3.42 (t, 1H), 2.85-2.77 (m, 1H), 1.28-1.20 (m, 18H), 1.08 (d, 3H), 0.98-0.88 (m, 1H), 0.59-0.50 (m, 1H), 0.41-0.32 (m, 1H), 0.30-0.24 (m, 1H), 0.22-0.16 (m, 1H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.86. LC-MS m/z (ESI) = 440.4 [M+1].

Compound 16-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.25-7.22 (m, 1H), 7.12 (d, 2H), 4.99-4.89 (m, 1H), 4.07-4.01 (m, 1H), 3.94-3.88 (m, 1H), 3.81-3.76 (m, 1H), 3.74-3.49 (m, 4H), 2.85-2.78 (m, 1H), 1.32 (d, 3H), 1.27 (d, 3H), 1.25-1.19 (m, 9H), 1.18 (d, 6H), 0.96-0.86 (m, 1H), 0.56-0.48 (m, 1H), 0.36-0.29 (m, 1H), 0.28-0.18 (m, 2H). ³¹ P NMR ( 162 MHz, CDCl ₃ ) δ 21.88. LC-MS m/z (ESI) = 440.4 [M+1].

Example 17

Isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)(propyl)phosphonium]amino]propionate ( Compound 17 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-propyl-phosphoryl]amino]propanoate

The first step: propyl phosphate ( 17B )

Propylphosphonic acid

Compound 17A (9.0 g, 50 mmol) was dissolved in acetonitrile (20 mL), trimethylbromohexane (23 g, 150 mmol) The reaction mixture was concentrated under reduced pressure to give the crude product compound 17B as a pale yellow oil (6.2 g of), without purification was used directly in the next step.

The second step: propylphosphonium dichloride ( 17C )

Propylphosphonic dichloride

Compound 17B (6.2 g, 50 mmol) was dissolved in dry dichloromethane <RTI ID=0.0>(20 </RTI><RTIID=0.0></RTI></RTI><RTIgt; The guanamine (0.5 mL) was added dropwise, and the mixture was naturally warmed to room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product compound 17C as a pale yellow oil (8.0 g), used without purification in the next step.

Step 3: Isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)(propyl)phosphonium]amino]propionate ( Compound 17 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-propyl-phosphoryl]amino]propanoate

Compound 17C (4.0 g, 25 mmol) was dissolved in dry dichloromethane <RTI ID=0.0>(25</RTI><RTIID=0.0></RTI></RTI><RTIgt; ), after the addition, the reaction was carried out at -20 ° C for 2 hours. L-Alanine isopropyl ester (6.5 g, 50 mmol) was added, and after completion, the reaction was continued to room temperature for 3 hours. Water (20 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was evaporated. EtOAc mjjjjjjjj , concentrated under reduced pressure, the resulting crude product was purified by silica gel column purification chromatography (petroleum ether: ethyl acetate (v / v) = 9: 1 ~ 7: 3) to give compound 17 using, as a pale yellow oil (2.0 g of, Yield 20%).

LC-MS m/z (ESI) = 398.3 [M+1].

Compound 17 (2.0 g) was isolated by supercritical fluid chromatography to give two optical isomers of compound 17-a (460 mg, retention time: 1.236 min, colorless oil, ee% = 100%), compound 17- b (970 mg, residence time: 3.071 min, white solid, ee% = 100%). Preparation conditions: instrument: Sepiatec pre100 SFC (SFC-12); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is isopropanol; gradient : B 25%; back pressure: 100 bar; period: 2.5 min; detection wavelength: 220 nm; flow rate: 50 mL/min.

Compound 17-a :

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11 (s, 3H), 5.04-4.95 (m, 1H), 4.11-4.00 (m, 1H), 3.51-3.40 (m, 2H), 3.07-2.96 (m, 1H), 2.03-1.83 (m, 2H), 1.83-1.68 (m, 2H), 1.25-1.18 (m, 18H), 1.09-1.05 (m, 3H), 1.02 (d, 3H). ³¹ P NMR ( 162MHz, CDCl3) δ 31.67. LC-MS m/z (ESI) = 398.3 [M+1].

Compound 17-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.10 (s, 3H), 4.97-4.87 (m, 1H), 4.05-3.94 (m, 1H), 3.50-3.37 (m, 2H), 3.35-3.26 (m, 1H), 2.00-1.83 (m, 2H), 1.83-1.67 (m, 2H), 1.33 (d, 3H), 1.22-1.20 (m, 12H), 1.17-1.14 (m, 6H), 1.09-1.05 ( m,3H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 31.30. LC-MS m/z (ESI)=398.3 [M+1].

Example 18

Isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropylphenoxy]-propyl-phosphonium]amino]propionate ( Compound 18 )

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]-propyl-phosphoryl]amino]propanoate

Compound 17C (4.0 g, 25 mmol) was dissolved in dry dichloromethane <RTI ID=0.0>(25</RTI><RTIID=0.0> Phenol (5.1 g, 25 mmol), triethylamine (10 g, 99 mmol) was slowly added dropwise, and the reaction was carried out at -20 ° C for 2 hours. L-alanine isopropyl ester (6.5 g, 50 mmol) was added, and the mixture was added. The reaction was allowed to rise to room temperature and continued for 3 hours. Water (20 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the mixture was evaporated. EtOAc mjjjjjjjj , concentrated under reduced pressure, the resulting crude product was purified by silica gel column purification chromatography (petroleum ether: ethyl acetate (v / v) = 9: 1 ~ 7: 3), to give compound 18 as a pale yellow oil (1.40 g of , yield 13%).

Compound 18 (1.4 g) was isolated by supercritical fluid chromatography to give two optical isomers of compound 18-a (330 mg, retention time: 1.468 min, colorless oil, ee% = 100%), compound 18- b (350 mg, residence time: 3.357 min, colorless oil, ee% = 100%). Preparation conditions: instrument: Sepiatec pre100 SFC (SFC-12); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm; column temperature: 38 ° C; mobile phase: phase A is carbon dioxide, phase B is isopropanol; gradient : B 25%; back pressure: 100 bar; period: 2.5 min; detection wavelength: 220 nm; flow rate: 60 mL/min.

Compound 18-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.28-7.23 (m, 1H), 7.15-7.08 (m, 2H), 5.02-4.96m, 1H), 4.08-3.97 (m, 1H), 3.42-3.35 (m , 1H), 3.03-2.92 (m, 1H), 2.75-2.70 (m, 1H), 2.00-1.81 (m, 2H), 1.81-1.65 (m, 2H), 1.29 (d, 3H), 1.27-1.18 (m, 12H), 1.07-1.03 (m, 3H), 1.01 (d, 3H), 0.97-0.86 (m, 1H), 0.60-0.50 (m, 1H), 0.40-0.31 (m, 1H), 0.30 -0.24 (m, 1H), 0.19-0.13 (m, 1H). ³¹ P NMR (162 M NMR, CDCl ₃ ) δ 31.51. LC-MS m/z (ESI) = 446.1 [M+23].

Compound 18-b:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26 - 7.21 (m, 1H), 7.14 - 7.08 (m, 2H), 4.97 - 4.88 (m, 1H), 4.03 - 3.90 (m, 1H), 3.45 - 3.36 ( m, 1H), 3.34-3.21 (m, 1H), 2.75-2.67 (m, 1H), 1.97-1.79 (m, 2H), 1.79-1.64 (m, 2H), 1.31 (d, 3H), 1.27 ( d, 3H), 1.23-1.13 (m, 12H), 1.08-1.04 (m, 3H), 0.97-0.87 (m, 1H), 0.59-0.48 (m, 1H), 0.40-0.30 (m, 1H), 0.30-0.15 (m, 2H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 31.17. LC-MS m/z (ESI) = 424.1 [M+1].

Example 19

Isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(morpholinylmethyl)phosphonium]amino]propionate ( Compound 19 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(morpholinomethyl)phosphoryl]amino]propanoate

Compound 14A (4.0 g, 8.6 mmol) was dissolved in tetrahydrofuran (20 mL), morpholine (2.3 g, 26.0 mmol) and triethylamine (4.4 g, 43.0 mmol). The reaction mixture was concentrated, the residue was purified by column chromatography using silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 1: 1), to give compound 19 as a yellow oil (2.5g, yield 64.0%).

LC-MS m/z (ESI) = 455.4 [M+1].

Compound 19 (2.0 g) was isolated by supercritical fluid chromatography to give two optical isomers compound 19-a (0.8 g, retention time 1.318 min, pale yellow oil, ee% = 100%), compound 19 -b (0.7 g, residence time 1.587 min, pale yellow oil, ee% = 99.54%). Preparation conditions: instrument: SFC-80 (Thar, Waters); chromatography column: CHIRLCEL IC (30 * 250mm 5μm) (Daicel); column temperature: 35 ° C; mobile phase: phase A is carbon dioxide, phase B is isopropanol Gradient: B 15%; Detection wavelength: 215 nm; Total flow: 45 g/min; Back pressure: 100 bar; Period: 10.2 min.

Compound 19-a:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12 (s, 3H), 5.02-4.96 (m, 1H), 4.12-4.06 (m, 1H), 3.74 - 3.68 (m, 4H), 3.61-3.55 (m, 3H), 3.13 - 2.85 (m, 2H), 2.85 - 2.62 (m, 4H), 1.31-1.15 (m, 18H), 1.05 (d, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 25.38. -MS m/z (ESI) = 455.3 [M+1].

Compound 19-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.97-4.91 (m, 1H), 4.07-4.01 (m, 1H), 3.72-3.65 (m, 5H), 3.53-3.46 (m, 2H), 3.94-2.90 (m, 2H), 2.75-2.67 (m, 4H), 1.38 (d, 3H) 1.25-1.17 (m, 18H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.29. MS m/z (ESI) = 455.3 [M + 1].

Example 20

Isopropyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]acetate ( Compound 20 )

Isopropyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]acetate

Compound 1C (7.98 g, 49.0 mmol) was dissolved in dichloromethane (100 mL), and 2,6-diisopropylphenol (8.70 g, 49.0 mmol) and triethylamine were added dropwise at -10 °C under nitrogen. A solution of the amine (19.8 g, 196 mmol) in dichloromethane (100 mL). After completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour, and glycine isopropyl ester hydrochloride (15.0 g, 98 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction solution was washed with 100 mL of a saturated aqueous sodium hydrogen sulfate solution, and then evaporated. The residue was purified by column chromatography using silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 1: 1), to give compound 20 as a yellow oil (7.0 g, 37.1% yield).

LC-MS (m/z) = 386.2 [M+1].

Compound 20 (7.0 g) was isolated by supercritical fluid chromatography to give two optical isomer compounds 20-a (3.04 g, retention time 1.28 min, off-white solid, ee% = 100%), compound 20-b (2.72 g, residence time 3.0 min, off-white solid, ee% = 100%). Preparation conditions: Instrument: Thar 200 preparative SFC (SFC-7); Column: ChiralPak AS, 300 × 50 mm ID, 10 μm; Column temperature: 38 ° C; Mobile phase: Phase A is carbon dioxide, Phase B is ethanol; Gradient: B 45%; detection wavelength: 220 nm; flow rate: 200 mL/min; back pressure: 100 bar; period: 7 min.

Compound 20-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.15-4.83 (m, 1H), 4.10-3.79 (m, 3H), 3.72-3.63 (m, 1H), 3.57-3.45 (m, 5H), 3.41-3.36 (m, 1H), 1.35-1.08 (m, 18H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 23.13. LC-MS (m/z) = 386.2 [M+1].

Compound 20-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.07-5.0 (m, 1H), 4.13-3.77 (m, 3H), 3.71-3.63 (m, 1H), 3.57-3.43 (m, 5H), 3.43-3.30 (m, 1H), 1.35-1.03 (m, 18H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.13. LC-MS (m/z) = 386.2 [M+1].

Example 21

Methyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]-2-methyl-propionate ( Compound 21 )

Methyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]-2-methyl-propa noate

Compound 1C (3.5 g, 21 mmol) was dissolved in 50 mL of dichloromethane, and 2,6-diisopropylphenol (3.8 g, 21 mmol) and triethylamine (8.7 g, A solution of 86 mmol) in 50 mL of dichloromethane was reacted at room temperature for 1 hour after the completion of the dropwise addition. Methyl-2-amino-2-methylpropanoate (5.0 g, 43 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction solution was washed with a saturated solution of sodium dihydrogen phosphate (100 mL), and the mixture was evaporated. :1~1:1) Compound 21 was obtained as a yellow oil (3.5 g, yield 42.2%).

LC-MS m/z = 386.2 [M+1].

Solution of compound 21 (3.5g) for separating the two optical isomers to obtain a compound 21-a (1.66g, retention time 2.51 min, pale yellow oil, ee% = 100%), compound 21-b (1.95 g, residence time 2.70 min, colorless oil, ee% = 98.4%). Preparation conditions: Instrument: MG II preparative SFC (SFC-1); chromatography column: Cellulose-2, 250 × 30 mm ID, 5 μm; mobile phase: phase A is CO ₂ and phase B is isopropanol; gradient: B 15%; Flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period : ~5 min.

Compound 21-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 3.93-3.76 (m, 3H), 3.69 (s, 3H), 3.67-3.52 (m, 2H), 3.47 (d, 3H), 1.52 (s, 3H), 1.38 (s, 3H), 1.23-1.20 (m, 12H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.39. LC-MS m/z = 386.2 [M+1].

Compound 21-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 3.86-3.83 (m, 3H), 3.69 (s, 3H), 3.65-3.53 (m, 2H), 3.47 (d, 3H), 1.52 (s, 3H), 1.38 (s, 3H), 1.23-1.20 (m, 12H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.41. LC-MS m/z = 386.1 [M+1].

Example 22

Ethyl (2S)-2-[[[2,6-bis[(1R)-1-cyclopropylethyl]phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( compound 22 )

Ethyl(2S)-2-[[[2,6-bis[(1R)-1-cyclopropylethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride ( 1C ) (4.0 g, 24.5 mmol) was dissolved in 50 mL of dichloromethane, and compound 22A (5.6 g, 24.5 mmol) was added dropwise at 0 ° C under nitrogen. A solution of triethylamine (9.9 g, 98 mmol) dissolved in 50 mL of dichloromethane was added dropwise, and the mixture was reacted at 40 ° C for 1 hour. And L-alanine ethyl ester (5.75 g, 49 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (100 mL), and then evaporated. =10:1~1:1) gave compound 22 as a yellow oil (3.0 g, yield 28.0%).

LC-MS m/z = 438.3 [M+1].

Compound 22 (3.0 g) was obtained for isolation to give two optical compound Compounds 22-a (1.31 g, retention time 2.79 min, colorless oil, ee% = 99.64%), Compound 22-b (1.35 g) , residence time 3.82 min, light yellow oil, ee% = 100%). Preparation conditions: Instrument: Thar 350 preparative SFC (SFC-9); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 25%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period : ~ 2.4 min.

Compound 22-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.34-7.23 (m, 2H), 7.16 (t, 1H), 4.18-4.13 (m, 2H), 4.07-4.03 (m, 1H), 3.89-3.69 (m, 2H), 3.47 (s, 3H), 3.31 (t, 1H), 2.84 - 2.64 (m, 2H), 1.28-1.20 (m, 9H), 1.13 (d, 3H), 1.04-0.81 (m, 2H) , 0.62-0.50 (m, 2H), 0.45-0.29 (m, 2H), 0.30-0.13 (m, 4H). 31 P NMR (162MHz, CDCl 3) δ 22.36.LC-MS m / z = 438.3 [m +1].

Compound 22-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.27 (d, 2H), 7.15 (t, 1H), 4.23-3.91 (m, 3H), 3.82 (m, 1H), 3.71 (m, 1H), 3.50-3.31 (m, 4H), 2.81-2.73 (m, 2H), 1.33 (d, 3H), 1.27 (d, 6H), 1.20 (t, 3H), 1.04-0.79 (m, 2H), 0.71 - 0.44 (m , 2H), 0.44-0.14 (m, 6H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.12. LC-MS m/z = 438.3 [M+1].

Example 23

Isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-[[(3S)-tetrahydrofuran-3-yl]oxymethyl]phosphonium]amino]propionate ( compound 23 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-[[(3S)-tetrahydrofuran-3-yl]oxymethyl]phosphoryl]amino]propanoate

First step: (S)-3-(chloromethoxy)tetrahydrofuran ( 23B )

(S)-3-(chloromethoxy)tetrahydrofuran

Compound 23A (10.0 g, 114 mmol) was dissolved in trimethylchloromethane (123 g, 1.13 mol), and paraformaldehyde (2.39 g, 79.5 mmol) was added and reacted at 30 ° C for 3 hours. The reaction mixture was concentrated to give Compound 23B , m.

The second step: (3S)-3-(diethoxyphosphonium methoxy)tetrahydrofuran ( 23C )

(3S)-3-(diethoxyphosphorylmethoxy)tetrahydrofuran

Compound 23B (7.75 g, 56.8 mmol) was dissolved in triethyl phosphite (9.43 g, 56.8 mmol) and reacted at 130 ° C for 3 hours. The reaction mixture was separated and purified by silica gel chromatography (ethyl ether (ethyl acetate) (v/v) = 10:1 to 1:1) to afford compound 23C as a yellow oil (6.75 g, yield 50.0%).

LC-MS m/z = 239.1 [M+1].

The third step: (3S)-3-(dichlorophosphonium methoxy)tetrahydrofuran ( 23D )

(3S)-3-(dichlorophosphorylmethoxy)tetrahydrofuran

23C (10.0 g, 42.0 mmol) was dissolved in 50 mL of acetonitrile and trimethylbromodecane (19.2 g, 126.0 mmol) was added at 50 ° C for 3 hours, concentrated, and the crude product was dissolved in 50 mL of dichloromethane. The mixture was added with hydrazine chloride (15.8 g, 126.0 mmol) under a nitrogen atmosphere, and the mixture was reacted at room temperature for 3 hours, and concentrated to give compound 23D (yield: 9.2 g, yield: 100.0%). .

The fourth step: isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-[[(3S)-tetrahydrofuran-3-yl]oxymethyl]phosphonio]amino Propionate ( compound 23 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-[[(3S)-tetrahydrofuran-3-yl]oxymethyl]phosphoryl]amino]propanoate

23D (5.0 g, 22.8 mmol) was dissolved in 50 mL of dichloromethane, and 2,6-diisopropylphenol (4.0 g, 22.8 mmol) and triethylamine (9.2 g) were added dropwise at 0 ° C under nitrogen. A solution of 91.34 mmol of methylene chloride (50 mL) was then evaporated and evaporated. And L-alanine isopropyl ester (5.9 g, 45.6 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction solution was washed with a saturated solution of sodium dihydrogen phosphate (100 mL), and the mixture was evaporated. : 1 to 1:1) Compound 23 was obtained as a yellow oil (5.0 g, yield 48.1%).

LC-MS m/z = 456.3 [M + 1].

Compound 23 (5.0 g) was used for isolation to give two optical isomers compound 23-a (2.10 g, retention time 2.78 min, colorless oil, ee% = 100%), compound 23-b (1.88 g) , residence time 4.13 min, yellow oil, ee% = 100%). Preparation conditions: Instrument: Thar 350 preparative SFC (SFC-6); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is methanol; gradient: B 25%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period : ~4 min.

Compound 23-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.03-4.96 (m, 1H), 4.36-4.11 (m, 1H), 4.15-3.76 (m, 7H), 3.67-3.49 (m, 2H), 3.44 (t, 1H), 2.20 - 1.92 (m, 2H), 1.31-1.12 (m, 18H), 1.07 (d, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 22.24. LC-MS m/z = 456.3 [M + 1].

Compound 23-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.93-4.91 (m, 1H), 4.35-4.18 (m, 1H), 4.15-3.73 (m, 7H), 3.58-3.53 (m, 3H), 2.00 (m, 2H), 1.33 (d, 3H), 1.22 (t, 12H), 1.17 (d, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.23. LC-MS m/z = 456.3[M+1].

Example 24

Isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-[[(3R)-tetrahydrofuran-3-yl]oxymethyl]phosphonium]amino]propionate ( Compound 24 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-[[(3R)-tetrahydrofuran-3-yl]oxymethyl]phosphoryl]amino]propanoate

First step: (R)-3-(chloromethyl)tetrahydrofuran ( 24B )

(R)-3-(chloromethoxy)tetrahydrofuran

Compound 24A (10.0 g, 114 mmol) was dissolved in trimethylchloromethane (123 g, 1.13 mol), and paraformaldehyde (2.39 g, 79.5 mmol) was added and reacted at 30 ° C for 3 hours. The reaction mixture was concentrated to give Compound 24B , m.

The second step: (3R)-3-(diethoxyphosphonium methoxy)tetrahydrofuran ( 24C )

(3R)-3-(diethoxyphosphorylmethoxy)tetrahydrofuran

Compound 24B (15.45 g, 113.6 mmol) was dissolved in triethyl phosphite (18.86 g, 113.6 mmol), reacted at 130 ° C for 3 hours and purified by gel column chromatography (petroleum ether: ethyl acetate (v/v) = 10:1 to 1:1) Compound 24C was obtained as a yellow oil (13.5 g, yield 50.0%).

LC-MS m/z = 239.7 [M + 1].

The third step: (3R)-3-(dichlorophosphonium methoxy)tetrahydrofuran ( 24D )

(3R)-3-(dichlorophosphorylmethoxy)tetrahydrofuran

Compound 24C (5.0 g, 21.0 mmol) was dissolved in 50 mL of acetonitrile and trimethylbromodecane (9.6 g, 63.0 mmol) was added at 50 ° C for 3 hours, concentrated, and the crude product was dissolved in 50 mL dichloromethane. Under ice-cooling, a solution of chloroform (7.9 g, 63.0 mmol) was added, and the mixture was reacted at room temperature for 3 hours, and concentrated to give compound 24D (yield: 4.6 g, yield: 100.0%). .

The fourth step: isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-[[(3R)-tetrahydrofuran-3-yl]oxymethyl]phosphonium]amino Propionate ( Compound 24 )

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-[[(3R)-tetrahydrofuran-3-yl]oxymethyl]phosphoryl]amino]propanoate

Compound 24D (5.0 g, 22.8 mmol) was dissolved in 50 mL of dichloromethane, and 2,6-diisopropylphenol (4.0 g, 22.8 mmol) and triethylamine (9.2) were added dropwise at 0 ° C under nitrogen. g, 91.3 mmol) was dissolved in 50 mL of dichloromethane, and the mixture was allowed to react at room temperature for 1 hour. And L-alanine isopropyl ester (5.9 g, 45.6 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction solution was washed with a saturated solution of sodium dihydrogen phosphate (100 mL), and the mixture was evaporated. :1~1:1) Compound 24 was obtained as a yellow oil (2.8 g, yield: 27.0%).

LC-MS m/z = 456.3 [M + 1].

Compound 24 (2.8 g) was used for isolation to give two optical isomers of compound 24-a (1.01 g, retention time 2.61 min, colorless oil, ee% = 100%), compound 24-b (1.20 g) , retention time 3.82 min, colorless oil, ee% = 96.33%). Preparation conditions: Instrument: Thar 350 preparative SFC (SFC-9); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is methanol; gradient: B 20%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period : ~4 min.

Compound 24-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.03-4.97 (m, 1H), 4.37-4.22 (m, 1H), 4.15-3.97 (m, 2H), 3.95-3.79 (m, 5H), 3.59-3.54 (m, 2H), 3.50-3.39 (m, 1H), 2.04-1.98 (m, 2H), 1.27-1.20 (m, 18H), 1.09 (d, 3H). ³¹ P NMR ( 162 MHz, CDCl ₃ ) δ 22.30. LC-MS m/z = 456.3 [M + 1].

Compound 24-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.96-4.90 (m, 1H), 4.25-4.24 (m, 1H), 4.10-4.04 (m, 1H), 3.99-3.77 (m, 6H), 3.58-3.49 (m, 3H), 2.13-1.95 (m, 2H), 1.33 (d, 3H), 1.26-1.08 (m, 18H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.27.

LC-MS m/z = 456.3 [M + 1].

Example 25

Ethyl (2R)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 25 )

Ethyl(2R)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

Compound 1C (5.0 g, 30.7 mmol) was dissolved in 50 mL of dichloromethane, and 2,6-diisopropylphenol (5.5 g, 30.7 mmol) and triethylamine (12.4) were added dropwise at 0 ° C under nitrogen. A solution of g, 122.7 mmol) in dichloromethane (50 mL). And D-alanine ethyl ester (7.2 g, 61.3 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (100 mL), and the mixture was evaporated. Compound 25 was obtained as a yellow oil (4.5 g, yield: 38.0%).

LC-MS m/z = 386.2 [M+1].

Compound 25 (4.5 g) was used for isolation to give two optical isomer compound 25-a (1.88 g, retention time 1.95 min, yellow oil, ee% = 100%), compound 25-b (1.91 g) , retention time 2.67 min, colorless oil, ee% = 100%). Preparation conditions: Instrument: MG II preparative SFC (SFC-11); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm.; mobile phase: phase A is CO ₂ and phase B is methanol; gradient: B 10%; Flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period: ~2.6 min.

Compound 25-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.26-4.05 (m, 3H), 3.91-3.88 (m, 2H), 3.61-3.35 (m, 6H), 1.28-1.16 (m, ^{18H). 31 P NMR (162MHz} , CDCl 3) δ 22.61.LC-MS m / z = 386.2 [m + 1].

Compound 25-b

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11 (s, 3H), 4.21-4.02 (m, 3H), 3.90-3.82 (m, 2H), 3.62-3.38 (m, 6H), 1.37 (d, 3H) , 311-1.06 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.58. LC-MS m/z = 386.3 [M+1].

Example 26

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(morpholinylmethyl)phosphonium]amino]propionate ( Compound 26 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(morpholinomethyl)phosphoryl]amino]propanoate

First step: ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methylsulfonyloxymethyl)phosphonium]amino]propionate ( 26A )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methylsulfonyloxymethyl)phosphoryl]amino]propanoate

Compound 11B (0.8 g, 4 mmol) was dissolved in dichloromethane (20 mL), and 2,6-diisopropylphenol (1.0 g, 5 mmol) and triethylamine were added dropwise at -10 ° C under nitrogen. A solution of 1 g, 10 mmol) in dichloromethane (10 mL) was reacted at room temperature for one hour. L-Alanine ethyl ester hydrochloride (0.9 g, 7 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (20 mL), and the mixture was evaporated. EtOAcjjjjjjjjjjjjj Compound 26A was obtained as a yellow oil (0.8 g, yield 50.0%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.15 (d, 3H), 4.80-4.41 (m, 2H), 4.37-3.98 (m, 3H), 3.85-3.28 (m, 3H), 3.13 (t, 3H) , 1.48-1.13 (m, 18H).

Second step: ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(morpholinylmethyl)phosphonium]amino]propionate ( compound 26 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(morpholinomethyl)phosphoryl]amino]propanoate

Compound 26A (5.0 g, 11.0 mmol) was dissolved in tetrahydrofuran (20 mL), morpholine (2.9 g, 33 mmol) and triethylamine (5.6 g, 56 mmol) were added, and the mixture was heated to 80 ° C for 8 hours. The reaction mixture was concentrated, the residue was purified by column chromatography using silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 1: 1), to give compound 26 as a yellow oil (4.0 g of, yield 82.5%).

LC-MS (m/z) = 441.4 [M+1].

Compound 26 (4.0 g) was obtained for isolation to give two optical compound of compound 26-a (yield of trifluoroacetic acid salt) (1.94 g, retention time 1.55 min, yellow oil, ee% = 100%). Compound 26-b (1.70 g, retention time 2.26 min, white solid, ee% = 98.14%). Preparation conditions: Instrument: Thar 350 preparative SFC (SFC-6); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 15%; Flow rate: 180 mL / min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period : ~ 2.5 min.

Compound 26-a

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.22-7.07 (m, 3H), 5.69-5.49 (m, 1H), 4.18-3.97 (m, 2H), 3.93-3.80 (m, 1H), 3.73 ( s, 4H), 3.55-3.45 (m, 4H), 3.05 (s, 4H), 1.24-1.07 (m, 18H). ³¹ P NMR (162 MHz, CD ₃ OD) δ 20.16. ¹⁹ F NMR (376 MHz, CD ₃ OD)δ -75.08.LC-MS m/z=441.4[M+1].

Compound 26-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.17-3.99 (m, 3H), 3.79-3.55 (m, 5H), 3.52-3.45 (m, 2H), 2.93-2.91 (m, 2H), 2.75 (s, 2H), 2.67 (s, 2H), 1.39 (d, 3H), 1.28-1.14 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.68. LC-MS m/ z=441.3[M+1].

Example 27

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-[(dimethylamino)methyl]phosphonium]amino]propionate ( Compound 27 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-[(dimethylamino)methyl]phosphoryl]amino]propanoate

Compound 26A (5.0 g, 11.1 mmol) was dissolved in dimethylamine in tetrahydrofuran (2 mol / L) (16.65 mL, 33.3 mmol), triethylamine (5.6 g, 55.6 mmol) was added and the tube was heated to 80 ° C Reaction for 8 hours. The reaction mixture was concentrated, the residue was purified by column chromatography using silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 1: 1), to give compound 27 as a yellow oil (3.0 g of, yield 67.8%).

LC-MS (m/z) = 399.3 [M+1].

Compound 27 (3.0 g) was used for the separation to give two optical compound 27-a (0.534 g, retention time 2.65 min, colorless oil, ee% = 100%), Compound 27-b (0.743 g , residence time 3.39 min, white solid, ee% = 100%). Preparation conditions: Instrument: Thar 350 preparative SFC (SFC-6); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 15%; Flow rate: 180 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period : ~2.5 min.

Compound 27-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.41-3.95 (m, 3H), 3.59-3.52 (m, 3H), 3.01-2.82 (m, 2H), 2.45 (s, 6H) , 1.31-1.18 (m, 15H), 1.10 (d, 3H). ³¹ P NMR (162 MHz, CD ₃ OD) δ 26.34. LC-MS m/z = 399.3 [M+1].

Compound 27-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.10 (s, 3H), 4.18-3.99 (m, 3H), 3.67 (t, 1H), 3.51-3.44 (m, 2H), 2.96-2.86 (m, 2H) , 2.24 (s, 6H), 1.38 (d, 3H), 1.26-1.13 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.08. LC-MS m/z = 399.3 [M+1].

Example 28

Ethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]acetate ( Compound 28 )

Ethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]acetate

Compound 1C (5.0 g, 30.7 mmol) was dissolved in 50 mL of dichloromethane, and 2,6-diisopropylphenol (5.5 g, 30.7 mmol) and triethylamine (12.4) were added dropwise at 0 ° C under nitrogen. A solution of g, 122.7 mmol) in dichloromethane (50 mL) was then reacted for 1 hour at room temperature. Glycine ethyl ester (6.3 g, 61.3 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction liquid was washed with 100 mL of a saturated aqueous solution of sodium dihydrochloride, and the organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography using silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 1: 1) to give compound 28 as a yellow oil (5.0g, yield 43.9%).

LC-MS m/z = 372.2 [M+1].

Solution of compound 28 (5.0g) for separating the two optical isomers to obtain a compound 28-a (2.23g, 3.18 min retention time, a pale yellow solid, ee% = 100%), compound 28-b (2.45g, Retention time 3.60 min, white solid, ee% = 100%). Preparation conditions: Instrument: MG II preparative SFC (SFC-11); chromatography column: ChiralPak IC, 250 × 30 mm ID, 10 μm.; Mobile phase: Phase A is CO ₂ and Phase B is isopropanol (0.1% NH ₃ H ₂ O); Gradient: B 40%; Flow rate: 60 mL/min; Back pressure: 100 bar; Column temperature: 38 ° C; Detection wavelength: 220 nm; Period : ~ 5.5 min.

Compound 28-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.20-4.15 (m, 2H), 3.98-3.87 (m, 3H), 3.75-3.68 (m, 1H), 3.57-3.43 (m, 5H), 3.41-3.37 (m, 1H), 1.27-1.21 (m, 15H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 23.13. LC-MS m/z = 372.2 [M+1].

Compound 28-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.13 (s, 3H), 4.20-4.15 (m, 2H), 3.99-3.85 (m, 3H), 3.77-3.62 (m, 1H), 3.57-3.47 (m, 5H), 3.37 (s, 1H) 1.32-1, 12 (m, 15H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 23.12. LC-MS m/z = 372.2 [M+1].

Example 29

Ethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]-2-methyl-propionate ( Compound 29 )

Ethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]-2-methyl-propanoate

Compound 1C (4.0 g, 25 mmol) was dissolved in 50 mL of dichloromethane, and 2,6-diisopropylphenol (5.6 g, 25 mmol) and triethylamine (9.9 g, 98 mmol) were added dropwise under a nitrogen atmosphere at 0 °C. A solution of dichloromethane (50 mL) was reacted at room temperature for 1 hour after the completion of the dropwise addition. Ethyl 2-aminoisobutyrate (10.3 g, 61.3 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (100 mL), and the mixture was evaporated. Compound 29 was obtained as a yellow oil (5.0 g, yield 50.1%).

LC-MS m/z = 400.2 [M + 1].

Compound 29 (5.0 g) was obtained for isolation to give two optical compound Compounds 29-a (2.08 g, retention time 3.45 min, pale yellow oil, ee% = 100%), compound 29-b (2.42) g, residence time 3.68 min, colorless oil, ee% = 100%). Preparation conditions: Instrument: MG II preparative SFC (SFC-14); chromatography column: Pheno Lux Cellulose-2, 250 × 30 mm ID, 5 μm.; Mobile phase: Phase A is CO ₂ and Phase B is isopropanol; Gradient: B 10%; flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period : ~4 min.

Compound 29-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.18-4.13 (m, 2H), 4.02-3.80 (m, 3H), 3.62-3.55 (m, 2H), 3.46 (s, 3H) , 1.53 (s, 3H), 1.38 (s, 3H), 1.29-1.15 (m, 15H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.38. LC-MS m/z = 400.2 [M+1].

Compound 29-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.18-4.13 (m, 2H), 3.92-3.83 (m, 3H), 3.62-3.55 (m, 2H), 3.47 (s, 3H) , 1.53 (s, 3H), 1.38 (s, 3H), 1.32-1.08 (m, 15H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.38. LC-MS m/z = 400.2 [M+1].

Example 30

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]-4-methyl-pentanoate ( Compound 30 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]-4-methyl-pentanoate

Compound 1C (5.0 g, 30.6 mmol) was dissolved in dichloromethane (50 mL), and 2,6-diisopropylphenol (5.5 g, 30.6 mmol) and triethylamine were added dropwise at 0 ° C under nitrogen. A solution of (12.4 g, 122.7 mmol) in dichloromethane (50 mL) was evaporated. (S)-Ethyl-2-amino-4-methylvalerate (12.0 g, 61.3 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (100 mL), and the mixture was evaporated. Compound 30 was obtained as a yellow oil (5.0 g, yield 38.11%).

LC-MS m/z = 428.3 [M+1].

Compound 30 (5.0 g) was used for the separation to give two crystals of compound 30-a (2.11 g, retention time 2.15 min, pale yellow oil, ee% = 99.68%), compound 30-b (2.15 g, residence time 3.56 min, light yellow oil, ee% = 100%). Preparation conditions: Instrument: MG II preparative SFC (SFC-13); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm.; Mobile phase: Phase A is CO ₂ and Phase B is methanol (0.1% NH ₃ .H ₂ O); Gradient: B 20%; Flow rate: 50 mL/min; Back pressure: 100 bar; Column temperature: 38 ° C; Detection wavelength: 220 nm; Period : ~6 min.

Compound 30-a

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11 (s, 3H), 4.23-4.09 (m, 2H), 4.05-3.99 (m, 1H), 3.94-3.82 (m, 2H), 3.59-3.52 (m, 2H), 3.49 (d, 3H), 3.13 (t, 1H), 1.49-1.34 (m, 1H), 1.32-1.12 (m, 17H), 0.71-0.68 (m, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.74. LC-MS m/z = 428.3 [M+1].

Compound 30-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.17-3.97 (m, 3H), 3.90-3.76 (m, 2H), 3.54-3.49 (m, 2H), 3.44 (d, 3H) , 3.32 (t, 1H), 1.76-1.70 (m, 1H), 1.58-1.43 (m, 2H), 1.23-1.16 (m, 15H), 0.93-0.90 (m, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.71. LC-MS m/z = 428.3 [M+1].

Example 31

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]-3-methyl-butyrate ( Compound 31 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]-3-methyl-butanoate

Compound 1C (5.0 g, 30.6 mmol) was dissolved in 50 mL of dichloromethane, and 2,6-diisopropylphenol (5.5 g, 30.6 mmol) and triethylamine (12.4) were added dropwise at 0 ° C under nitrogen. A solution of g, 122.7 mmol) in dichloromethane (50 mL) was then reacted for 1 hour at room temperature. (S) 2-Amino-3-methylbutyric acid ethyl ester hydrochloride (11.14 g, 61.37 mmol) was added at this temperature. The reaction was carried out for 2 hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (100 mL), and the mixture was evaporated. Compound 31 was obtained as a yellow oil (3.6 g, yield: 28.0%).

LC-MS m/z = 414.3 [M + 1].

Compound 31 (3.6 g) was used for the separation to give two optical compound Compounds 31-a (1.69 g, retention time 1.56 min, colorless oil, ee% = 100%), Compound 31-b (1.69 g) , residence time 2.55min, light yellow oil, ee% = 100%). Preparation conditions: Instrument: MG II preparative SFC (SFC-15); chromatography column: ChiralPak AD, 250 × 30mm ID, 5μm.; mobile phase: phase A is CO ₂ and phase B is isopropanol (0.1% NH ₃ .H ₂ O); Gradient: B 20%; Flow rate: 50 mL/min; Back pressure: 100 bar; Column temperature: 38 ° C; Detection wavelength: 220 nn; Period : ~ 4.8 min.

Compound 31-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.13 (s, 3H), 4.29-4.09 (m, 2H), 4.01-3.76 (m, 3H), 3.61-3.54 (m, 2H), 3.47 (d, 3H) , 3.29 (t, 1H), 2.01-1.87 (m, 1H), 1.32-1.14 (m, 15H), 0.77-0.51 (m, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.95. LC-MS m/z = 414.3 [M + 1].

Compound 31-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.07-3.76 (m, 5H), 3.57-3.48 (m, 2H), 3.45 (d, 3H), 3.38 (t, 1H), 2.02 -1.94 (m, 1H), 1.28-1.11 (m, 15H), 0.94-0.88 (m, 6H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 22.24. LC-MS m/z = 414.3 [M+1 ].

Example 32

Ethyl (2S)-2-[[[3-(3-ethyl-1-methyl-azepan-3-yl)phenoxy]-(methoxymethyl)phosphonium] Amino]propionate ( compound 32 )

Ethyl(2S)-2-[[[3-(3-ethyl-1-methyl-azepan-3-yl)phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (3.0 g, 18.4 mmol) was dissolved in dichloromethane (50 mL), and then, at 0 ° C, under nitrogen, 32A (3.0 g, 12.8 mmol) and triethylamine (7.4 g, 73.6 mmol) a solution of dichloromethane (50 mL). L-Alanine ethyl ester (4.3 g, 36.8 mmol) was added and allowed to react at room temperature for two hours. 100mL with a saturated solution of sodium dihydrogen phosphate reaction solution was washed, separated, dried over anhydrous sodium sulfate organic phase was concentrated to give compound 32 as a yellow oil (3.0 g of, yield 37.0%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.26-7.03 (m, 4H), 4.23-4.10 (m, 4H), 3.89-3.71 (m, 2H), 3.52-3.37 (m, 4H), 2.72-2.32 ( m, 5H), 1.43-1.36 (m, 6H), 1.35-1.22 (m, 9H), 0.58 (t, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 25.12, 23.85, 22.47. LC-MS m /z=441.2[M+1].

Example 33

2-(((((((((((((((((((((((((((((((((((())))))))))) 1H-4,12-Methyl-based benzofuran [3,2-e]isoquinolin-9-yl)oxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 33 )

(2S)-ethyl 2-((((4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro -1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphonium dichloride (3.0 g, 18.4 mmol) was dissolved in 50 mL of dichloromethane, and then, under a nitrogen atmosphere, 33A (3.0 g, 9.2 mmol) and triethylamine (7.4) A solution of g, 73.6 mmol) in dichloromethane (50 mL) was evaporated and evaporated. L-Alanine ethyl ester (4.3 g, 36.8 mmol) was added and allowed to react at room temperature for two hours. The reaction liquid was washed with 100 mL of a saturated aqueous solution of sodium dihydrochloride, and the organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography using silica gel (petroleum ether: ethyl acetate (v / v) = 10: 1 ~ 1: 1) to give compound 33 as a yellow oil (5.0g, yield 50.8%)

LC-MS m/z = 535.2 [M+1].

Solution of compound 33 (5.0g) for separating, to obtain two optical isomers of the compounds 33-a (0.606g, 4.02 min retention time, a light yellow oil, ee% = 90.24%), compound 33-b (0.582 g, residence time 4.99 min, light yellow oil, ee% = 86.90%). Preparation Conditions: Instrument: Thar 200 preparative SFC (SFC- 7); column: ChiralPak AS, 300 × 50mm ID , 10μm; mobile phase: A phase is CO _2; B phase is ethanol; Gradient: B 45%; flow rate : 200 mL / min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; cycle : ~ 7 min.

Compound 33-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.10 (m, 1H), 6.68 (d, 1H), 5.93-5.74 (m, 1H), 5.25 (m, 2H), 4.74 (s, 1H), 4.28-4.05 (m, 4H), 4.04-3.89 (m, 2H), 3.57 (d, 3H), 3.25-3.02 (m, 5H), 2.62 (m, 2H), 2.45 (m, 1H), 2.27 (m, 1H) ), 2.20-2.06 (m, 1H), 1.90 (t, 2H), 1.62-1.45 (m, 2H), 1.26 (t, 3H), 1.05 (d, 3H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 26.61. LC-MS m/z = 535.2 [M+1].

Compound 33-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (d, 1H), 6.69 (d, 1H), 5.96 (s, 1H), 5.32 (d, 2H), 4.78 (s, 1H), 4.28-4.06 (m , 3H), 4.02 (m, 1H), 3.97-3.80 (m, 2H), 3.59-3.38 (m, 4H), 3.21 (m, 4H), 2.70 (s, 2H), 2.37-2.12 (m, 3H) ), 1.71-1.48 (m, 3H), 1.38 (d, 3H), 1.24 (t, 4H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.99. LC-MS m/z = 535.2 [M+1] .

Example 34

Benzyl (2S)-2-[[[(3R,4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,4,5,6,7a,13- Hexahydro-1H-4,12-methylbenzofuro[3,2-e]isoquinolin-9-yl]oxy-(methoxymethyl)phosphonium]amino]propionate ( Compound 34 )

Benzyl (2S)-2-[[[(3R,4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H- 4,12-methanobenzofuro[3,2-e]isoquinoline-9-yl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphine dichloride (2.0 g, 12.27 mmol) was dissolved in dichloromethane (50 mL), and L-alanine benzyl ester (1.7 g) was added dropwise at -40 ° C under nitrogen. A solution of 9.8 mmol) and triethylamine (4.9 g, 49.0 mmol) in dichloromethane (50 mL). At this temperature, 33A (2.0 g, 6.1 mmol) was added. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated solution of sodium dihydrogen phosphate (100 mL), and then evaporated. Compound 34 was obtained as a yellow oil (0.5 g, yield: 13.7%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.41-7.28 (m, 5H), 7.09 (t, 1H), 6.68-6.65 (m, 1H), 5.86 (s, 1H), 5.34-5.09 (m, 4H) , 4.71 (d, 1H), 4.32-4.15 (m, 1H), 4.05-3.78 (m, 2H), 3.52 (s, 3H), 3.18-3.04 (m, 4H), 2.54 (d, 3H), 2.33 -2.21 (m, 1H), 2.18-1.87 (m, 2H), 1.64-1.48 (m, 3H), 1.39 (d, 2H), 1.26 (s, 2H), 1.07 (d, 1H). LC-MS m/z = 597.3 [M+1].

Example 35

Benzyl (2S)-2-[[[(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a, 13-Hexahydro-1H-4,12-methylbenzofuro[3,2-e]isoquinolin-9-yl]oxy-(methoxymethyl)phosphonium]amino]propionic acid Ester ( compound 35 )

Benzyl (2S)-2-[[[(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H- 4,12-methanobenzofuro[3,2-e]isoquinoline-9-yl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphine dichloride (0.2 g, 1.2 mmol) was dissolved in 10 mL of dichloromethane, and L-alanine benzyl ester (0.2 g, 1.2) was added dropwise at -40 ° C under nitrogen. A solution of mmol) and triethylamine (0.5 g, 4.9 mmol) in dichloromethane (10 mL). At this temperature, 35A (0.2 g, 0.61 mmol) was added. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated solution of sodium dihydrogen phosphate (100 mL), and then evaporated. Compound 35 was obtained as a yellow oil (0.18 g, yield 46.8%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.33-7.21 (m, 5H), 7.06-6.96 (m, 1H), 6.59-6.56 (m, 1H), 5.15-4.98 (m, 2H), 4.64 (d, 1H), 4.27-3.70 (m, 4H), 3.42 (t, 3H), 3.19 (s, 1H), 3.10-2.88 (m, 2H), 2.67 (s, 1H), 2.55 (d, 1H), 2.38 (s, 3H), 2.25-2.21 (m, 1H), 2.06-2.03 (m, 1H), 1.93-1.85 (m, 1H), 1.63-1.39 (m, 3H), 1.34 (d, 2H), 0.99 (d, 2H), 0.51 (d, 2H), 0.11 (s, 2H). LC-MS m/z = 611.3 [M + 1].

Example 36

Isopropyl (2R)-2-[[[4-[(1E,6E)-7-[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo- Ethyl])phosphonium]oxy-3-methoxyphenyl]-3,5-dioxohepta-1,6-dienyl]-2-methoxyphenoxy]-(A Oxymethyl)phosphonium]amino]propionate

Isopropyl(2R)-2-[[[4-[(1E,6E)-7-[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl) )phosphoryl]oxy-3-methoxy-phenyl]-3,5-dioxo-hepta-1,6-dienyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

1 C (1.63 g, 10 mmol) was dissolved in 20 mL of dry dichloromethane and cooled to -30 ° C under nitrogen. A solution of triethylamine (4.05 g, 40 mmol) and L-alanine isopropyl ester (1.44 g, 11 mmol) in dichloromethane (20 mL) was added dropwise, and the mixture was reacted for 30 min, and 36A (1.84 g, 5 mmol) was added. The reaction was carried out for 2 hours at room temperature. It was washed once with 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, and washed twice with 20 mL of brine. The residue was separated and purified by silica gel column chromatography, and ethyl acetate/petroleum ether = 1/1 to 1/0 was used as a solvent. Compound 36 was obtained as a yellow solid (0.200 g, yield 4.93%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.59 (d, 2H), 7.36 (d, 2H), 7.12 (m, 4H), 6.54 (d, 2H), 5.85 (s, 1H), 5.07-4.89 (m , 2H), 4.18-4.04 (m, 2H), 4.01-3.64 (m, 12H), 3.51 (d, 6H), 1.33 (d, 3H), 1.27-1.17 (m, 15H). LC-MS m/z = 811.3 [M + 1].

Example 37

Isopropyl (2S)-2-[[[4-[(1E,6E)-7-(4-hydroxy-3-methoxy-phenyl)-3,5-dioxo-heptane-1, 6-dienyl]-2-methoxyphenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 37 )

Isopropyl(2S)-2-[[[4-[(1E,6E)-7-(4-hydroxy-3-methoxy-phenyl)-3,5-dioxo-hepta-1,6-dienyl]-2- Methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

1C (0.815 g, 5 mmol) was dissolved in 20 mL of dry methylene chloride, and then evaporated, and then, triethylamine (2.02 g, 20 mmol), isopropyl L-alanine (0.656 g, 5 mmol) was added dropwise at -30 °C. The mixture was reacted for 30 min after the completion of the dropwise addition, and 36A (2.76 g, 7.5 mmol) was added thereto , and the mixture was reacted at room temperature for 2 hours. It was washed once with 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, and washed twice with 20 mL of brine. The residue was separated and purified by silica gel column chromatography, and ethyl acetate/petroleum ether = 1/1 to 1/0 was used as a solvent. Compound 37 was obtained as a yellow solid (0.200 g, yield 6.78%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.59 (t, 2H), 7.35 (d, 1H), 7.17-7.00 (m, 4H), 6.93 (d, 1H), 6.50 (t, 2H), 5.82 (s , 1H), 5.04-4.89 (m, 1H), 4.12 (m, 1H), 4.00-3.80 (m, 10H), 3.51 (d, 3H), 1.29-1.15 (m, 9H). LC-MS m/ z=590.2[M+1].

Example 38

Isopropyl (2S)-2-[[(4-carbamimido-2-methoxy-phenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 38 )

Isopropyl(2S)-2-[[(4-formyl-2-methoxy-phenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

1C (4.0g, 25mmol) was dissolved in 40mL of dry dichloromethane, and a mixture of triethylamine (6.7g, 66mmol) and 38A (2.5g, 16mmol) was added dropwise at -30 °C. Reaction for 30 min. L-Alanine isopropyl ester (2.4 g, 18 mmol) was added to react at room temperature for 2 hours. It was washed once with 20 mL of a saturated aqueous solution of sodium hydrogencarbonate, and washed twice with 20 mL of brine. The residue was separated and purified on a silica gel column, and ethyl acetate/petroleum ether = 1/10 to 1/1 was used as a solvent. Compound 38 was obtained as a colorless oil (1.00 g, yield: 16.7%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.92 (d, 1H), 7.58-7.38 (m, 3H), 4.96 (m, 1H), 4.11 (s, 1H), 4.01-3.69 (m, 6H), 3.52 (m, 3H), 1.33 (d, 2H), 1.26-1.16 (m, 7H). LC-MS m/z = 374.1 [M+1].

Example 39

Isopropyl ester (2S)-2-[[methoxymethyl-(4-methyl-2-oxo-benzopyran-7-yl)oxy-phosphonium]amino]propionate ( Compound 39 )

Isopropyl(2S)-2-[[methoxymethyl-(4-methyl-2-oxo-chromen-7-yl)oxy-phosphoryl]amino]propanoate

1C (3.5 g, 21 mmol) was dissolved in 50 mL of dry dichloromethane, and then a mixture of triethylamine (5.7 g, 57 mmol) and 39A (2.5 g, 14 mmol) was added dropwise at -30 ° C. After 30 min, L-alanine isopropyl ester (2.0 g, 16 mmol) was added to react at room temperature for 2 hours. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure, column chromatography, ethyl acetate / petroleum ether = 1/10~1 Agent. Compound 39 was obtained as a colorless oil (1.6 g, yield 28.8%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.56 (d, 1H), 7.28-7.24 (m, 1H), 7.20 (m, 1H), 6.24 (d, 1H), 5.08-4.93 (m, 1H), 4.12 (m, 1H), 3.91-3.78 (m, 2H), 3.68 (d, 1H), 3.48 (m, 3H), 2.42 (d, 3H), 1.35 (m, 3H), 1.29-1.16 (m, 6H) ). LC-MS m/z = 398.1 [M+1].

Example 40

Isopropyl (2S)-2-[[[4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy- 2-methyl-4,4a,6,7,8,8a-hexahydropyran[3,2-d][1,3]dioxine-6-yl]oxy]-8- Oxo-5a,6,8a,9-tetrahydro-5H-isobenzofuran [6,5-f][1,3]benzodioxol-9-yl]-2,6- Dimethoxy-phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 40 )

Isopropyl(2S)-2-[[[4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl -4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a,9-tetrahydro-5H -isobenzofuro[6,5-f][1,3]benzodioxol-9-yl]-2,6-dimethoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.46 g, 2.82 mmol) was dissolved in 20 mL of dry methylene chloride, EtOAc (m.) A mixture of isopropyl alanate (0.37 g, 28.2 mmol) was reacted for 30 min after the dropwise addition, and 40A (1.66 g, 28.2 mmol) was added, and the mixture was reacted at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure, column chromatography, eluting with ethyl acetate / petroleum ether = 1/1 to 1/0 Agent. The title compound 40 was obtained as a white solid (1.0 g, yield 43.7%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.02 (s, 1H), 6.53 (d, 1H), 6.24 (d, 2H), 6.03 (s, 2H), 5.19-5.11 (m, 1H), 4.95 (d, 1H), 4.93-4.85 (m, 1H), 4.74-4.71 (m, 1H), 4.59-4.56 (m, 2H), 4.33-4.21 (m, 2H), 4.12-3.95 (m, 2H) , 3.88-3.69 (m, 2H), 3.63 (d, 6H), 3.51 (t, 1H), 3.38-3.28 (m, 7H), 3.27-3.03 (m, 3H), 2.92-2.88 (m, 1H) , 1.24 (dd, 6H), 1.21-1.16 (m, 6H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 26.22, 25.57. LC-MS m/z (ESI) = 810.2 [M+1].

Compound 40 (2.5 g) was used for chiral separation to give two diastereomeric compounds 40-a (white solid: 0.8 g, retention time 3.10 min, ee% = 100%), compound 40-b (white solid) 1.5 g, residence time 4.82 min, ee% = 100%). Separation method: Instrument: MG II preparative SFC (SFC-15); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm.; mobile phase: phase A is CO ₂ and phase B is isopropanol (0.1% NH ₃ H ₂ O); Gradient: B 40%; Flow rate: 50 mL/min; Back pressure: 100 bar; Column temperature: 38 ° C; Wavelength: 220 nm; Period: ~ 7.5 min.

Compound 40-a :

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.83 (s, 1H), 6.50 (s, 1H), 6.25 (s, 2H), 5.97 (dd, 2H), 5.03-4.97 (m, 1H), 4.90 (d , 1H), 4.75-4.72 (m, 1H), 4.59 (t, 2H), 4.47-4.36 (m, 1H), 4.24 - 4.14 (m, 2H), 4.14 - 4.05 (m, 1H), 4.02-3.96 (m, 1H), 3.98-3.83 (m, 3H), 3.75-3.65 (m, 7H), 3.61-3.50 (m, 1H), 3.47 (d, 3H), 3.43-3.37 (m, 1H), 3.34 - 3.26 (m, 3H), 2.94 - 2.77 (m, 1H), 1.37 (d, 3H), 1.26-1.21. (m, 9H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 26.19. LC-MS m/z (ESI)=810.1[M+1].

Compound 40-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.82 (s, 1H), 6.48 (s, 1H), 6.23 (s, 2H), 5.96 (dd, 2H), 5.02-4.96 (m, 1H), 4.90 (d , 1H), 4.74-4.71 (m, 1H), 4.61-4.53 (m, 2H), 4.42-4.37 (m, 1H), 4.27-4.07 (m, 4H), 4.05-3.79 (m, 3H), 3.73 -3.63 (m, 7H), 3.58-3.52 (m, 1H), 3.46 (d, 3H), 3.43-3.26 (m, 4H), 3.01-2.69 (m, 1H), 1.38 (t, 6H), 1.22 -1.20 (m, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 26.11. LC-MS m/z (ESI)=810.2[M+1].

Example 41

Isopropyl (2S)-2-[[[3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-2-oxo-indoline- 1-yl]-(methoxymethyl)phosphonium]amino]propionate ( Compound 41 )

Isopropyl(2S)-2-[[[(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-2-oxo-indolin-1-yl]-(methoxymethyl)phosphoryl ]amino]propanoate

(Methoxy group-based) phosphine dichloride (4.1 g, 25 mmol) was dissolved in 50 mL of dry dichloromethane, nitrogen-protected, triethylamine (10 g, 100 mmol) was added dropwise at -30 ° C, L-alanine A mixture of isopropyl ester (3.3 g, 25 mmol) was reacted for 30 min after the completion of the dropwise addition to obtain a reaction solution 1. Compound 41A (3.0 g, 13 mmol) was dissolved in 30 mL of tetrahydrofuran, and nitrogen-protected, and butyl lithium was added dropwise at -78 ° C (15.6). mL, 25 mmol, 1.6 mol/L), the reaction was carried out for 30 min after the completion of the dropwise addition to obtain a reaction liquid 2, and the reaction liquid 1 was added dropwise to the reaction liquid 2, and the mixture was slowly warmed to room temperature for 2 hours. Wash once with 20 mL of saturated aqueous solution of sodium dihydrogen phosphate, wash once with 50 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure, and column chromatography, using dichloromethane / methanol = 100/1~20/1 as a solvent . Obtained as a yellow solid (0.7 g, yield 10%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 12.78 (s, 1H), 7.93-7.86 (m, 1H), 7.77 (d, 1H), 7.61 (s, 1H), 7.14-7.02 (m, 2H) , 6.09 (d, 1H), 6.01-5.95 (m, 1H), 4.67-4.54 (m, 1H), 4.28-4.24 (m, 1H), 4.06-3.86 (m, 2H), 3.35 (d, 3H) , 2.33 (d, 6H), 1.30 (d, 3H), 0.84 (d, 3H), 0.79 (d, 3H). ^{31 P NMR (162MHz, DMSO- d} 6) δ 23.56.LC-MS m / z (ESI) = 482.1 [M + 23].

Example 42

Isopropyl (2S)-2-[[[4-[(5-fluoro-2,4-dioxo-pyrimidin-1-yl)methyl]phenoxy]-(methoxymethyl)phosphine Mercapto]amino]propionate ( compound 42 )

Isopropyl(2S)-2-[[[4-[(5-fluoro-2,4-dioxo-pyrimidin-1-yl)methyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

First step: 4-(hydroxymethyl)phenyl acetate ( 42A )

4-(hydroxymethyl)phenyl acetate

4-(Hydroxymethyl)phenol (0.5 g, 4.0 mmol) was dissolved in 10 mL of tetrahydrofuran and triethylamine (0.81 g, 8.1 mmol). Ethyl chloride (0.47 g, 6.0 mmol) was added dropwise at 0 ° C, and the mixture was reacted for 2 h. After adding 30 mL of water, the mixture was extracted twice with 50 mL of ethyl acetate, and then washed twice with 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 42A was obtained as a colorless oil (0.3 g, yield 40%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.34 (d, 2H), 7.12-7.00 (m, 2H), 5.19 (t, 1H), 4.49 (d, 2H), 2.25 (s, 3H). LC-MS.m/z (ESI) = 189.0 [M+23].

Second step: 4-(bromomethyl)phenyl acetate ( 42B )

4-(bromomethyl)phenyl acetate

Compound 42A (0.1 g, 0.6 mmol) was dissolved in 5 mL dichloromethane, triphenylphosphine (0.197 g, 0.752 mmol) was added, and dichloromethane (0.249 mmol, 0.752 mmol) of dichloromethane was added dropwise at 0 °C. 1 mL of the solution was reacted at room temperature for 30 min. Concentrate directly under reduced pressure, column chromatography, using ethyl acetate / petroleum ether = 1/10 ~ 1 / 5 as a solvent. Compound 42B was obtained as a white solid (0.08 g, yield 60%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.49 (d, 2H), 7.12 (d, 2H), 4.72 (s, 2H), 2.27 (d, 3H).

Step 3: 4((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phenyl ester ( 42C )

4-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phenyl acetate

5-Fluorouracil (0.3 g, 2 mmol) was dissolved in 15 mL of N,N-dimethylformamide, potassium carbonate (0.05 g, 0.3 mmol) was added, and compound 42B (0.05 g, 0.2 mmol) was added dropwise at 0 °C. 5 mL of N,N-dimethylformamide solution was reacted at room temperature for 2 h after the completion of the dropwise addition. Add 20 mL of water, 20 ml of ethyl acetate to dissolve the residue, the aqueous phase is extracted twice with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, column chromatography, ethyl acetate / petroleum ether = 1/10~1 /1 was used as a solvent to give Compound 42C as a white solid (0.05 g, yield 80%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 11.84 (d, 1H), 8.23 (d, 1H), 7.37 (d, 2H), 7.12 (d, 2H), 4.82 (s, 2H), 2.26 (d , 3H). LC-MS.m/z (ESI)=279.0 [M+1].

Step 4: 5-Fluoro-1-(4-hydroxybenzyl)pyrimidine-2,4(1H,3H)-dione ( 42D )

5-fluoro-1-(4-hydroxybenzyl)pyrimidine-2,4(1H,3H)-dione

Compound 42C (5.0 g, 18.0 mmol) was dissolved in 50 mL MeOH. Stir at room temperature for 2 h. Was added 50mL of water, with dilute hydrochloric acid to pH 1N = 4, extracted twice with 100mL of ethyl acetate, washed with 30mL saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 42D, as a white solid (3.5g, yield 82%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 11.79 (d, 1H), 9.45 (s, 1H), 8.15 (d, 1H), 7.16 (dd, 2H), 6.82-6.65 (m, 2H), 4.69 (s, 2H).

Step 5: Isopropyl (2S)-2-[[[4-[(5-fluoro-2,4-dioxo-pyrimidin-1-yl)methyl]phenoxy]-(methoxy) Methyl)phosphonium]amino]propionate ( Compound 42 )

Isopropyl(2S)-2-[[[4-[(5-fluoro-2,4-dioxo-pyrimidin-1-yl)methyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (1.0 g, 6.14 mmol) was dissolved in 20 mL of dry methylene chloride, and then filtered with nitrogen, and triethylamine (2.48 g, 24.5 mmol) was added dropwise at -30 ° C, L- A mixture of isopropyl alanate (0.805 g, 6.14 mmol) was reacted for 30 min after the dropwise addition, and compound 42D (1.45 g, 6.14 mmol) was added and reacted at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure, column chromatography, eluting with ethyl acetate / petroleum ether = 1/1 to 1/0 Agent. Compound 42 was obtained as a white oil (1.0 g, yield 36%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.88 (s, 1H), 7.28-7.25 (m, 4H), 7.23-7.21 (m, 1H), 5.05-4.89 (m, 1H), 4.84 (s, 2H) , 4.15-3.99 (m, 1H), 3.93-3.75 (m, 3H), 3.46 (dd, 3H), 1.32 (dd, 3H), 1.30-1.13 (m, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.61, 23.76. LC-MS m/z (ESI)=458.1 [M+1].

Example 43

Isopropyl (2S)-2-[[methoxymethyl-(4-pyridylamino)phosphonium]amino]propionate ( Compound 43 )

Isopropyl(2S)-2-[[methoxymethyl-(4-pyridylamino)phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (0.69g, 4.23mmol) was dissolved in 20mL dry dichloromethane, nitrogen, -30 deg.] C was added dropwise triethylamine (1.71g, 16.9mmol), 43A ( A mixture of 0.399, 4.23 mmol) was reacted for 30 min after the completion of the dropwise addition. L-alanine isopropyl ester (0.555 g, 4.23 mmol) was added, and the mixture was reacted at room temperature for 2 h. Wash once with 20 mL of saturated aqueous solution of sodium dihydrogen phosphate, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrated under reduced pressure, and column chromatography, using dichloromethane / methanol = 100/1~10/1 as a solvent Compound 43 was obtained as a red oil (0.7 g, yield 50%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.23 (d, 2H), 7.14-7.10 (m, 2H), 5.32-5.23 (m, 1H), 4.89-4.80 (m, 1H), 3.86-3.73 ( m,1H), 3.71-3.67 (t, 2H), 3.35 (dd, 3H), 1.20 (d, 3H), 1.19-1.14 (m, 6H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 18.35 , 18.12. LC-MS m/z (ESI) = 316.1 [M+1].

Example 44

Benzyl (2S)-2-[[[[(Z)-C-[4-[[5-[(3-ethoxy-3-oxo-propyl)-(2-pyridyl))) Mercapto]-1-methyl-benzimidazol-2-yl]methylamino]phenyl]-N-hexyloxycarbonylimino]amino]-(methoxymethyl)phosphonium]amino] Propionate ( Compound 44 )

Benzyl (2S)-2-[[[[(Z)-C-[4-[[5-[(3-ethoxy-3-oxo-propyl)-(2-pyridyl)carbamoyl]-1-methyl-benzimidazol -2-yl]methylamino]phenyl]-N-hexoxycarbonyl-carbonimidoyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (0.23g, 1.4mmol) was dissolved in 20mL dry dichloromethane, nitrogen, -30 deg.] C was added dropwise triethylamine (0.29g, 2.9mmol), 44A ( A mixture of 0.6, 0.96 mmol) was reacted for 30 minutes after the completion of the dropwise addition, and L-alanine benzyl ester (0.51 g, 2.9 mmol) was added, and the mixture was reacted at room temperature for 2 h. Washed with 20mL of saturated sodium dihydrogen phosphate solution and once with 20mL saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, column chromatography, using dichloromethane / methanol = 100/1 do punch stripping agent, to give compound 44 .

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 10.01 (s, 1H), 8.45-8.39 (m, 1H), 7.72 (d, 1H), 7.55-7.52 (m, 2H), 7.38-7.28 (m, 7H) , 7.13 (d, 1H), 7.00-6.96 (m, 1H), 6.75-6.61 (m, 3H), 5.26 (t, 1H), 5.21-5.05 (m, 2H), 4.50 (d, 2H), 4.43 (t, 2H), 4.25-4.12 (m, 1H), 4.12-4.02 (m, 4H), 3.78-3.66 (m, 5H), 3.41 (dd, 3H), 3.37-3.25 (m, 1H), 2.81 (t, 2H), 1.67.1-55 (m, 2H), 1.46-1.37 (m, 3H), 1.37-1.24 (m, 6H), 1.24-1.18 (m, 3H), 0.89-0.86 (m, 3H) ³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.58. LC-MS m/z (ESI)

Example 45

Isopropyl (2S)-2-[[2-[4-[(E)-4-chloro-1,2-diphenyl-but-1-enyl]phenoxy]ethoxy-(A) Oxymethyl)phosphonium]amino]propionate ( Compound 45 )

Isopropyl(2S)-2-[[2-[4-[(E)-4-chloro-1,2-diphenyl-but-1-enyl]phenoxy]ethoxy-(methoxymethyl)phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (0.46g, 2.8mmol) was dissolved in 20mL dry dichloromethane, nitrogen, -30 deg.] C was added dropwise triethylamine (1.1g, 11mmol), 45A ( 1.1 A mixture of 2.8 mmol) was reacted for 30 minutes after the dropwise addition, and L-alanine isopropyl ester (0.37 g, 2.8 mmol) was added, and the mixture was reacted at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure, column chromatography, eluting with ethyl acetate / petroleum ether = 1/1 to 1/0 To give compound 45 as a white solid (1.0 g, yield 59%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.40 (t, 2H), 7.36-7.27 (m, 3H), 7.27-7.12 (m, 5H), 6.76 (dd, 2H), 6.70-6.56 (m, 2H), 5.23-5.16 (m, 1H), 4.88-4.82 (m, 1H), 4.20-4.05 (m, 2H), 4.06-3.95 (m, 2H), 3.87-3.72 (m, 1H), 3.62 3.48 (m, 2H), 3.43 (t, 2H), 3.27 (dd, 3H), 2.85 (t, 2H), 1.24-1.20 (m, 3H), 1.18-1.12 (m, 6H). ^{31 P NMR (162MHz, DMSO- d} 6) δ 26.72,26.14.LC-MS m / z (ESI) = 622.3 [M + 23].

Example 46

Isopropyl (2S)-2-[[[3-[[(1R,2R)-3-[(3S,4aS,8aS)-3-(T-butylaminomethylmethyl)-3,4, 4a,5,6,7,8,8 ^a octahydro-1H-isoquinolin-2-yl]-2-hydroxy-1-(phenylthiomethyl)propyl]carbamoyl]-2 -Methyl-phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 46 )

Isopropyl(2S)-2-[[[3-[[(1R,2R)-3-[(3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7 ,8,8a-octahydro-1H-isoquinolin-2-yl]-2-hydroxy-1-(phenylsulfanylmethyl)propyl]carbamoyl]-2-methyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (2.3 g, 14.1 mmol) was dissolved in 20 mL of dry dichloromethane, and then filtered, and then triethylamine (5.71 g, 56.5 mmol) was added dropwise at -30 ° C, L- A mixture of isopropyl alanate (1.85 g, 14.1 mmol) was reacted for 30 minutes after the dropwise addition, and 46A (1.87 g, 2.82 mmol) was added, and the mixture was reacted at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure, column chromatography, eluting with ethyl acetate / petroleum ether = 1 / 1 to 1 / 0 Agent. Compound 46 was obtained as a white solid (0.8 g, yield 7%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.06 (d, 1H), 7.54-7.41 (m, 3H), 7.39-7.31 (m, 1H), 7.27 (t, 2H), 7.21-7.09 (m, 3H), 5.78-5.61 (m, 1H), 4.91-4.84 (m, 1H), 4.83-4.79 (m, 1H), 4.38-4.28 (m, 1H), 3.99-3.81 (m, 2H), 3.80- 3.76 (m, 2H), 3.61-3.56 (m, 1H), 3.37 (dd, 3H), 3.20-3.14 (m, 1H), 2.95 (d, 1H), 2.58-2.52 (m, 1H), 2.24 ( d, 3H), 2.09-1.97 (m, 2H), 1.95-1.85 (m, 1H), 1.75-1.62 (m, 2H), 1.56-1.50 (m, 2H), 1.50-1.44 (m, 2H), 1.40-1.24 (m, 4H), 1.23 (d, 1H), 1.21 (d, 2H), 1.20-1.16 (m, 8H), 1.14 (s, 9H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.82, 24.06. LC-MS m/z (ESI) = 789.4 [M+1].

Example 47

Ethyl(2S)-2-[[[4-[[(3R,4R)-4-[(3,4-dimethoxyphenyl)methyl]-2-oxo-tetrahydrofuran-3-yl) ]methyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 47 )

Ethy (2S)-2-[[[4-[[(3R,4R)-4-[(3,4-dimethoxyphenyl)methyl]-2-oxo-tetrahydrofuran-3-yl]methyl]-2-methoxy-phenoxy ]-(methoxymethyl)phosphoryl]amino]propanoate

The starting material (methoxymethyl)phosphine ruthenium dichloride (0.984 g, 6.04 mmol) was dissolved in 20 mL of dry methylene chloride, and then filtered with nitrogen, and triethylamine (1.63 g, 16.1 mmol) was added dropwise at -30 ° C, 47A ( A mixture of 1.5 g, 4.03 mmol) was reacted for 30 min after the dropwise addition, and ethyl L-alaninate (1.42 g, 12.1 mmol) was added, and the mixture was reacted at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure, column chromatography, ethyl acetate / petroleum ether = 1/10~1 Compound 47 gave a colorless oil (1.5 g, yield 56%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.24-7.11 (m, 1H), 6.91 (dd, 1H), 6.82 (d, 1H), 6.73-6.70 (m, 1H), 6.67 (s, 1H) , 6.61-6.57 (m, 1H), 5.55-5.38 (m, 1H), 4.11-3.99 (m, 4H), 3.97-3.85 (m, 2H), 3.80-3.65 (m, 11H), 3.35 (dd, 3H), 2.92-2.88 (m, 1H), 2.85-2.72 (m, 2H), 2.52-2.46 (m, 2H), 1.18-1.12 (m, 6H). ³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 25.07, 24.38. LC-MS m/z (ESI) = 580.3 [M+1].

Example 48

Ethyl (2S)-2-[[[2-methoxy-4-[(E)-3-methoxy-3-oxo-prop-1-enyl]phenoxy]-(methoxy) Methyl)phosphonium]amino]propionate ( Compound 48 )

Ethyl(2S)-2-[[[2-methoxy-4-[(E)-3-methoxy-3-oxo-prop-1-enyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (3.52g, 21.60mmol) was dissolved in dichloromethane (20mL), the at -5 deg.] C, was added 48A (3.00g, 14.41mmol) and triethylamine (4.37 g of , a solution of a mixture of 43.19 mmol) in dichloromethane (10 mL). After stirring at this temperature for 30 min, L-alanine ethyl ester (5.06 g, 43.19 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (30 mL) was added and washed with a saturated solution of sodium dihydrogen phosphate (30 mL) and a saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. purification (ethyl acetate / petroleum ether = (v / v) 4/ 1 ~ 1/1) to give compound 48, to give a yellow oil (1.2g, yield 20.05%).

Compound 48 was separated to give compound 48-a (380mg retention time 5.81min, ee% = 100%) , as a pale yellow oil, compound 48-b (380mg, retention time 6.99min, ee% = 99.7%) , pale Yellow oil. Separation conditions: experimental equipment: MG II preparative SFC (SFC-13); chromatography column: Chiral Pak AD, 250 × 30 mm ID, 5 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 40 %; flow rate: 50 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period : ~7 min.

Compound 48-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.62 (d, 1H), 7.37-7.30 (m, 1H), 7.08 (d, 2H), 6.36 (d, 1H), 4.26-4.03 (m, 3H), 3.91 (d, 3H), 3.89-3.85 (m, 1H), 3.83-3.77 (m, 4H), 3.49 (d, 4H), 1.35 (d, 3H), 1.24-1.20 (m, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 25.03. LC-MS m/z (ESI) = 416.1 [M+1].

Compound 48-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.65 (d, 1H), 7.38-7.35 (m, 1H), 7.18-7.02 (m, 2H), 6.38 (d, 1H), 4.23-4.05 (m, 3H) , 3.96-3.90 (m, 4H), 3.82 (d, 3H), 3.74-3.68 (m, 1H), 3.54 (d, 3H), 3.50 (s, 1H), 1.29-1.22 (m, 6H). 31 P NMR (162 MHz, CDCl ₃ ) δ 25.62. LC-MS m/z (ESI) = 416.2 [M+1].

Example 49

(S)-Isopropyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxy-3,4,12,14-tetra-1H-pyridyl) [[',4':6,7]pyridazine[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 49 )

(S)-isopropyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4' :6,7]indolizino[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate.

(Methoxymethyl)phosphine dichloride (5 g, 30.69 mmol) was dissolved in dichloromethane (50 mL), and isopropyl L-alanine (4.00 g, 30.49 mmol) was slowly added dropwise at -30 °C. A solution of a mixture of triethylamine (7.75 g, 76.63 mmol) in dichloromethane (20 mL). After stirring at this temperature for 30 min, 49A (6 g, 15.29 mmol) was then evaporated. After cooling to room temperature, dichloromethane (100 mL) was added, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen sulfate (50 mL) and a saturated solution of sodium carbonate (50 mL×3), dried over anhydrous sodium sulfate and evaporated. ( Compound 49 ) (9 g, yield 95.93%). Compound 49 was isolated: Compound 49-a (4 g retention time 3.83 min, ee% = 100%), pale yellow solid; Compound 49-b (2 g, </ RTI></RTI> 9.96 min, ee% = 99.4%), pale yellow solid . Separation conditions: Instrument: Thar 350 preparative SFC (SFC-6); column: ChiralPak AD, 300 x 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is isopropanol; gradient: B 50% Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period : ~9 min.

Compound 49-a

^{1 H NMR (400MHz, CDCl3)} δ 8.25 (d, 1H), 7.99 (s, 1H), 7.79-7.62 (m, 2H), 5.73 (d, 1H), 5.37-5.24 (m, 3H), 5.05- 4.90 (m, 1H), 4.23-4.09 (m, 1H), 3.92-3.90 (m, 2H), 3.78-3.70 (m, 1H), 3.54 (d, 3H), 3.20-3.16 (m, 2H), 1.92-1.84 (m, 2H), 1.44-1.30 (m, 6H), 1.22-1.20 (m, 6H), 1.03 (t, 3H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 25.17. LC-MS m /z(ESI)=614.2[M+1].

Compound 49-b

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, 1H), 8.04-7.97 (m, 1H), 7.70-7.65 (m, 2H), 5.73 (d, 1H), 5.33-5.23 (m, 3H) , 5.03-4.96 (m, 1H), 4.22-4.10 (m, 1H), 3.92-3.84 (m, 3H), 3.49 (d, 3H), 3.20-3.14 (m, 2H), 1.92-1.87 (m, 2H), 1.41-1.35 (m, 6H), 1.24-1.18 (m, 6H), 1.03 (t, 3H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.32. LC-MS m/z (ESI) = 614.2 [M+1].

Example 50

Isopropyl (2S)-2-[[[4-[[(3R,4R)-4-[(3,4-dimethoxyphenyl)methyl]-2-oxo-tetrahydrofuran-3- Methyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 50 )

Isopropyl(2S)-2-[[[4-[[(3R,4R)-4-[(3,4-dimethoxyphenyl)methyl]-2-oxo-tetrahydrofuran-3-yl]methyl]-2-methoxy- Phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate.

(Methoxymethyl)phosphonium dichloride (1.31 g, 8.06 mmol) was dissolved in dichloromethane (10 mL), at -10 ° C, 47A (2.00 g, 5.37 mmol) and triethylamine (2.17 g) , 21.48 mmol) of a mixture of dichloromethane (10 mL)). After stirring at this temperature for 30 min, L-alanine isopropyl ester (2.11 g, 16.11 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (30 mL) was added and washed with a saturated solution of sodium dihydrogen phosphate (30 mL) and a saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Separation and purification (ethyl acetate / petroleum ether = (v / v) 5 / 1 to 1 / 1) gave Compound 50 as pale yellow oil (1.6 g, yield 50.19%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.24 (d, 1H), 6.78-6.76 (m, 2H), 6.64 (t, 1H), 6.57-6.52 (m, 2H), 5.06-4.82 (m, 1H) , 4.3-4.00 (m, 2H), 3.95-3.71 (m, 13H), 3.49 (d, 3H), 2.96-2.94 (m, 2H), 2.72-2.43 (m, 4H), 1.31 (d, 2H) , 1.24-1.14 (m, 7H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.52, 24.82. LC-MS m/z (ESI) = 594.3 [M+1].

Example 51

Isopropyl-(2S)-2-[[[4-[(E)-2-[3,5-bis[[[[(1)] Oxoethyl]amino]-(methoxymethyl)phosphonium]oxy]phenyl]vinyl]phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 51 )

Isopropyl(2S)-2-[[[4-[(E)-2-[3,5-bis[[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]- (methoxymethyl)phosphoryl]oxy]phenyl]vinyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (2 g, 12.27 mmol) was dissolved in dichloromethane (20 mL), and isopropyl L-alanine (1.6 g, 12.20 mmol) was slowly added dropwise at -30 °C. A solution of a mixture of triethylamine (4 g, 39.55 mmol) in dichloromethane (10 mL). After stirring at this temperature for 30 min, 51A (0.5 g, 2.20 mmol) was then evaporated. After cooling to room temperature, dichloromethane (50 mL) was added, and respectively, a saturated solution of sodium dihydrogen phosphate (50 mL) and a saturated solution of sodium chloride (50 mL) were successively washed, dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by column chromatography (ethyl acetate / petroleum ether = (v/v) 5/1 to 1 / 1) gave Compound 51 as a yellow oil (1 g, yield 50.97%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.44 (d, 2H), 7.25-7.22 (m, 4H), 7.10-7.00 (m, 2H), 6.91 (d, 1H), 5.07-4.93 (m, 3H) , 4.15-4.05 (m, 3H), 3.90-3.78 (m, 6H), 3.78-3.52 (m, 3H), 3.50 (d, 3H), 3.46-3.38 (m, 6H), 1.35-1.31 (m, 9H), 1.25-1.21 (m, 18H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 24.51, 24.49, 24.16, 23.53, 23.45, 23.24. LC-MS m/z (ESI) = 446.6 [M/2+ 1].

Example 52

Isopropyl (2S)-2-[[(4-allyl-2-methoxy-phenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 52 )

Isopropyl (2S)-2-[[(4-allyl-2-methoxy-phenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (2.22g, 13.62mmol) was dissolved in dichloromethane (20mL) in, at -20 deg.] C, was added 52A (1.5g, 9.14mmol) and triethylamine (4.05 g of , 40.05 mmol) of a mixture of dichloromethane (10 mL)). After stirring at this temperature for 30 min, L-alanine isopropyl ester (3.50 g, 26.68 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (50 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (30 mL) and a saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. purification (ethyl acetate / petroleum ether = (v / v) 10/ 1 ~ 1/1), to give compound 52 as a pale yellow oil (2g, 56.81% yield), isolated compound 52 to give compound 52 -a (0.6 g retention time 3.81 min, ee% = 100%), light yellow oil; compound 52-b (0.5 g, </ RTI></RTI> 5.05 min, ee% = 100%), pale yellow oil. Separation conditions: Instrument: Thar 200 preparative SFC (SFC-5); chromatography column: ChiralPak AS, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 35%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period : ~5 min.

Compound 52-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.22 (dd, 1H), 6.73 (dd, 2H), 6.00-5.82 (m, 1H), 5.12-5.07 (m, 1H), 5.06-5.04 (m, 1H) , 5.01-4.95 (m, 1H), 4.10-4.02 (m, 1H), 3.91-3.82 (m, 5H), 3.72-3.64 (m, 1H), 3.51 (d, 3H), 3.34 (d, 2H) , 1.26-1.16 (m, 9H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 25.36. LC-MS m/z (ESI)= 386.1 [M+1].

Compound 52-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.22 (dd, 1H), 6.74 (s, 1H), 6.71 (dd, 1H), 6.17-5.74 (m, 1H), 5.11-5.07 (m, 1H), 5.05 (d, 1H), 4.98-4.92 (m, 1H), 4.17-3.98 (m, 1H), 3.93-3.76 (m, 6H), 3.49 (d, 3H), 3.34 (d, 2H), 1.32 (d) , 3H), 1.20-1.18 (m, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.79. LC-MS m/z (ESI) = 386.1 [M+1].

Example 53

Isopropyl (2S)-2-[[[2-methoxy-4-[(E)-3-methoxy-3-oxo-prop-1-enyl]phenoxy]-(A) Oxymethyl)phosphonium]amino]propionate ( compound 53 )

Isopropyl(2S)-2-[[[2-methoxy-4-[(E)-3-methoxy-3-oxo-prop-1-enyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (1.17g, 7.18mmol) was dissolved in dichloromethane (10 mL) in at -20 deg.] C, was added 48A (1g, 4.80mmol) and triethylamine (1.81 g of, A solution of 17.90 mmol) of dichloromethane (10 mL)). After stirring at this temperature for 30 min, L-alanine isopropyl ester (1.88 g, 14.34 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (50 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (30 mL) and a saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Separation and purification (ethyl acetate / petroleum ether = (v/v) 8/1 to 1/1) gave Compound 53 as pale yellow oil (1 g, yield 48.52%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.62 (d, 1H), 7.36-7.32 (m, 1H), 7.10-7.06 (m, 2H), 6.36 (dd, 1H), 5.03-4.87 (m, 1H) , 4.17-4.03 (m, 1H), 3.94-3.84 (m, 5H), 3.82-3.57 (m, 4H), 3.51 (dd, 3H), 1.33 (d, 2H), 1.24-1.15 (m, 7H) ³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.57, 25.07. LC-MS m/z (ESI)=430.1[M+1].

Example 54

Isopropyl (2S)-2-[[methoxymethyl-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]benzene) Oxy]phosphonium]amino]propionate ( Compound 54 )

Isopropyl(2S)-2-[[methoxymethyl-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenoxy]phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (1.54g, 9.48mmol) was dissolved in dichloromethane (20mL) in, at -20 deg.] C, was added 54A (2g, 6.32mmol) and triethylamine (2.56 g of, A solution of 25.28 mmol) of the mixture in dichloromethane (10 mL). After stirring at this temperature for 30 min, L-alanine isopropyl ester (2.48 g, 18.91 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (50 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (30 mL) and a saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Isolation and purification (ethyl acetate / petroleum ether = (v/v) 10:1 to 1:1) gave compound 54 as pale yellow oil (2 g, yield 58.88%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.25-7.23 (m, 1H), 7.08-7.04 (m, 1H), 6.78 (d, 1H), 6.48 (d, 2H), 6.44 (d, 2H), 5.05 -4.95 (m, 1H), 4.14 - 4.00 (m, 1H), 3.90-3.77 (m, 9H), 3.69 (d, 6H), 3.48 (dd, 3H), 1.32 (d, 2H), 1.25-1.18 (m, 7H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.29, 24.67. LC-MS m/z (ESI)=538.2[M+1].

Example 55

Isopropyl (2S)-2-[[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7, 8,9,11,12,14,15-Decahydro-1H-cyclopenta[a]phenanthr-3-yl]oxy-(methoxymethyl)phosphonium]amino]propionate ( Compound 55 )

Isopropyl(2S)-2-[[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9, 11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (1.40g, 8.59mmol) was dissolved in dichloromethane (20mL) in, at -20 deg.] C, was added 55A (2g, 5.72mmol) and triethylamine (2.32 g of, A solution of the mixture of 22.90 mmol) in dichloromethane (10 mL). After stirring at this temperature for 30 min, L-alanine isopropyl ester (2.25 g, 17.15 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (50 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (30 mL) and a saturated aqueous solution of sodium chloride (30 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Separation and purification (ethyl acetate / petroleum ether = (v/v) 3/1 - 1/2) gave Compound 55 as pale yellow oil (1.2 g, yield: 36.76%). Compound 55 was separated to give compound 55-a (350mg retention time 2.17min, ee% = 100%) , as a pale yellow oil; Compound 55-b (300mg, retention time 2.80min, ee% = 100%) , a pale Yellow oil. Separation conditions: Instrument: MG II preparative SFC (SFC-13); column: ChiralCel OD, 250 × 30 mm ID, 5 μm.; Mobile phase: Phase A is CO ₂ and Phase B is isopropanol; Gradient: B 40 %; flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period : ~ 5.3 min.

Compound 55-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.62 (s, 1H), 8.46 (d, 1H), 7.67 (d, 1H), 7.26-7.19 (m, 1H), 6.00 (dd, 1H), 5.42 (d , 1H), 5.11-4.89 (m, 1H), 4.45-4.21 (m, 1H), 4.09-3.91 (m, 1H), 3.73-3.61 (m, 2H), 3.42 (d, 3H), 3.25 (t , 1H), 2.54-2.42 (m, 2H), 2.26-2.24 (m, 1H), 2.11-2.00 (m, 3H), 1.82-1.40 (m, 8H), 1.37 (d, 3H), 1.25 (t , 7H), 1.18-1.01 (m, 8H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.30. LC-MS m/z (ESI) = 571.5 [M+1].

Compound 55-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.63 (s, 1H), 8.48 (d, 1H), 7.77 (d, 1H), 7.33 (dd, 1H), 6.13-5.97 (m, 1H), 5.39 (d , 1H), 5.07-5.01 (m, 1H), 4.40-4.21 (m, 1H), 4.11-3.97 (m, 1H), 3.69-3.65 (m, 2H), 3.45 (s, 3H), 3.29 (t , 1H), 2.50-2.36 (m, 2H), 2.31-2.25 (m, 1H), 2.11-2.01 (m, 3H), 1.88-1.42 (m, 8H), 1.42 (t, 3H), 1.26 (t , 7H), 1.14-1.01 (m, 8H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 24.98. LC-MS m/z (ESI) = 571.5 [M+1].

Example 56

(E)-3-[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium] Oxy-3-methoxy-phenyl]prop-2-enoic acid ( compound 56 )

(E)-3-[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-3-methoxy-phenyl]prop-2- Enoic acid

(Methoxymethyl)phosphine dichloride (2.52 g, 15.47 mmol) was dissolved in dichloromethane (20 mL), and isopropyl L-alanine (2.03 g, 15.48) was slowly added dropwise at -30 °C. A mixture of mmol) and triethylamine (4 g, 39.55 mmol) in dichloromethane (10 mL). After stirring at this temperature for 30 min, 56A (1.5 g, 7.72 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (50 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (50 mL) and a saturated aqueous solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Separation and purification (ethyl acetate / petroleum ether = (v/v) 1/2~3/1) gave Compound 56 as a yellow oil (0.5 g, yield 15.59%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.65 (dd, 1H), 7.42-7.32 (m, 1H), 7.12-7.08 (m, 2H), 6.34 (dd, 1H), 5.03-4.90 (m, 1H) , 4.17-4.06 (m, 1H), 4.05-3.76 (m, 6H), 3.52 (dd, 3H), 1.36-1.18 (m, 9H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 26.06, 25.66. -MS m/z (ESI) = 416.2 [M+1].

Example 57

Isopropyl (2S)-2-[[[4-[4-[6-amino-5-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]] -3-pyridyl]pyrazol-1-yl]-1-acridinyl]-(methoxymethyl)phosphonium]amino]propionate ( Compound 57 )

Isopropyl(2S)-2-[[[4-[4-[6-amino-5-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]pyrazol -1-yl]-1-piperidyl]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphine dichloride (1.62 g, 9.94 mmol) was dissolved in dichloromethane (20 mL), and isopropyl L-alanine (1.30 g, 9.99) was slowly added dropwise at -30 °C. A mixture of mmol) and triethylamine (4 g, 39.55 mmol) in dichloromethane (10 mL). After stirring at this temperature for 30 min, 57A (1.5 g, 3.33 mmol) was then evaporated. After cooling to room temperature, dichloromethane (50 mL) was added, and respectively, a saturated solution of sodium dihydrogen phosphate (50 mL) and a saturated solution of sodium chloride (50 mL) were successively washed, dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by column chromatography (dichloromethane / methanol = (v/v) 100/1~30/1) gave Compound 57 as pale yellow solid (0.55 g, yield: 24.60%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.74 (d, 1H), 7.56 (d, 1H), 7.48 (d, 1H), 7.33-7.29 (m, 1H), 7.05 (t, 1H), 6.88 (d , 1H), 6.10-6.05 (m, 1H), 5.06-5.00 (m, 1H), 4.89 (s, 2H), 4.30-4.12 (m, 1H), 4.10-3.90 (m, 1H), 3.90-3.75 (m, 2H), 3.75-3.62 (m, 2H), 3.52-3.32 (m, 4H), 2.90-2.84 (m, 2H), 2.14-2.10 (m, 2H), 1.96-1.78 (m, 5H) , 1.13 (dd, 3H), 1.25 (d, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.20, 23.70. LC-MS m/z (ESI) = 67 I.1 [M+1].

Example 58

(2S)-isopropyl 2-(((((4(4,4,4,7,7,5,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,4,5,6,7,7,4,4,5,6,7, 7a-octahydro-1H-4,12-methyl benzofuran [3,2-e]isoquinolin-9-yl)oxy)(methoxymethyl)phosphonium)amino)propanoic acid Ester ( compound 58 )

(2S)-isopropyl 2-((((((((((((((((((((((((((((((((((((((((((())))))))))))))) -1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphine dichloride (0.52 g, 3.16 mmol) was dissolved in dichloromethane (10 mL), and isopropyl L-alanine (0.37 g, 2.85) was slowly added dropwise at -30 °C. A mixture of mmol) and triethylamine (0.64 g, 6.33 mmol) in dichloromethane (5 mL). After stirring at this temperature for 30 min, 58A (0.26 g, 0.79 mmol) was then evaporated. After cooling to room temperature, dichloromethane (20 mL) was added, and respectively, a saturated solution of sodium dihydrogen phosphate (20 mL) and a saturated solution of sodium chloride (20 mL) were successively washed, dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by column chromatography (dichloromethane/methanol = (v/v) 100/1~30/1) gave Compound 58 as pale yellow oil (0.06 g, yield 13.84%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.10 (dd, 1H), 6.67 (dd, 1H), 5.94-5.74 (m, 1H), 5.23 (t, 2H), 5.08-4.95 (m, 1H), 4.73 (d, 1H), 4.25-3.74 (m, 4H), 3.54 (dd, 3H), 3.30-2.89 (m, 5H), 2.64-2.58 (m, 2H), 2.46-2.36 (m, 1H), 2.32 -2.22 (m, 1H), 2.16-2.10 (m, 1H), 2.05-1.85 (m, 2H), 1.62-1.51 (m, 2H), 1.38-1.31 (m, 2H), 1.26-1.20 (m, 7H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 26.58, 25.94. LC-MS m/z (ESI) = 549.3 [M+1].

Example 59

Isopropyl (2S)-2-[[[4-(2-acetoxy-5-allyl-phenyl)-2-allyl-phenoxy]-(methoxymethyl) Phosphonic]amino]propionate ( compound 59 )

Isopropyl (2S)-2-[[[4-(2-acetoxy-5-allyl-phenyl)-2-allyl-phenoxy]-(methoxymethyl)phosp Horyl]amino]propanoate

59A (1g, 3.75mmol) was dissolved in dichloromethane (20mL). Ethyl chloride (0.3g, 3.82mmol) was slowly added dropwise at 0 ° C. After the addition was completed, the mixture was warmed to room temperature and stirred for 30 min. (30 mL), respectively, washed with a 1% sodium hydroxide solution (20 mL×3) and a saturated solution of sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by chromatography (ethyl acetate / petroleum ether = (v/v) 1/10 to 4/1) gave Compound 59B (yield:

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.24 (s, 1H), 7.20-7.12 (m, 2H), 7.08 (d, 1H), 6.98 (dd, 1H), 6.82 (dd, 2H), 6.04 - 5.86 (m, 2H), 5.17 - 4.96 (m, 4H), 3.39 (d, 2H), 3.27 (t, 2H), 1.99 (s, 3H). LC-MS m/z (ESI) = 309.1 [ M+1].

(Methoxymethyl)phosphine dichloride (0.48 g, 2.92 mmol) was dissolved in dichloromethane (10 mL), and isopropyl L-alanine (0.38 g, 2.92) was slowly added dropwise at -30 °C. A solution of a mixture of mmol) and triethylamine (0.78 g, 7.78 mmol) in dichloromethane (5 mL). After stirring at this temperature for 30 min, compound 59B (0.30 g, 0.9. After cooling to room temperature, dichloromethane (20 mL) was added, and respectively, a saturated solution of sodium dihydrogen phosphate (20 mL) and a saturated solution of sodium chloride (20 mL) were successively washed, dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by column chromatography (ethyl acetate / petroleum ether = (v/v) 1 / 6 - 3 / 1) gave Compound 59 as pale yellow oily liquid (0.2 g, yield 38.82%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.36 (d, 1H), 7.14 (d, 2H), 7.09-6.97 (m, 3H), 6.13-5.72 (m, 1H), 5.11-4.95 (m, 4H) , 4.93-4.76 (m, 1H), 3.90-3.70 (m, 1H), 3.66-3.22 (m, 7H), 3.21-3.02 (m, 3H), 2.02-1.91 (m, 3H), 1.23-1.17 ( m, 1H), 1.14-1.03 (m, 8H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 24.90, 23.91. LC-MS m/z (ESI)=530.2[M+1].

Example 60

(E)-6-[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium] Oxy-6-methoxy-7-methyl-3-oxo-1H-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid ( Compound 60 )

(E)-6-[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-6-methoxy-7-methyl-3- oxo-1H-isobenzofuran-5-yl]-4-methyl-hex-4-enoicacid

(Methoxymethyl)phosphine dichloride (1.5 g, 9.21 mmol) was dissolved in dichloromethane (20 mL), and isopropyl L-alanine (1.21 g, 9.21) was slowly added dropwise at -30 °C. A solution of a mixture of mmol) and triethylamine (3.03 g, 29.96 mmol) in dichloromethane (5 mL). After stirring at this temperature for 30 min, 60A (1 g 3.12 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (20 mL) was added and washed with a saturated aqueous solution of sodium hydrogen sulfate (20 mL) and a saturated aqueous solution of sodium chloride (20 mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Separation and purification (dichloromethane/methanol = (v/v) 100/1~30/1) gave Compound 60 as a pale yellow oily liquid (0.2 g, yield 11.84%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.27-5.13 (m, 3H), 5.05-4.80 (m, 1H), 4.74-4.66 (m, 1H), 4.17-3.92 (m, 3H), 3.82-3.69 ( m, 4H), 3.58-3.39 (m, 4H), 2.42 (t, 2H), 2.29 (t, 2H), 2.23 - 2.14 (m, 3H), 1.79 (s, 3H), 1.37 (d, 2H) , 1.28-1.19 (m, 3H), 1.12 (d, 2H), 1.08 (d, 2H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 27.24, 26.30. LC-MS m/z (ESI) = 542.3 [ M+1].

Example 61

(2S)-2,2,2-trifluoroethyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 61 )

(2S)-2,2,2-trifluoroethyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

First step: 2,2,2-trifluoroethyl(2S)-2-(t-butoxycarbonylamino)propionate ( 61B )

2,2,2-trifluoroethyl(2S)-2-(tert-butoxycarbonylamino)propanoate

61A (15g, 79.277mmol) was suspended in 100 mL of dichloromethane, trifluoroethanol (8.7240 g, 87.205 mmol), 4-dimethylaminopyridine (14.528 g, 118.92 mmol) and 1-(3-dimethylaminopropyl). 3-ethylcarbodiimide hydrochloride (22.796 g, 118.92 mmol), stirred at room temperature for 2 h. Wash with saturated aqueous sodium dihydrogen phosphate solution (50 mL×2), wash once with 50 mL of brine, dried over anhydrous sodium sulfate A solvent was obtained to obtain 61B as a colorless oil (15 g, yield 69.760%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.96 (s, 1H), 4.61 (d, 1H), 4.40 (d, 2H), 1.45 (s, 9H), 1.43 (d, 3H). LC-MS m/ z=294.1 [M+23].

Second step: 2,2,2-trifluoroethyl(2S)-2-aminopropionate hydrochloride ( 61C )

2,2,2-trifluoroethyl(2S)-2-aminopropanoatehydrochloride

61B (15 g, 55.3 mmol) was dissolved in 50 mL of ethyl acetate. Direct filtration gave 61 C , white solid (10 g, yield 87.1%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.75 (s, 3H), 5.08-4.72 (m, 2H), 4.25 (d, 1H), 1.46 (d, 3H) .LC-MS m / z = 172.0 [M+1].

The third step: (2S)-2,2,2-trifluoroethyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propanoic acid Ester ( compound 61 )

(2S)-2,2,2-trifluoroethyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphine dichloride (5.0 g, 30.6 mmol) was dissolved in 100 mL of dichloromethane, and propofol (5.4 g, 30.6 mmol) and three were added dropwise at -10 ° C under nitrogen. A solution of ethylamine (12.4 g, 122.7 mmol) in 20 mL of dichloromethane was added and the mixture was stirred at room temperature for 1 hour. Was added and 61C (12.7g, 61.3mmol) at this temperature, the reaction at room temperature for two hours. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (500 mL), and the organic layer was dried over anhydrous sodium sulfate, and the residue was purified and purified with EtOAc (EtOAc) 1) Compound 61 was obtained as a yellow oil (5 g, yield 37.8%).

LC-MS m/z = 440.2 [M + 1].

Compound 61 (5 g) was dissolved in 120 mL of methanol for chiral preparation to afford two optical isomer compounds 61-a (2.23 g, white solid, retention time 2.19 min, ee% = 100%) and compound 61 -b (2.66 g, colorless oil, retention time 7.17 min, ee% = 99.877%). Preparation conditions: instrument: MG II preparative SFC (SFC-13); chromatography column: ChiralPak AS, 250 × 30 mm ID, 5 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 40%; Flow rate: 40 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~6 min; injection: 3 mL per injection.

Compound 61-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.13 (s, 3H), 4.61-4.56 (m, 1H), 4.42-4.36 (m, 1H), 4.32-4.17 (m, 1H), 4.05-3.77 (m, 2H), 3.58-3.43 (m, 5H), 3.33 (t, 1H), 1.23-1.21 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.34. LC-MS m/z = 440.2 [M + 1].

Compound 61-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.13 (s, 3H), 4.61-4.56 (m, 1H), 4.42-4.36 (m, 1H), 4.28-4.23 (m, 1H), 3.95-3.86 (m, 2H), 3.55-3.48 (m, 5H), 3.33 (t, 1H), 1.23-1.21 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.21. LC-MS m/z = 440.2 [M + 1].

Example 62

[(2S)-2-[[(2,6-Diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propanyl]oxymethyl 2,2-dimethyl Propionate ( compound 62 )

[(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoyl]oxymethyl 2,2-dimethylpropanoate

First step: [(2S)-2-(t-butoxycarbonylamino)propanyl]oxymethyl 2,2-dimethylpropionate ( 62A )

[(2S)-2-(tert-butoxycarbonylamino)propanoyl]oxymethyl 2,2-dimethylpropanoate

61A (12.0 g, 63.4 mmol), methyl iodide (18.4 g, 76.1 mmol) and potassium carbonate (17.5 g, 126.8 mmol) were added to 200 mL of N,N-dimethylformamide. The temperature was reacted for 8 hours. The reaction solution was added to 200 mL of water, and extracted with ethyl acetate (100 mL×3). The organic phase was combined and washed once with 100 mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography. : ethyl acetate (v / v) = 50:1 ~ 5:1) to give 62A , colorless oil (12g, yield 62.3%).

LC-MS m/z = 326.1 [M+23]

Second step: [(2S)-2-aminopropionyl]oxymethyl 2,2-dimethylpropionate hydrochloride ( 62B )

[(2S)-2-aminopropanoyl]oxymethyl 2,2-dimethylpropanoate hydrochloride

The 62A (12.0g, 39.6mmol), was dissolved in 100mL of ethyl acetate, hydrogen chloride gas at room temperature through the reaction for 4 hours, the precipitated white solid was filtered, dried under reduced pressure to give 62B, as a white solid (8.8 g of, Yield 93.6%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.75 (s, 3H), 5.86 (d, 1H), 5.77 (d, 1H), 4.14-4.12 (m, 1H), 1.41 (d, 3H), 1.16 (s, 9H).

The third step: [(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propanyl]oxymethyl 2, 2-dimethylpropionate ( compound 62 )

[(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoyl]oxymethyl 2,2-dimethylpropanoate

(Methoxymethyl)phosphine dichloride (5.0 g, 30.6 mmol) was dissolved in 100 mL of dichloromethane, and propofol (5.4 g, 30.6 mmol) and three were added dropwise at -10 ° C under nitrogen. A solution of ethylamine (12.4 g, 122.7 mmol) in 20 mL of dichloromethane was added and the mixture was stirred at room temperature for 1 hour. 62B (8.8 g, 36.8 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (500 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated ~ 1:1) Compound 62 was obtained as a yellow oil (5 g, yield: 34.5%).

LC-MS m/z = 472.2 [M+1].

4.5 g of compound 62 were isolated to give two optical isomer compounds 62-a (1.5 g, colorless oil, retention time 2.71 min, ee% = 100%), compound 62-b (2.0 g, yellow oil) Material, residence time 5.59min, ee% = 100%). Preparation conditions: instrument: Thar 200 preparative SFC (SFC-5); chromatography column: ChiralPak AS, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is methanol; gradient: B 30%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~4 min; sample preparation: dissolve the compound in ~150 mL methanol / dichloromethane; injection: 14 mL / injection.

Compound 62-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.83 (d, 1H), 5.71 (d, 1H), 4.22-4.16 (m, 1H), 4.01-3.84 (m, 2H), 3.59 - 3.31 (m, 6H), 1.28-1.04 (m, 24H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.48. LC-MS m/z = 472.2 [M+1].

Compound 62-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.75 (d, 1H), 5.65 (d, 1H), 4.34-4.02 (m, 1H), 3.93-3.79 (m, 2H), 3.62 -3.33 (m, 6H), 1.36 (d, 3H), 1.31-1.04 (m, 21H). ³¹ P NM [R (162 MHz, CDCl ₃ ) δ 21.36. LC-MS m/z = 472.2 [M+1].

Example 63

(2S)-2-methoxyethyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 63 )

(2S)-2-methoxyethyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

First step: (S)-2-methoxyethyl 2-((t-butoxycarbonyl)amino)propionate ( 63B )

(S)-2-methoxyethyl 2-((tert-butoxycarbonyl)amino)propanoate

Dichloromethane (10 rmL) was added to 61A (2 g, 10.57 mmol), then ethyl acetate monomethyl ether (1.21, 15.86 mmol), DMAP (1.94, 15.96 mmol) and EDCI (3.06 g, 15.96 mmol), nitrogen The mixture was stirred at room temperature overnight under protection. Ethyl acetate (30 mL) was added, and brine (10 mL×3) was washed. The organic layer was dried and concentrated, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = (v / v) 1/ 10 ~ 4/1), to give 63B, as a yellow oil (2.4 g of, producing The rate is 91.81%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.09 (s, 1H), 4.42-4.11 (m, 3H), 3.60 (t, 2H), 3.38 (s, 3H), 1.45 (s, 9H), 1.40 (d , 3H). LC-MS m/z = 270.1 [M+23].

Step 2: (S)-2-Methoxyethyl 2-aminopropionate hydrochloride ( 63C )

(S)-2-methoxyethyl 2-aminopropanoate hydrochloride

The compound 63B (38 g, 153.67 mmol) was dissolved in ethyl acetate (300 mL). 63C (26g, yield 92.14%).

_{1H NMR (400MHz, CDCl 3)} δ 8.70 (s, 3H), 4.52-4.21 (m, 3H), 3.63 (t, 2H), 3.38 (s, 3H), 1.73 (d, 3H). LC-MS m/z = 148.1 [M+1].

The third step: (2S)-2-methoxyethyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionate ( compound) 63 )

(2S)-2-methoxyethyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphine dichloride (5.0 g, 30.6 mmol) was dissolved in 100 mL of dichloromethane, and propofol (5.4 g, 30.6 mmol) and three were added dropwise at -10 ° C under nitrogen. A solution of ethylamine (12.4 g, 122.7 mmol) in 20 mL of dichloromethane was added and the mixture was stirred at room temperature for 1 hour. At this temperature, 63 C (6.7 g, 36.8 mmol) was added. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (500 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated ~1:1) gave compound 63 as a yellow oil (4 g, yield 31.7%).

LC-MS m/z = 416.2 [M+1].

Preparation of chiral compounds taken 63 (4g) to give the two optical isomers of the compounds 63-a (1.5g, as a colorless oil, retention time 3.58min, ee% = 100%) , compound 63-b (2.0 g, colorless oil, residence time 5.53 min, ee% = 100%). Preparation conditions: Instrument: Thar 350 preparative SFC (SFC-6); Column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; Mobile phase: Phase A is CO ₂ and Phase B is isopropanol; Gradient: B 30 %; flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~6 min; sample preparation: the compound was dissolved in ~100 mL of methanol; injection: 15 mL / injection.

Compound 63-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.37-4.11 (m, 3H), 3.96-3.85 (m, 2H), 3.62-3.39 (m, 8H), 3.36 (s, 3H) , 1.300-1.09 (m, 15H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 22.61. LC-MS m/z = 416.2 [M+1].

Compound 63-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.33-4.07 (m, 3H), 3.93-3.79 (m, 2H), 3.63-3.41 (m, 8H), 3.35 (s, 3H) , 1.39 (d, 3H), 1.23-1.20 (m, 12H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.51. LC-MS m/z = 416.2 [M+1].

Example 64

(2S)-Ethyl 3-acetoxy-2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 64 )

(2S)-ethyl 3-acetoxy-2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

First step: (S)-ethyl 2-amino-3-hydroxypropionate ( 64B )

(S)-ethyl 2-amino-3-hydroxypropanoate

64A (10.0g, 95.1mmol) was dissolved in 100mL of ethanol, and the hydrazine chloride (22.6g, 190.3mmol) was added dropwise under ice bath. After the dropwise addition, the reaction was carried out at 70 ° C for 8 hours, concentrated, and the crude product was dissolved. The pH was adjusted to 9 with potassium carbonate in 100 mL of water. Extracted with ethyl acetate (200mL × 3) and the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to give the compound 64B is, as a colorless oil (10g, 78.9% yield).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.30-4.10 (m, 2H), 3.82-3.79 (m, 1H), 3.77-3.64 (m, 1H), 3.57-3.55 (m, 1H), 2.42 (s, 3H), 1.37-1.17 (m, 3H). LC-MS m/z = 134.1 [M + 1].

Second step: (S)-ethyl 2-((t-butoxycarbonyl)amino)-3-hydroxypropionate ( 64C )

(S)-ethyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate

64B (10.0 g, 75.1 mmol) was dissolved in 100 mL of dichloromethane, and triethylamine (22.7 g, 225.3 mmol) was added at room temperature, then dibutyl succinate (16.3 g, 75.1) was added dropwise. Mm). Rt overnight and washed with saturated sodium dihydrogen phosphate solution was washed with 100mL reaction solution was separated, dried over anhydrous sodium sulfate, and concentrated to give 64C, as a colorless oil (15g, 85.6% yield).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.48 (s, 1H), 4.33 (d, 1H), 4.28-4.21 (m, 2H), 3.96-3.89 (m, 2H), 2.44 (s, 1H), 1.46 (d, 9H), 1.29 (dd, 3H). LC-MS m/z = 256.2 [M+23].

Step 3: (S)-Ethyl-3-ethoxycarbonyl-2-((t-butoxycarbonyl)amino)propionate ( 64D )

(S)-ethyl3-acetoxy-2-((tert-butoxycarbonyl)amino)propanoate

The 64C (15.0g, 64.3mmol) was dissolved in 100mL methylene chloride and triethylamine were added at room temperature (13.0g, 128.6mmol) and acetyl chloride (6.0g, 77.1mmol). Rt overnight and washed with saturated sodium dihydrogen phosphate solution was washed with 100mL reaction solution, separated, dried over anhydrous sulfate, and concentrated to give the compound 64D, as a colorless oil (15g, 84.7% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.41-5.24 (m, 1H), 4.55 - 4.53 (m, 1H), 4.60 - 4.49 (m, 1H), 4.47 - 4.43 (m, 1H), 4.26 - 4.19 ( m, 2H), 2.05 (s, 3H), 1.46 (s, 9H), 1.24 (t, 3H). LC-MS m/z = 298.1 [M+23].

Step 4: (S)-Ethyl 3-acetoxy-2-aminopropionate hydrochloride ( 64E )

(S)-ethyl 3-acetoxy-2-aminopropanoate hydrochloride

64D (15.0 g, 54.4 mmol) was dissolved in 100 mL of ethyl acetate, and hydrogen chloride gas was passed at room temperature for 4 hours, and a white solid was precipitated, filtered, and concentrated to give the compound 64E as a white solid (7.0 g, Yield 60.7%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.94 (s, 3H), 4.51-4.46 (m, 1H), 4.42-4.35 (m, 2H), 4.30-4.14 (m, 2H), 2.04 (s, 3H), 1.23 (t, 3H). LC-MS m/z = 176.1 [M + 1].

Step 5: (2S)-Ethyl 3-acetoxy-2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 64 )

(2S)-ethyl 3-acetoxy-2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphine dichloride (5.0 g, 30.6 mmol) was dissolved in 100 mL of dichloromethane, and propofol (5.4 g, 30.6 mmol) and three were added dropwise at -10 ° C under nitrogen. A solution of ethylamine (12.4 g, 122.7 mmol) in 20 mL of dichloromethane was added and the mixture was stirred at room temperature for 1 hour. At this temperature, 64E (6.4 g, 30.6 mmol) was added. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with saturated sodium dihydrogen phosphate solution (500 mL), and the organic layer was evaporated, evaporated and evaporated. ~ 1:1) gave compound 64 as a yellow oil (4.5 g, yield 33.0%).

LC-MS m/z = 444.3 [M + 1].

Solution of compound 64 (4.5g) for separating the two optical isomers to obtain a compound 64-a (1.23g, retention time 2.96 min, a colorless oil, ee% = 99.758%), compound 64-b (2.94g , residence time 4.8 min, white solid, ee% = 100%). Preparation conditions: instrument: Thar 200 preparative SFC (SFC-5); chromatography column: ChiralPak AS, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is methanol; gradient: B 25%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~ 1.5 min; sample preparation: the compound was dissolved in ~90 mL of methanol; injection: 2 mL / injection.

Compound 64-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.41-4.26 (m, 2H), 4.22-4.16 (m, 2H), 4.03-3.89 (m, 2H), 3.89-3.76 (m, 1H), 3.69 (t, 1H), 3.61-3.42 (m, 5H), 1.89 (s, 3H), 1.32-1.16 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.79. LC-MS m/z = 444.2 [M+1].

Compound 64-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.41-4.22 (m, 3H), 4.18-4.06 (m, 2H), 3.94-3.81 (m, 2H), 3.75-3.63 (m, 1H), 3.56-3.40 (m, 5H), 2.05 (s, 3H), 1.28-1.13 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.57. LC-MS m/z = 444.3 [M + 1].

Example 65

(2S)-((isopropoxycarbonyl)oxy)methyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 65 )

(2S)-((isopropoxycarbonyl)oxy)2- 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

First step: (S)-((isopropoxycarbonyl)oxy)methyl 2-((t-butoxycarbonyl)amino)propionate ( 65A )

(S)-((isopropoxycarbonyl)oxy)methyl 2-((tert-butoxycarbonyl)amino)propanoate

61A (15.0 g, 79.2 mmol), isopropyl chloromethyl carbonate (14.5 g, 95.1 mmol) and potassium carbonate (21.9 g, 158.7 mmol) were added to 200 mL of N,N-dimethylformamide. The reaction was carried out for 8 hours at room temperature. The reaction solution was added to 200 mL of water, and extracted with ethyl acetate (100 mL×3). The organic phase was combined and washed with 100 mL of water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by gel column chromatography ( petroleum ether: Ethyl acetate (v/v) = 50:1 to 5:1) gave 65A as a colorless oil (15 g, yield 61.9%).

LC-MS m/z = 328.1 [M+23].

Second step: (S)-((isopropoxycarbonyl)oxy)methyl 2-aminopropionate hydrochloride ( 65B )

(S)-((isopropoxycarbonyl)oxy)methyl 2-aminopropanoate hydrochloride

65A (15.0g, 49.1mmol) was dissolved in 100mL of ethyl acetate. At room temperature, hydrogen chloride gas was introduced and reacted for 4 hours. A white solid was precipitated, filtered and concentrated to give 65B , white solid (10 g. The rate is 84.2%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.91 (s, 3H), 5.83-5.77 (m, 2H), 4.87-4.81 (m, 1H), 4.17-4.12 (m, 1H), 1.47 (d, 3H), 1.26 (d, 6H).

Third step: (2S)-((isopropoxycarbonyl)oxy)methyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino Propionate ( Compound 65 )

(2S)-((isopropoxycarbonyl)oxy)2- 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphine dichloride (5.0 g, 30.6 mmol) was dissolved in 100 mL of dichloromethane, and propofol (5.4 g, 30.6 mmol) and three were added dropwise at -10 ° C under nitrogen. A solution of ethylamine (12.4 g, 122.7 mmol) in 20 mL of dichloromethane was added and the mixture was stirred at room temperature for 1 hour. At this temperature, 65B (14.7 g, 61.3 mmol) was added. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium dihydrochloride (500 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated ~ 1:1) Compound 65 was obtained as a yellow oil (4.8 g, yield 33.0%).

LC-MS m/z = 474.2 [M + 1].

Solution of compound 65 (4.8g) used in the preparation of a chiral, two optical isomers to obtain a compound 65-a (1.5g, retention time 3.51 min, a colorless oil, ee% = 100%), compound 65-b ( 2.6 g, residence time 5.27 min, colorless oil, ee% = 100%). Preparation conditions: Instrument: MG II preparative SFC (SFC-15); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm.; mobile phase: phase A is CO ₂ and phase B is isopropanol (0.1% NH ₃ H ₂ O); Gradient: B 40%; Flow rate: 60 mL/min; Back pressure: 100 bar; Column temperature: 38 ° C; Wavelength: 220 nm; Period: ~ 3.6 min; Sample preparation: Compound dissolved in ~150 mL of methanol; : 2mL / injection.

Compound 65-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.80 (d, 1H), 5.72 (d, 1H), 4.94-4.88 (m, 1H), 4.24-4.18 (m, 1H), 4.00 -3.81 (m, 2H), 3.57-3.44 (m, 5H), 3.38 (t, 1H), 1.32-1.30 (m, 6H), 1.25-1.15 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.46. LC-MS m/z = 474.2 [M + 1].

Compound 65-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.72 (d, 1H), 5.66 (d, 1H), 4.94-4.88 (m, 1H), 4.30-4.14 (m, 1H), 3.93 - 3.79 (m, 2H), 3.60-3.39 (m, 6H), 1.38 (d, 3H), 1.31 (d, 6H), 1.23-1.18 (m, 12H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.26. LC-MS m/z = 474.2 [M + 1].

Example 66

[(1S)-1-methylpropyl](2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 66 )

[(1S)-1-methylpropyl](2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

First step: [(1S)-1-methylpropyl](2S)-2-(t-butoxycarbonylamino)propionate ( 66A )

[(1S)-1-methylpropyl](2S)-2-(tert-butoxycarbonylamino)propanoate

61A (28 g, 148.4 mmol) was dissolved in dichloromethane (100 mL). S-2-butanol (10 g, 135 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide Amine hydrochloride (38.82 g, 202.5 mmol) and 4-dimethylaminopyridine (9.9 g, 81 mmol). The reaction at room temperature for 4 hours, treated with saturated sodium dihydrogen phosphate solution (100 mL) The reaction solution was washed, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give residue that is 66A, as a colorless liquid (23.15 g , yield 63.77%).

LC-MS m/z = 268.1 [M+23].

Second step: [(1S)-1-methylpropyl](2S)-2-aminopropionate ( 66B )

[(1S)-1-methylpropyl](2S)-2-aminopropanoate

66A (20 g, 81.63 mmol) was dissolved in ethyl acetate (60 mL). EtOAc m. ) after extraction, the organic phase discarded, the aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate and extracted with dichloromethane (100mL × 4), organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 66B , colorless liquid (7.7 g, yield 65.08%).

LC-MS m/z = 146.1 [M+1].

The third step: [(1S)-1-methylpropyl](2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino Propionate ( Compound 66 )

[(1S)-1-methylpropyl](2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (4.5 g, 27.60 mmol) was dissolved in dichloromethane (50 mL) at -30 ° C under a nitrogen atmosphere, propofol (5.4 g, 30.37 mmol) and A solution of a mixture of triethylamine (11.17 g, 110.43 mmol) in dichloromethane (50 mL) was evaporated. 66B (4.0 g, 27.60 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with aq. EtOAc EtOAc (EtOAc) v) = 10:1 to 1:1) gave Compound 66 as a pale yellow liquid (4.3 g, yield 37.71%).

LC-MS m/z = 414.2 [M+1].

Compound 66 (4.3 g) was used for separation, and two optical isomer compounds 66-a were obtained after separation (retention time: 2.46 min, 1.83 g, pale yellow liquid, ee% = 99.8%), compound 66-b ( Residence time: 4.03 min, 1.79 g, pale yellow liquid, ee% = 100%). Preparation conditions: instrument: Thar 350 preparative SFC (SFC-6); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 25%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~2.5 min; sample preparation: the compound was dissolved in ~150 mL of methanol; injection: 7 mL / injection.

Compound 66-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.87-4.82 (m, 1H), 4.14-4.08 (m, 1H), 3.94-3.84 (m, 2H), 3.57-3.51 (m, 2H), 3.50-3.43 (m, 4H), 1.57-1.55 (m, 2H), 1.23-1.20 (m, 15H), 1.15 (d, 3H), 0.87 (t, 3H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.61. LC-MS m/z = 414.2 [M+1].

Compound 66-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.83-4.78 (m, 1H), 4.10 (m, 1H), 3.90-3.79 (m, 2H), 3.63-3.47 (m, 3H) , 3.46 (d, 3H), 1.56-1.50 (m, 2H), 1.37 (d, 3H), 1.23-1.20 (m, 12H), 1.15 (d, 3H), 0.85 (t, 3H). LC-MS m/z = 414.2 [M + 1]. ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.62.

Example 67

[(1R)-1-methylpropyl](2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 67 )

[(1R)-1-methylpropyl](2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

First step: [(1R)-1-methylpropyl](2S)-2-(t-butoxycarbonylamino)propionate ( 67A )

[(1R)-1-methylpropyl](2S)-2-(tert-butoxycarbonylamino)propanoate

61A (28g, 148.4mmol) was dissolved in dichloromethane (100mL), then added R-2-butanol (10g, 135mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide Amine hydrochloride (38.82 g, 202.5 mmol) and 4-dimethylaminopyridine (9.9 g, 81 mmol). The reaction at room temperature for 4 hours, an aqueous solution (100 mL) The reaction solution was washed and partitioned with saturated sodium dihydrogen phosphate, the organic phase was dried over anhydrous sodium sulfate, and filtered to give 67A, as a colorless liquid (22.10 g, it was concentrated under reduced pressure to yield 60.88 %).

LC-MS m/z = 268.1 [M+23].

Second step: [(1R)-1-methylpropyl](2S)-2-aminopropionate ( 67B )

[(1R)-1-methylpropyl](2S)-2-aminopropanoate

67A (20 g, 81.53 mmol) was dissolved in ethyl acetate (60 mL). EtOAc m. ×2) Extraction, the organic phase was separated, the aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate, and extracted with dichloromethane (100 mL×4). The organic phase was combined and dried over anhydrous sodium sulfate. Compound 67B was obtained as a colorless liquid (8.4 g, yield 71.00%).

LC-MS m/z = 146.1 [M+1].

Third step: [(1R)-1-methylpropyl](2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino Propionate ( Compound 67 )

[(1R)-1-methylpropyl](2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propano Ate

(Methoxymethyl)phosphonium dichloride (7.8 g, 47.85 mmol) was dissolved in dichloromethane (100 mL) at -30 ° C under a nitrogen atmosphere, propofol (9.37 g, 52.63 mmol) and A solution of triethylamine (19.37 g, 191.41 mmol) in dichloromethane (50 mL) was evaporated. 67B (6.93 g, 47.85 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with aq. EtOAc (EtOAc) (EtOAc) v) = 10:1 to 1:1) Compound 67 was obtained as a pale yellow liquid (7 g, yield 35.42%).

LC-MS m/z = 414.2 [M+1].

Compound 67 (7.0 g) was used for separation, and two optical isomer compounds 67-a were obtained after separation (retention time 2.42 min, 2.66 g, pale yellow liquid, ee% = 99.8%), compound 67-b (retention) Time 4.03 min, 3.23 g, pale yellow liquid, ee% = 99.2%). Preparation conditions: instrument: Thar 350 preparative SFC (SFC-6); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 25%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~2.5 min; sample preparation: the compound was dissolved in ~200 mL of methanol; injection: 7 mL / injection.

Compound 67-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.87-4.82 (m, 1H), 4.14-4.08 (m, 1H), 3.93-3.83 (m, 2H), 3.57-3.50 (m, 2H), 3.48-3.45 (m, 4H), 1.64-1.50 (m, 2H), 1.23-1.14 (m, 18H), 0.90-0.85 (t, 3H). LC-MS m/z = 414.2 [M+ 1]. ³¹ P NMR (162MHz, CDCl ₃ ) δ 22.60

Compound 67-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.82-4.77 (m, 1H), 4.11-4.09 (m, 1H), 3.92-3.79 (m, 2H), 3.64-3.49 (m, 3H), 3.47 (d, 3H), 1.57-1.47 (m, 2H), 1.36 (d, 3H), 1.22-1.20 (m, 12H), 1.15 (d, 3H), 0.86-0.82 (t, 3H) .LC-MS m/z = 414.2 [M + 1]. ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.59.

Example 68

Isobutyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 68 )

Isobutyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

First step: isobutyl (2S)-2-(t-butoxycarbonylamino)propionate ( 68A )

Isobutyl(2S)-2-(tert-butoxycarbonylamino)propanoate

61A (28 g, 148 mmol) was dissolved in dichloromethane (100 mL) and isobutanol (10 g, 135 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38.82 g, 202.5 mmol) and 4-dimethylaminopyridine (9.9 g, 81 mmol). The reaction at room temperature for 4 hours, treated with aqueous sodium dihydrogen phosphate saturated (100 mL) The reaction solution was washed, separated, the organic phase was dried over anhydrous sodium sulfate, and filtered to give 68A, as a colorless liquid (20.5 g of, and concentrated under reduced pressure to yield 56.47 %).

LC-MS m/z = 268.1 [M+23].

The second step: isobutyl (2S)-2-aminopropionate ( 68B )

Isobutyl(2S)-2-aminopropanoate

68A (20 g, 81.63 mmol) was dissolved in ethyl acetate (60 mL). EtOAc (EtOAc m. 2), the organic phase is separated, the aqueous phase is adjusted to pH 8-9 with saturated sodium hydrogen carbonate, and extracted with dichloromethane (100 mL×4). After that, 68B was obtained as a colorless liquid (7.9 g, yield 66.78%).

LC-MS m/z = 146.1 [M+1].

The third step: isobutyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 68 )

Isobutyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (6.1 g, 37.4 mmol) was dissolved in dichloromethane (60 mL) at -30 ° C under a nitrogen atmosphere, propofol (7.32 g, 41.1 mmol) and A solution of a mixture of triethylamine (15.13 g, 149.6 mmol) in dichloromethane (50 mL) was evaporated. 68B (5.42 g, 37.4 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with aq. EtOAc EtOAc (EtOAc) v) = 10:1 to 1:1) Compound 68 was obtained as a pale yellow liquid (5.8 g, yield: 37.56%). LC-MS m/z = 414.5 [M + 1].

Compound 68 (5.8 g) was used for separation, and two optical isomer compounds 68-a were obtained after separation (residence time: 2.52 min, 2.43 g, pale yellow liquid, ee% = 100%), compound 68-b ( Residence time: 3.9 min, 3.45 g, pale yellow liquid, ee% = 100%). Preparation conditions: equipment: MG II preparative SFC (SFC-15); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 20%; Flow rate: 50 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~5 min; sample preparation: dissolve the compound in ~100 mL of methanol; injection: 2 mL / injection.

Compound 68-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.16-4.14 (m, 1H), 3.94-3.83 (m, 4H), 3.56-3.5 (m, 2H), 3.48-3.42 (m, 4H), 1.95-1.89 (m, 1H), 1.25-1.15 (m, 15H), 0.92-0.88 (d, 6H). ³¹ P NMR (162MHz, CDCl ₃ ) δ 22.61. LC-MS m/z = 414.5 [M+1].

Compound 68-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.15-4.13 (m, 1H), 3.94-3.78 (m, 4H), 3.61-3.50 (m, 3H), 3.46-3.45 (m, 3H), 1.92-1.83 (m, 1H), 1.37 (d, 3H), 1.24-1.10 (m, 12H), 0.89 (d, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.61. LC-MS m/z = 414.5 [M + 1].

Example 69

2-methylbutyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 69 )

2-methylbutyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

First step: 2-methylbutyl (2S)-2-(t-butoxycarbonylamino)propionate ( 69A )

2-methylbutyl(2S)-2-(tert-butoxycarbonylamino)propanoate

61A (23.58 g, 124.78 mmol) was dissolved in dichloromethane (100 mL) and 2-methyl-1-butanol (10 g, 113.45 mmol), 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (32.62 g, 170.17 mmol) and 4-dimethylaminopyridine (8.3 g, 68.07 mmol) were reacted at room temperature for 4 hours, and washed with a saturated aqueous solution of sodium dihydrogen phosphate (100 mL). solution, after liquid separation, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that is. 69A, as a colorless liquid (18.75 g, 58.03% yield).

LC-MS m/z = 282.1 [M+23].

Second step: 2-methylbutyl (2S)-2-aminopropionate ( 69B )

2-methylbutyl(2S)-2-aminopropanoate

69A (18 g, 69.41 mmol) was dissolved in ethyl acetate (60 mL). EtOAc (EtOAc m. 2), the organic phase is separated, the aqueous phase is adjusted to pH 8-9 with saturated sodium hydrogen carbonate, and extracted with dichloromethane (100 mL×4). After that, 69B was obtained as a colorless liquid (7.7 g, yield: 69.68%).

LC-MS m/z = 160.1 [M + 1].

The third step: 2-methylbutyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( compound) 69 )

2-methylbutyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (7.2 g, 44.17 mmol) was dissolved in dichloromethane (80 mL), and the mixture was stirred at 30 ° C under N2, and propofol (8.64 g, 48.59 mmol) and A solution of triethylamine (17.87 g, 176.68 mmol) in dichloromethane (50 mL) was evaporated. 69B (7.02 g, 44.17 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with aq. EtOAc EtOAc (EtOAc) v) = 10:1~1:1) to give compound 69 as a pale yellow liquid (5.9 g, yield 37.71%)

LC-MS m/z = 428.5 [M+1].

Compound 69 (5.9 g) was used for separation, and after separation, two groups of isomer compounds 69-a were obtained (retention time: 2.45 min, 2.51 g, pale yellow liquid, ee% = 100%), compound 69-b (retention) Time: 4.07 min, 2.93 g, pale yellow liquid, ee% = 100%). Preparation conditions: equipment: Thar 200 preparative SFC (SFC-7); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol (0.1% NH ₃ H ₂ O); Gradient: B 25%; Flow rate: 200 mL/min Back pressure: 100 bar; Column temperature: 38 ° C; Wavelength: 220 nm; Period: ~3.5 min; Sample preparation: Compound dissolved in ~100 mL of methanol; Injection: 6 mL/ Every injection.

Compound 69-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.13 (s, 3H), 4.18-4.12 (m, 1H), 3.95-3.84 (m, 4H), 3.56-3.51 (m, 2H), 3.51-3.49 (d, 4H), 1.77-1.66 (m, 2H), 1.40-1.33 (m, 1H), 1.24-1.19 (m, 12H), 1.16 (d, 3H), 0.91 - 0.87 (m, 6H). LC-MS m /z=428.5[M+1].

Compound 69-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.17-4.11 (m, 1H), 3.94-3.79 (m, 4H), 3.61-3.47 (m, 3H), 3.46 (d, 3H) , 1.69-1.64 (m, 2H), 1.38 (d, 3H), 1.24-1.18 (m, 12H), 1.19-1.12 (m, 1H), 0.90-0.86 (m, 6H). LC-MS m/z =428.5[M+1].

Example 70

1-ethylpropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 70 )

1-ethylpropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

First step: 1-ethylpropyl (2S)-2-(t-butoxycarbonylamino)propionate ( 70A )

1-ethylpropyl(2S)-2-(tert-butoxycarbonylamino)propanoate

61A (28 g, 148 mmol) was dissolved in dichloromethane (100 mL), 3-pentanol (10 g, 135 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Salt (38.82 g, 202.5 mmol) and 4-dimethylaminopyridine (9.9 g, 81 mmol). Reacted at room temperature for 4 hours with saturated aqueous sodium dihydrogen phosphate (100 mL) The reaction solution was washed, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 70A, as a colorless liquid (18.75 g, yield 58.03%).

LC-MS m/z = 282.1 [M+23]

Second step: 1-ethylpropyl (2S)-2-aminopropionate ( 70B )

1-ethylpropyl(2S)-2-aminopropanoate

70A (20 g, 77.11 mmol) was dissolved in ethyl acetate (60 mL). EtOAc (EtOAc m. 2), the organic phase is separated, the aqueous phase is adjusted to pH 8 with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane (100 mL×4). The organic phase is combined and dried over anhydrous sodium sulfate. 70B was obtained as a colorless liquid (7.7 g, yield: 69.68%).

LC-MS m/z = 160.1 [M + 1].

Third step: 1-ethylpropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate (compound) 70)

1-ethylpropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (5 g, 30.67 mmol) was dissolved in dichloromethane (50 mL) at -30 ° C under N2, and propofol (6.01 g, 33.74 mmol) and three were added dropwise. A solution of a mixture of ethylamine (12.41 g, 122.68 mmol) in dichloromethane (50 mL) was evaporated and evaporated. 70B (4.87 g, 30.67 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with saturated aqueous sodium hydrogen sulfate (100 mL), and evaporated, evaporated, evaporated. /v) = 10:1 to 1:1) Compound 70 was obtained as a pale yellow liquid (4.8 g, yield 37.71%). LC-MS m/z = 428.4 [M+1]..

Compound 70 (4.8 g) was used for separation, and two optical isomer compounds 70-a were obtained after separation (residence time: 2.45 min, 1.313 g, pale yellow liquid, ee% = 100%), compound 70-b ( Residence time: 4.07 min, 2.65 g, pale yellow liquid, ee% = 100%). Preparation conditions: equipment: Thar 200 preparative SFC (SFC-7); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol (0.1% NH ₃ H ₂ O); Gradient: B 25%; Flow rate: 200 mL/min; Back pressure: 100 bar; Column temperature: 38 ° C; Wavelength: 220 nm; Period: ~4 min; Sample preparation: Compound dissolved in ~100 mL of methanol; Injection: 6 mL/ Every injection.

Compound 70-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.78-4.75 (m, 1H), 4.15-4.13 (m, 1H), 3.94-3.83 (m, 2H), 3.58-3.51 (m, 2H), 3.48-3.44 (m, 4H), 1.61-1.52 (m, 4H), 1.23-1.21 (m, 12H), 1.17 (d, 3H), 0.89-0.84 (m, 6H). ³¹ P NMR ( 162 MHz, CDCl ₃ ) δ 22.62. LC-MS m/z = 428.4 [M+1].

Compound 70-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.77-4.62 (m, 1H), 4.14-4.12 (m, 1H), 3.89-3.79 (m, 2H), 3.63 (t, 1H) , 3.55-3.48 (m, 2H), 3.46 (d, 3H), 1.56-1.48 (m, 4H), 1.39 (d, 3H), 1.23-1.21 (m, 12H), 0.85-0.80 (m, 6H) ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.66. LC-MS m/z = 428.4 [M+1].

Example 71

1-cyclopropylethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 71 )

1-cyclopropylethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

First step: (2S)-2-(benzyloxycarbonylamino)propionic acid ( 71B )

(2S)-2-(benzyloxycarbonylamino)propanoic acid

71A (15g, 168.54mmol) was dissolved in a mixed solution of tetrahydrofuran (100mL) and water (50mL), sodium hydrogencarbonate (28.31g, 337mmol) was added, and benzyl chloroformate (28.75g, 168.54) was slowly added dropwise at 0 °C. Methyl), after the addition was completed, the reaction was carried out at room temperature overnight, the reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (150 mL×2), the organic phase was discarded, and the aqueous phase was adjusted to pH 2 with 2 mol/L of diluted hydrochloric acid. (150mL × 4) was extracted with ethyl acetate, the combined organic phases, the organic phase was washed with saturated aqueous sodium chloride (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 71B after, as a colorless liquid (14.3 g of, Yield 38.05%). LC-MS m/z = 224.1 [M + 1].

Second step: 1-cyclopropylethyl (2S)-2-(benzyloxycarbonylamino)propionate ( 71C )

1-cyclopropylethyl(2S)-2-(benzyloxycarbonylamino)propanoate

71B (14.3 g, 64.12 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI></RTI><RTIgt; Carbodiimide hydrochloride (18.43 g, 96.18 mmol) and 4-dimethylaminopyridine (4.7 g, 38.47 mmol). After reacting for 4 hours at room temperature, the reaction mixture was washed with aq. Ether: ethyl acetate (v/v) = 25:1 to 4:1) Compound 71C was obtained as a colorless liquid (11.2 g, yield: 60.05%).

LC-MS m/z = 314.1 [M+23].

The third step: 1-cyclopropylethyl (2S)-2-aminopropionate ( 71D )

1-cyclopropylethyl(2S)-2-aminopropanoate

71C (11.2g, 38.48mmol) was dissolved in tetrahydrofuran (30mL), palladium carbon (10g) was added, and it was reacted under hydrogen for 4 hours at room temperature. The reaction solution was filtered with diatomaceous earth and tetrahydrofuran (40 mL×2) ), dried combined organic phase was concentrated under reduced pressure to give the residue was separated and purified by column chromatography silica gel (methylene chloride: methanol (v / v) to give compound 71D using, as a colorless liquid (4.5g 1): = 50: 1 ~ 20 , yield 74.50%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.58-4.14 (m, 1H), 3.58-3.51 (m, 1H), 2.13 (s, 2H), 1.39-1.22 (m, 6H), 0.98 (m, 1H) , 0.64-0.12 (m, 4H). LC-MS m/z = 158.1 [M+1].

Fourth step: 1-cyclopropylethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 71 )

1-cyclopropylethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (4.5 g, 27.6 mmol) was dissolved in dichloromethane (60 mL) at -30 ° C under N2, and propofol (5.4 g, 30.36 mmol) and A solution of a mixture of triethylamine (11.17 g, 110.4 mmol) in dichloromethane (50 mL) was evaporated. 71D (4.36 g, 27.60 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with aq. EtOAc (EtOAc) (EtOAc) v/v) = 10:1 to 1:1) gave Compound 71 as a colorless liquid (4.2 g, yield: 35.80%).

LC-MS m/z = 426.4 [M+1].

Compound 71 (4.2 g) was used for separation, and after separation, four optical isomer compounds 71-a were obtained (retention time: 3.34 min, 410 mg, pale yellow liquid, ee% = 100%), compound 71-b (retention) Time: 3.45 min, 450 mg, pale yellow liquid, ee% = 100%), compound 71-c (retention time: 5.19 min, 637.41 mg, pale yellow liquid, ee% = 100%), compound 71-d (retention time) : 5.77 min, 737.89 g, pale yellow liquid, ee% = 100%). Preparation conditions: Equipment: MG II preparative SFC (SFC-15); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm.; mobile phase: phase A is CO ₂ and phase B is isopropanol; gradient: B 30 %; flow rate: 50 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~6 min; sample preparation: the compound was dissolved in ~100 mL of methanol; injection: 2.5 rmL / injection.

Compound 71-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.35-4.30 (m, 1H), 4.16-4.10 (m, 1H), 3.91-3.83 (m, 2H), 3.57-3.50 (m, 2H), 3.49-3.43 (m, 4H), 1.27 (d, 3H), 1.23-1.21 (m, 12H), 1.15 (d, 3H), 1.01-0.94 (m, 1H), 0.53-0.20 (m, 4H). LC-MS m/z = 426.4 [M+1]. ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.60.

Compound 71-b:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12 (s, 3H), 4.37-4.33 (m, 1H), 4.12-4.10 (m, 1H), 3.90-3.85 (m, 2H), 3.57-3.50 (m, 2H), 3.48-3.43 (d, 4H), 1.29 (d, 3H), 1.25-1.21 (m, 12H), 1.17 (d, 3H), 1.03-0.91 (m, 1H), 0.58-0.16 (m, 4H). LC-MS m/z = 426.4 [M+1]. ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.62.

Compound 71-c:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (s, 3H), 4.35-4.21 (m, 1H), 4.17-4.08 (m, 1H), 3.89-3.82 (m, 2H), 3.52-3.47 (m, 2H), 3.63-3.59 (m, 1H), 3.46 (d, 3H), 1.36 (d, 3H), 1.25-1.19 (m, 15H), 0.95-0.91 (m, 1H), 0.58-0.13 (m, 4H). LC-MS m/z = 426.4 [M+1]. ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.64.

Compound 71-d:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10 (s, 3H), 4.33-4.28 (m, 1H), 4.11-4.07 (m, 1H), 3.92-3.79 (m, 2H), 3.54-3.48 (m, 2H), 3.62-3.55 (m, 1H), 3.46-3.45 (m, 3H), 1.38 (d, 3H), 1.25-1.19 (m, 15H), 0.99-0.86 (m, 1H), 0.51-0.19 ( m, 4H). LC-MS m/z = 426.4 [M+1]. ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.61.

Example 72

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(dimethylaminomethyl)phosphonium]amino]propionate D-tartrate ( Compound 72 ); Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(dimethylaminomethyl)phosphoryl]amino]propanoate-D-tartrate.

27-a (1g, 2.5lmmol) was dissolved in tetrahydrofuran (5mL), heated to 40 ° C for 0.5 hour, the reaction was cooled to room temperature, D-tartaric acid in dichloromethane (5mL) was added, and precipitated after addition. large amount of solid, the solid was filtered, the solid washed with a small amount of tetrahydrofuran, solid residue was dried under reduced pressure to give compound 72 as a white solid (0.41 g, yield 29.92%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.10 (s, 3H), 5.32-5.27 (m, 1H), 4.29 (s, 2H), 4.04-3.98 (m, 2H), 3.93-3.86 (m, 1H), 3.60 (t, 1H), 3.50-3.45 (m, 2H), 3.04-2.97 (m, 1H), 2.84-2.78 (m, 1H), 2.34 (s, 6H), 1.77-1.74 (m, 1H), 1.28 (d, 3H), 1.20-1.03 (m, 15H). LC-MS m/z = 399.2 [M+1].

Example 73

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(dimethylaminomethyl)phosphonium]amino]propionate oxalate ( Compound 73 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(dimethylaminomethyl)phosphoryl]amino]propanoate oxalate

27-a (1 g, 2.51 mmol) was dissolved in tetrahydrofuran (5 mL), heated to 40 ° C for 0.5 hour, the reaction was cooled to room temperature, and anhydrous oxalic acid in dichloromethane (5 mL) was added. After 0.5 hours, methyl tert-butyl ether (4.5 mL) was added dropwise, a large amount of solid was precipitated, the solid was filtered, and the solid was washed with a small amount of tetrahydrofuran. The solid was concentrated under reduced pressure to give compound 73 as a white solid (0.55 g, Yield 45.08%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.60 (s, 2H), 7.12 (s, 3H), 5.63-5.57 (m, 1H), 3.96-3.88 (m, 3H), 3.48-3.40 (m, 3H), 3.31-3.28 (m, 1H), 2.64 (s, 6H), 1.26 (d, 3H), 1.14-1.07 (m, 15H). LC-MS m/z = 399.2 [M+1].

Example 74

(2S)-Benzyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 74 )

(2S)-benzyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

1C (5.0 g, 30.6 mmol) was dissolved in 100 mL of dichloromethane, and L-alanine benzyl ester (4.3 g, 24.5 mmol) and triethylamine (12.4 g) were added dropwise at 50 ° C under N2. A mixed solution of 122.7 mmol) in 20 mL of dichloromethane was added dropwise and allowed to react at room temperature for 1 hour. Propofol (6.0 g, 33.7 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated solution of sodium dihydrogen phosphate (500 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated ~ 1:1) Compound 74 was obtained as a yellow oil (5 g, yield 36.4%).

LC-MS m/z = 448.3 [M+1].

Compound 74 (4.5 g) was isolated to give two optical compoundes of compound 74-a (1.22 g, retention time: 4.31 min, colorless oil, ee% = 100%), compound 74-b (2.0 g, Residence time: 6.89 min, colorless oil, ee% = 100%). Preparation conditions: Equipment: MG II preparative SFC (SFC-15); chromatography column: ChiralPak AD, 250 × 30 mm ID, 5 μm.; mobile phase: phase A is CO ₂ and phase B is isopropanol; gradient: B 40 %; flow rate: 50 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~7 min; sample preparation: the compound was dissolved in ~100 mL of methanol; injection: 3 mL / injection.

Compound 74-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.40-7.27 (m, 5H), 7.11 (s, 3H), 5.19-5.10 (m, 2H), 4.22-4.19 (m, 1H), 3.95-3.78 (m, 2H), 3.56-3.49 (m, 2H), 3.44 - 3.42 (m, 4H), 1.27-1.17 (m, 15H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.69. LC-MS m/z = 448.3 [M+1].

Compound 74-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.37-7.26 (m, 5H), 7.11 (s, 3H), 5.16-5.00 (m, 2H), 4.12-4.16 (m, 1H), 3.91-3.77 (m, 2H), 3.61-3.47 (m, 3H), 3.41 (d, 3H), 1.37 (d, 3H), 1.21-1.19 (m, 12H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.71. LC-MS m/z = 448.3 M+1].

Example 75

Cyclopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 75 )

Cyclopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

First step: cyclopropyl (2S)-2-(tris-butoxycarbonylamino)propionate ( 75A )

Cyclopropyl(2S)-2-(tert-butoxycarbonylamino)propanoate

61A (25.24 g, 133.52 mmol) was dissolved in dichloromethane (100 mL) and cyclopropanol (7 g, 121.39 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (34.9 g, 182.18 mmol) and 4-dimethylaminopyridine (8.9 g, 72.83 mmol) were reacted for 4 hours at room temperature. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (100 mL), and then evaporated. :1~4:1) Compound 75A was obtained as a colorless liquid (25.10 g, yield: 82.08%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.04 (s, 1H), 4.20-4.18 (m, 1H), 4.16-3.98 (m, 1H), 1.43 (s, 9H), 1.31 (d, 3H), 0.78 -0.51 (m, 4H). LC-MS m/z = 252.2 [M+23].

Second step: cyclopropyl (2S)-2-aminopropionate ( 75B )

Cyclopropyl(2S)-2-aminopropanoate

75A (20g, 87.33mmol) was dissolved in ethyl acetate (40mL), HCl was evaporated to dryness at room temperature for 4 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved in water (50mL) The organic phase was extracted with methylene chloride (50 mL×2), and the aqueous phase was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane (50 mL×4). Compound 75B , white solid (8.1 g, yield 71.93%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.15 (m, 1H), 3.55-3.34 (m, 1H), 1.92 (s, 2H), 1.61-1.05 (d, 3H), 0.74-0.67 (m, 2H) , 0.57-0.45 (m, 2H). LC-MS m/z = 130.1 [M+1].

The third step: cyclopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 75 )

Cyclopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (8.2 g, 50.3 mmol) was dissolved in dichloromethane (100 mL) at -30 ° C under a nitrogen atmosphere, propofol (9.85 g, 55.3 mmol) and A solution of triethylamine (20.36 g, 201.22 mmol) in dichloromethane (60 mL) was evaporated. 75B (6.5 g, 50.3 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with aq. EtOAc EtOAc (EtOAc) v) = 10:1 to 1:1) gave Compound 75 as a pale yellow oil (7.8 g, yield: 39.06%).

LC-MS m/z = 398.2 [M+1].

Compound 75 (7.8 g) was used for separation to give two optical isomer compounds 75-a (3.13 g, retention time: 2.96 min, pale yellow liquid, ee% = 100%), compound 75-b (retention time) : 4.31 min, 3.83 g, pale yellow liquid, ee% = 100%). Preparation conditions: equipment: Thar 350 preparative SFC (SFC-6); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm.; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 20%; Flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~ 4.2 min; sample preparation: dissolve the compound in ~150 mL of methanol; injection: 6 mL / injection.

Compound 75-a:

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10 (s, 3H), 4.14 - 4.06 (m, 2H), 3.93-3.94 (m, 2H), 3.54-3.48 (m, 1H), 3.48 (d, 3H) , 3.42 (s, 2H), 1.21-1.19 (m, 12H), 1.12 (d, 3H), 0.76-0.54 (m, 4H). LC-MS m/z = 398.2 [M+1]. ³¹ P NMR (162MHz, CDCl ₃ ) δ 22.62

Compound 75-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.10 (s, 3H), 4.08-4.06 (m, 2H), 3.88-3.80 (m, 2H), 3.56-3.46 (m, 2H), 3.46 (d, 3H) , 3.42 (s, 1H), 1.32 (d, 3H), 1.21-1.19 (m, 12H), 0.68-0.60 (m, 4H). LC-MS m/z = 398.2 [M+1]. ³¹ P NMR (162MHz, CDCl ₃ ) δ 21.54.

Example 76

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(phenoxymethyl)phosphonium]amino]propionate ( Compound 76 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(phenoxymethyl)phosphoryl]amino]propanoate

First step: diethoxyphosphonium methyl 4-methylbenzenesulfonate ( 76A )

Diethoxyphosphorylmethyl4-methylbenzenesulfonate

1A (20g, 119mmol) was dissolved in dichloromethane (100mL), triethylamine (20g, 297.5mmol) was added at room temperature, and added, p-toluenesulfonium chloride (45.35g, 238mmol) was slowly added dropwise at 0 °C. ), after completion of the dropwise addition, react at room temperature overnight. The reaction mixture was diluted with methylene chloride (100 mL), EtOAc (EtOAc (EtOAc) v/v) = 20:1 to 3:1) gave Compound 76A as a colorless liquid (27.25 g, yield 71.15%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.81-7.79 (d, 2H), 7.36 (d, 2H), 4.18 (d, 2H), 4.16-4.08 (m, 4H), 2.45 (s, 3H), 1.31 (m, 6H).

LC-MS m/z = 323.0 [M + 1].

The second step: diethoxyphosphonyl methoxybenzene ( 76B )

Diethoxyphosphorylmethoxybenzene

76A (27.25 g, 84.63 mmol) was dissolved in dimethyl hydrazine (80 mL), phenol (11.95 g, 126.94 mmol) was added, and after addition, potassium tert-butoxide (19 g, 169.25 mmol) was added in portions at 0 °C. ), react at room temperature overnight. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) v/v)=15:1~4:1), compound 76B , colorless liquid (7.8 g, yield 37.78%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.32-7.26 (m, 2H), 7.03-6.86 (m, 3H), 4.28-4.19 (m, 6H), 1.35 (t, 6H).

LC-MS m/z = 245.1 [M + 1].

The third step: dichlorophosphonium methoxybenzene ( 76C )

Dichlorophosphorylmethoxybenzene

76B (4.2 g, 17.21 mmol) was dissolved in acetonitrile (50 mL), trimethylbromodecane (7.9 g, 51.64 mmol) was added, and the mixture was reacted at 50 ° C for 3 hours, the reaction was cooled to room temperature, and the solvent was evaporated. The residue was dissolved in dry methylene chloride (40 mL). EtOAc (EtOAc m. g, 51.64 mmol), reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove the solvent, to give compound 76C, a brown liquid (3G, yield 77.92%).

LC-MS m/z = 217.6 [M + 1].

Fourth step: ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(phenoxymethyl)phosphonium]amino]propionate ( compound 76 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(phenoxymethyl)phosphoryl]amino]propanoate

76C (3g, 13.4mmol) was dissolved in dichloromethane (40 mL), EtOAc (2. <RTI ID=0.0></RTI></RTI><RTIgt; A solution of dichloromethane (50 mL) was added dropwise and allowed to react at room temperature for 1 hour. L-Alanine ethyl ester hydrochloride (2.26 g, 14.74 mmol) was added at this temperature and allowed to react at room temperature for two hours. The reaction mixture was washed with aq. EtOAc EtOAc. = 10:1~2:1) gave Compound 76 as a pale yellow oil (2.8 g, yield 46.82%).

LC-MS m/z = 448.2 [M+1].

Compound 76 (2.8 g) was used for separation to give two optical isomer compounds 76-a (retention time: 3.9 min, 1.32 g, pale yellow liquid, ee% = 100%), compound 76-b (retention time) : 4.7 min, 1.13 g, pale yellow liquid, ee% = 100%).

Preparation conditions: equipment: Thar 200 preparative SFC (SFC-7); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 25%; flow rate : 200 mL / min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nrm; cycle: ~ 4 min; sample preparation: the compound was dissolved in ~ 150 mL of methanol; injection: 5 mL / injection.

Compound 76-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.34-7.30 (m, 2H), 7.13 (s, 3H), 7.03-6.96 (m, 3H), 4.52-4.39 (m, 2H), 4.20-4.06 (m, 3H), 3.66-3.53 (m, 3H), 1.26-1.17 (m, 18H).

LC-MS m/z = 448.2 [M+1].

³¹ P NMR (162 MHz, CDCl ₃ ) δ 20.72.

Compound 76-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.34-7.29 (m, 2H), 7.13 (s, 3H), 7.05-6.99 (t, 1H), 6.97-6.94 (m, 2H), 4.49-4.34 (m, 2H), 4.23-4.16 (m, 1H), 4.07-3.97 (m, 2H), 3.72-3.56 (m, 3H), 1.35 (d, 3H), 1.23 (d, 6H), 1.21-1.12 (m, 9H).

LC-MS m/z = 448.2 [M+1].

³¹ P NMR (162 MHz, CDCl ₃ ) δ 19.61.

Example 77

(2S) 2,6-Diisopropylphenyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 77 )

(2S)-2,6-diisopropylphenyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

First step: (S)-2,6-diisopropylphenyl 2-(t-butoxycarbonyl)amino)propionate ( 77A )

(S)-2,6-diisopropylphenyl 2-((tert-butoxycarbonyl)amino)propanoate

61A (10.0 g, 52.85 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.26 g, 105.70 mmol), 4-dimethylaminopyridine (0.6 g) , 5.0 mmol) and propofol (8.47 g, 47.56 mmol) were added to 200 mL of dichloromethane, and reacted at room temperature for 8 hours. The reaction solution was added to 200 mL of water, extracted with dichloromethane (100 mL×3), and the organic phase was combined, washed with 100 mL of water, dried over anhydrous sodium sulfate, and concentrated and purified by silica gel column chromatography ( petroleum ether: acetic acid The ester (v/v) = 50:1 to 5:1) gave Compound 77A as a colorless oil (10.0 g, yield 54.14%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.26-7.15 (m, 3H), 5.11 (s, 1H), 4.69-4.45 (m, 1H), 2.92 (s, 2H), 1.61 (d, 3H), 1.47 (s, 9H), 1.19 (m, 12H).

Step 2: (S)-2,6-Diisopropylphenyl 2-aminopropionate hydrochloride ( 77B )

(S)-2,6-diisopropylphenyl 2-aminopropanoate hydrochloride

The 77A (10.0 g, 28.61 mmol) was dissolved in 100 mL of ethyl acetate, and then hydrogen chloride gas was reacted at room temperature for 4 hours, and a white solid was precipitated, which was filtered and concentrated to give compound 77B , white solid (6.0 g, yield 84.08%).

LC-MS m/z = 250.2 [M + 1].

The third step: (2S)-2,6-diisopropylphenyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphonium)amino)propionic acid Ester ( compound 77 )

(2S)-2,6-diisopropylphenyl 2-((2,6-diisopropylphenoxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphonium dichloride (5.0 g, 30.6 mmol) was dissolved in 100 mL of dichloromethane, and propofol (5.4 g, 30.6 mmol) and three were added dropwise under a nitrogen atmosphere at minus 10 ° C under nitrogen. A mixed solution of ethylamine (12.4 g, 122.7 mmol) in 20 mL of dichloromethane was added dropwise, and the mixture was reacted at room temperature for 1 hour. 77B (8.7 g, 30.6 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. The reaction mixture was washed with a saturated solution of sodium dihydrogen phosphate (500 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated ~1:1) gave compound 77 as a yellow oil (5.4 g, yield: 34.5%).

LC-MS m/z = 518.3 [M + 1].

Solution of compound 77 (4.5g) was separated to give two optical isomers of the compounds 77-a (1.5g, retention time: 2.6min, colorless oil, ee% = 100%), compound 77-b (2.0g, Residence time: 4.62 min, yellow oil, ee% = 100%).

Preparation conditions: equipment: Thar 200 preparative SFC (SFC-7); chromatography column: ChiralPak AD, 300 × 50 mm ID, 10 μm; mobile phase: phase A is CO ₂ and phase B is ethanol; gradient: B 25%; flow rate: 200 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~4 min; sample preparation: the compound was dissolved in ~150 mL of methanol; injection: 5 mL / injection.

Compound 77-a:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.24-7.09 (m, 6H), 4.63-4.44 (m, 1H), 4.01-3.77 (m, 2H), 3.63-3.49 (m, 3H), 3.47 (d, 3H), 2.86 (s, 2H), 1.41 (d, 3H), 1.28-1.20 (m, 12H), 1.16 (m, 12H)

³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.56.

LC-MS m/z = 518.3 [M + 1].

Compound 77-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.23-7.09 (m, 6H), 4.54-4.49 (m, 1H), 3.96-3.84 (m, 2H), 3.73-3.68 (m, 1H), 3.58-3.52 ( m, 2H), 3.49 (d, 3H), 2.74 (s, 2H), 1.66 (d, 3H), 1.22 (d, 12H), 1.09 (d, 12H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.46.

LC-MS m/z = 518.3 [M + 1].

Example 78

(2S)-ethyl 2-(((4'-hydroxy-3,3',5,5'-tetraisopropyl[1,1'-biphenyl]-4-yl)oxy) ( Methoxymethyl)phosphonium)amino)propionate ( Compound 78 )

(2S)-ethyl 2-(((4'-hydroxy-3,3',5,5'-tetraisopropyl-[1,1'-biphenyl]-4-yl)oxy)(methoxymethyl)phosphoryl)amino) Propanoate

1C (0.3 g, 1.8 mmol) was dissolved in 100 mL of dichloromethane, and at a temperature of minus 50 ° under nitrogen, 3,3',5,5'-tetraisopropyl[1,1'-biphenyl] was added. A mixed solution of a diol (0.5 g, 1.4 mmol) and triethylamine (0.6 g, 5.9 mmol) in 20 mL of dichloromethane was reacted for 1 hour at room temperature. 5 mL of a solution of L-alanine ethyl ester (0.5 g, 4.2 mmol) in dichloromethane was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with a saturated aqueous solution of sodium dihydrogen phosphate (500 mL), and the organic layer was dried over anhydrous sodium sulfate, and the residue was purified and purified by chromatography (ethyl ether: ethyl acetate (v/v) = 10:1 1:1) gave Compound 78 as a yellow oil (0.2 g, yield: 25.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23 (d, 2H), 7.18 (d, 2H), 4.21-4.09 (m, 3H), 3.97-3.80 (m, 2H), 3.63-3.43 (m, 6H) , 3.27-3.13 (m, 2H), 1.34-1.32 (m, 12H), 1.30-1.22 (m, 18H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 22.86, 21.82.

LC-MS m/z = 562.3 [M + 1].

Example 79

Isopropyl (2S)-2-(((4-(2-(dimethylamino))-1-(1-hydroxycyclohexyl)ethyl)phenoxy)(methoxymethyl)phosphonium Amino)propionate ( compound 79 )

Isopropyl(2S)-2-[[[4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

L-Alanine isopropyl ester hydrochloride (3.35 g, 20 mmol) was dispersed in 30 mL of dry ethyl acetate. Triethylamine (4.04 g, 40 mmol) was added and stirred at room temperature for 1 hour, then filtered and filtered. The cake was washed with 15 mL of dry ethyl acetate and the filtrate was taken and triethylamine (2.02 g, 20 mmol).

(Methoxymethyl)phosphine dichloride (3.26 g, 20 mmol) was dissolved in 50 mL of dry ethyl acetate, and the above-mentioned L-alanine isopropyl ester and triethylamine were added dropwise at -30 °C. The mixture was added dropwise, and the mixture was reacted for 30 min, and then, then, 79A (5.27 g, 20 mmol) was added. The reaction solution was filtered, and the filtrate was washed with 50 mL of ethyl acetate. The filtrate was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate and evaporated. ~1/20) gave Compound 79 as a yellow oil (1.1 g, yield 11.35%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.25 (d, 2H), 7.10 (dd, 2H), 5.66 (m, 1H), 4.86 (m, 1H), 3.78 (m, 3H), 3.39 (m , 3H), 2.95 (m, 2H), 2.38 (m, 6H), 1.23 (m, 21H).

LC-MS m/z = 485.4 [M+1].

Example 80

Isopropyl (2S)-2-[[(2-acetamido-5-methoxy-phenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 80 )

Isopropyl(2S)-2-[[(2-acetyl-5-methoxy-phenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

L-Alanine isopropyl ester hydrochloride (5.03 g, 30 mmol) was dispersed in 30 mL of dry ethyl acetate. Triethylamine (6.06 g, 60 mmol) was added, and the mixture was stirred at room temperature for 1 hour, then filtered and filtered. The cake was washed with 15 mL of dry ethyl acetate and the filtrate was taken and triethylamine (3.03 g, 30 mmol).

(Methoxymethyl)phosphine dichloride (4.89 g, 30 mmol) was dissolved in 75 mL of dry ethyl acetate, and the above-mentioned L-alanine isopropyl ester and triethylamine were added dropwise at -30 °C. The mixture was reacted for 30 min after the dropwise addition, and 80A (4.99 g, 30 mmol) was added, and the mixture was allowed to react at room temperature overnight. The reaction solution was filtered, and the filtered cake was washed with 50 mL of ethyl acetate. The filtrate was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate and evaporated. 10~1/3), Compound 80 was obtained as a colorless oil (1 g, yield 8.61%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.73 (dd, 1H), 7.07 (s, 1H), 6.74 (m, 1H), 4.98 (m, 1H), 4.08 (m, 2H), 3.87 (m, 5H ), 3.46 (dd, 3H), 2.57 (d, 3H), 1.23 (m, 9H).

LC-MS m/z = 388.3 [M+1].

Example 81

Isopropyl (2S)-2-[[(2-isopropyl-5-methyl-phenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 81 )

Isopropyl(2S)-2-[[(2-isopropyl-5-methyl-phenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphine dichloride (2.4 g, 15 mmol) dissolved in 30 mL of dry dichloromethane, protected with nitrogen, triethylamine (4 g, 40 mmol) and L-alanine were added dropwise at -30 °C. A mixture of propyl ester (3.9 g, 30 mmol) was added dropwise, and the mixture was reacted for 30 min, and then, 81A (1.5 g, 10 mmol) was added and allowed to react at room temperature for 2 h. Washed with saturated aqueous sodium dihydrogen phosphate (20 mL), EtOAc (EtOAc) Compound 81 was obtained as a colorless oil (0.4 g, yield 10%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.22 (d, 1H), 7.13 (d, 1H), 6.92 (d, 1H), 4.99 (m, 1H), 4.19-4.03 (m, 1H), 3.90-3.72 (m, 2H), 3.65-3.50 (m, 1H), 3.44 (dd, 3H), 3.37-3.22 (m, 1H), 2.29 (s, 3H), 1.32 (dd, 3H), 1.24-1.17 (m , 12H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.25, 22.36.

LC-MS m/z = 372.2 [M + 1].

Example 82

Isopropyl (2S)-2-[[[(8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16 ,17-Decahydro-6H-cyclopenta[a]phenanthr-3-yl]oxy-(methoxymethyl)phosphonium]amino]propionate ( Compound 82 )

Isopropyl(2S)-2-[[[(8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17- Decahydrocyclopenta[a]phenanthren-3-yl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphine dichloride (1.22 g, 7.50 mmol) was dissolved in dichloromethane (10 mL), and isopropyl L-alanine (0.98 g, 7.50) was slowly added dropwise at -30 °C. A mixture of mmol) and triethylamine (1.52 g, 15 mmol) in dichloromethane (5 mL). After stirring at this temperature for 30 min, a solution of 82A (1 g, 3.. Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (20 mL×1) and a saturated solution of sodium chloride (20 mL×1), dried over anhydrous sodium sulfate and concentrated. The column chromatography was separated and purified (ethyl acetate / petroleum ether = (v/v) 1/3 to 1/1) to afford Compound 82 (0.5 g, yield: 27.60%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.21 (d, 1H), 6.96 (t, 2H), 5.00 (m, 1H), 4.11 (m, 1H), 3.77 (m, 3H), 3.46 (m, 4H ), 2.83 (m, 2H), 2.20 (m, 3H), 1.95 (m, 1H), 1.87 (m, 1H), 1.44 (m, 4H), 1.33 (m, 4H), 1.22 (m, 10H) , 0.78 (s, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.74, 22.90

LC-MS m/z = 494.2 [M+1].

Example 83

Isopropyl (2S)-2-[[[(8R,9S,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl-7,8,9,11,12,14, 15,16-octahydro-6H-cyclopenta[a]phenanthr-3-yl]oxy-(methoxymethyl)phosphonium]amino]propionate ( Compound 83 )

Isopropyl(2S)-2-[[[(8R,9S,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl-7,8,9,11,12,1 4,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-yl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphine dichloride (0.22 g, 1.35 mmol) was dissolved in dichloromethane (5 mL), and isopropyl L-alanine (0.18 g, 1.35) was slowly added dropwise at -30 °C. A solution of a mixture of mmol) and triethylamine (0.3 g, 3 mmol) in dichloromethane (5 mL). Stirred at this temperature for 30min, added 83A (0.2g, 0.67mmol) in dichloromethane (5mL) solution, warmed to room temperature stirring was continued for 30min. Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (20 mL×1) and a saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (ethyl acetate / petroleum ether = (v/v) 1/3 to 1/1) afforded Compound 83 (0.18 g, yield 51.91%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (d, 1H), 6.96 (t, 2H), 5.00 (m, 1H), 4.11 (m, 1H), 3.78 (m, 2H), 3.48 (m, 4H) ), 2.84 (dd, 2H), 2.34 (m, 2H), 2.23 (m, 1H), 2.04 (m, 1H), 1.76 (m, 7H), 1.43 (m, 3H), 1.34 (m, 3H) , 1.23 (m, 6H), 0.88 (s, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.74, 22.90

LC-MS m/z = 518.3 [M + 1].

Example 84

Ethyl (2S)-2-[[[(3S,8R,9S,10R,13S,14S)-10,13-diethyl-17-(3-pyridine)-2,3,4,7,8 ,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthr-3-yl]oxy-(methoxymethyl)phosphonium]amino]propionate ( compound 84 )

Ethyl(2S)-2-[[[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-(3-pyridyl)-2,3,4,7,8,9, 11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

The (methoxymethyl) dichloro acyl phosphine (0.71g, 4.29mmol) was dissolved in dichloromethane (20mL) in, at -20 deg.] C, was added 55A (1g, 2.86mmol) and triethylamine (1.16 g, 11.45 mmol) of dichloromethane (10 mL)) mixed solution. After stirring at this temperature for 30 min, L-alanine ethyl ester (1 g, 8.58 mmol) was added, warmed to room temperature and stirred for 30 min. Dichloromethane (50 mL) was added, and the mixture was washed with EtOAc EtOAc (EtOAc) Ethyl ester/petroleum ether = (v/v) 1/3~2/1) gave compound 84 (0.2 g, yield 12.56%) as pale yellow oil.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.64 (d, 1H), 8.48 (dd, 1H), 7.71 (d, 1H), 7.28 (m, 1H), 6.03 (s, 1H), 5.40 (m, 1H ), 4.29 (m, 1H), 4.19 (m, 2H), 4.07 (m, 1H), 3.67 (m, 3H), 3.43 (dd, 3H), 3.28 (m, 1H), 2.43 (m, 2H) , 2.27 (m, 1H), 2.06 (m, 3H), 1.74 (m, 8H), 1.41 (m, 3H), 1.28 (m, 3H), 1.10 (m, 8H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.98, 24.23

LC-MS m/z = 557.3 [M+1].

Example 85

(2S)-isopropyl 2-(((4-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2 -f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)ethinylamino)phenoxy)(methoxymethyl)phosphonium Amino)propionate ( compound 85 )

(2S)-isopropyl 2-((4-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2 ,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)phenoxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphonium dichloride (0.53 g, 3.26 mmol) was dissolved in dichloromethane (10 mL), and isopropyl L-alanine (0.43 g, 3.26) was slowly added dropwise at -30 °C. A solution of a mixture of mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (5 mL). Stirred at this temperature for 30min, added 85A (0.8g, 1.63mmol) in dichloromethane (10 mL) solution was warmed to room temperature stirring was continued for 30min. Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (20 mL×1) and a saturated sodium chloride solution (20 mL×1), dried over anhydrous sodium sulfate, and concentrated. Purification by column chromatography (dichloromethane/methanol = (v/v) 100/1~20/1) gave Compound 85 ( white solid, 0.4 g, yield 34.41%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.18 (d, 1H), 7.54 (d, 2H), 7.41 (d, 2H), 7.32 (d, 2H), 7.14 (m, 2H), 5.00 (m, 1H ), 4.68 (dd, 1H), 4.07 (m, 1H), 3.79 (m, 3H), 3.61 (m, 2H), 3.47 (s, 1H), 3.41 (s, 2H), 2.71 (d, 3H) , 2.41 (s, 3H), 1.68 (s, 3H), 1.25 (m, 9H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.14, 23.14

LC-MS m/z = 713.2 [M+1].

Example 86

Isopropyl (2S)-2-[[(N-[4-[(2,2-dimethyl-3-oxo-4H-pyridine[3,2-b][1,4]oxazine- 6-yl)amino]-5-fluoro-pyrimidin-2-yl]-3,4,5-trimethoxy-phenylamino)-(methoxymethyl)phosphonium]amino)propionate ( compound) 86 )

Isopropyl(2S)-2-[[(N-[4-[(2,2-dimethyl-3-oxo-4H-pyrido[3,2-b][1,4]oxazin-6-yl)amino]] -5-fluoro-pyrimidin-2-yl]-3,4,5-trimethoxy-ani1ino)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.65 g, 4.0 mmol) dissolved in 30 mL of dry dichloromethane, nitrogen-protected, triethylamine (1.6 g, 16 mmol) dropwise at -30 ° C, L-propylamine A mixture of isopropyl acid (0.52 g, 4.0 mmol) was added dropwise, and the mixture was reacted for 30 min, then 86A (0.94 g, 2.0 mmol) was added and allowed to react at room temperature for 2 h. Wash once with 20 mL of a saturated aqueous solution of sodium dihydrogen phosphate, and wash once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then purified by column chromatography (dichloromethane/methanol = 100/1~20/1) to give compound 86 , white solid (0.4 g, yield 30%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 10.79 (d, 1H), 9.57 (d, 1H), 8.14 (t, 1H), 7.03 (m, 2H), 6.49 (d, 2H), 5.18 (t , 1H), 4.80 (m, 1H), 4.14 (m, 1H), 3.99 (m, 2H), 3.70 (m, 9H), 3.37 (m, 3H), 1.42 (m, 6H), 1.19 (m, 6H), 1.02 (m, 3H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.42, 24.31

LC-MS m/z = 692.2 [M+1].

Example 87

Isopropyl (2S)-2-[[[2-(2-chlorophenyl)-7-hydroxy-8-[(3R,4S)-3-hydroxy-1-methyl-4-indolyl] 4-oxo-benzopyran-5-yl]oxy-(methoxymethyl)phosphonium]amino]propionate ( Compound 87 )

Isopropyl(2S)-2-[[[2-(2-chlorophenyl)-7-hydroxy-8-[(3R,4S)-3-hydroxy-1-methyl-4-piperidyl]-4-oxo-chromen- 5-yl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.46 g, 2.82 mmol) was dissolved in 30 mL of dry dichloromethane, EtOAc (EtOAc) A mixture of isopropyl ester (0.37 g, 2.82 mmol) was reacted for 30 min after the dropwise addition, and 87A (0.619 g, 1.41 mmol) was added, and the mixture was reacted at room temperature for 2 h. The organic layer was washed with saturated aqueous sodium hydrogen sulfate (20 mL) and brine (20 mL). Compound 87 was obtained as a yellow solid (0.16 g, yield 9.1%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.02 (m, 1H), 7.83 (m, 1H), 7.70 (m, 1H), 7.63 (m, 1H), 7.57 (m, 1H), 6.56 (t , 1H), 6.36 (m, 1H), 4.85 (m, 2H), 4.60 (s, 1H), 3.68 (m, 1H), 3.17 (m, 3H), 3.04 (m, 3H), 2.92 (m, 2H), 2.50 (m, 5H), 2.33 (s, 2H), 1.15 (m, 9H).

LC-MS m/z = 623.1 [M + 1].

Example 88

Ethyl(2S)-2-[[[4-[(1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxoheptane-1,6-di Alkene-2-methoxyphenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 88 )

Ethyl(2S)-2-[[[4-[(1E,6E)-7-(4-hydroxy-3-methoxy-phenyl)-3,5-dioxo-hepta-1,6-dienyl]-2- Methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphine dichloride (0.815 g, 5 mmol) dissolved in 20 mL of dry dichloromethane, nitrogen-protected, triethylamine (2.02 g, 20 mmol) and L-alanine were added dropwise at -30 °C A mixture of ethyl ester (0.586 g, 5 mmol) was reacted for 30 min after the dropwise addition, and 88A (2.76 g, 7.5 mmol) was added and allowed to react at room temperature for 2 h. The mixture was washed with saturated aqueous sodium hydrogen sulfate (20 mL) EtOAc (EtOAc) . Compound 88 was obtained as a yellow solid (0.5 g, yield: 20%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.66 (s, 1H), 7.58 (d, 2H), 7.51-7.40 (m, 1H), 7.39-7.22 (m, 3H), 7.17 (dd, 1H) , 6.91 (dd, 1H), 6.81 (dd, 2H), 5.70-5.57 (m, 1H), 4.13-3.91 (m, 4H), 3.90-3.73 (m, 8H), 3.39 (dd, 3H), 1.24 -1.15 (m, 6H).

Example 89

Isopropyl (2S)-2-[[(N-[4-[(2,3-dimethylcarbazol-6-yl)-methyl-amino]pyrimidin-2-yl]-4-methyl) -3-Aminosulfonyl-phenylamino)-(methoxymethyl)phosphonium]amino)propionate ( Compound 89 )

Isopropyl(2S)-2-[[(N-[4-[(2,3-dimethylindazol-6-yl)-methyl-amino]pyrimidin-2-yl]-4-methyl-3-su1famoyl-anilino)- (methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.326 g, 2 mmol) was dissolved in 20 mL of dry dichloromethane, and then filtered with nitrogen, and triethylamine (0.809 g, 7.79 mmol) and L-propyl were added dropwise at -30 °C. A mixture of isopropyl isopropyl ester (0.262 g, 2 mmol) was reacted for 30 min after completion of dropwise addition to obtain a reaction mixture 1. The starting material 89A (0.437 g, 1 mmol) was dissolved in 30 mL of tetrahydrofuran, and was then filtered under nitrogen, and butyl lithium (1.25 mL, 2 mmol, 1.6 mol/L) was added dropwise at -78 ° C. After the completion of the reaction, the reaction mixture was obtained for 30 min. 1 reaction solution was added dropwise to the reaction solution 2, and the mixture was slowly warmed to room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen sulfate (20 mL), EtOAc (EtOAc) Compound 89 was obtained as a white solid (0.2 g, yield 30%).

1H NMR (400MHz, DMSO- d ₆ ) δ 9.67 (d, 2H), 8.43 (s, 1H), 7.77 (dd, 2H), 7.58-7.40 (m, 2H), 7.02 (d, 1H), 6.88 ( Dd,1H), 5.76(q,1H), 4.84(m,1H), 4.15-4.00(m,3H),3.81(s,2H),3.62-3.46(m,3H),3.44-3.36(m, 2H), 3.18 (d, 3H), 3.02 (m, 3H), 2.64 (d, 3H), 1.24-1.13 (m, 9H).

LC-MS m/z = 659.2 [M+1].

Example 90

Isopropyl (2S)-2-[[[4-[(E)-2-(3,5-dihydroxyphenyl)vinyl]phenoxy]-(methoxymethyl)phosphonium] Amino]propionate ( compound 90-1 )

Isopropyl(2S)-2-[[[4-[(E)-2-(3,5-dihydroxyphenyl)vinyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Isopropyl (2S)-2-[[[3-hydroxy-5-[(E)-2-(4-hydroxyphenyl)vinyl]phenoxy]-(methoxymethyl)phosphonium) Amino]propionate ( compound 90-2 ); isopropyl(2S)-2-[[[3-hydroxy-5-[(E)-2-(4-hydroxyphenyl)vinyl]phenoxy]-(methoxymethyl)phosphoryl ]amino]propanoate

(Methoxymethyl)phosphine dichloride (2.14 g, 13.14 mmol) was dissolved in dichloromethane (30 mL), and isopropyl L-alanine (1.72 g, 13.11) was slowly added dropwise at -30 °C. A solution of a mixture of mmol and triethylamine (3.03 g, 30 mmol) in dichloromethane (10 mL). After stirring at this temperature for 30 min, the mixture was slowly added to a solution of 90A (3 g, 13.14 mmol Dichloromethane (100 mL) was added and washed successively with a saturated solution of sodium dihydrogen phosphate (50 mL×1) and a saturated solution of sodium chloride (50 mL×1). After drying over anhydrous sodium sulfate, the organic layer was concentrated. Separation and purification by column chromatography (ethyl acetate / petroleum ether = (v / v) 1 / 5 / 2 / 1) to give a crude product (a mixture of compound 90-1 and compound 90-2 ) as a pale yellow solid (2.2 g , yield 37.25%).

The crude product was isolated to give the two isomers 90-1a of compound 90-1 ( yield : 290 mg as white solid, </ RTI></RTI></RTI></RTI> ee% = 100%), 90-1b (light yellow solid, 400 mg, retention time 24.630 min) , ee% = 100%), two isomers 90-2a of compound 90-2 (white solid 190 mg, retention time 6.329 min, ee% = 100%), 90-2b (white solid 260 mg, retention time 13.295 min) , ee%=100%).

Separation conditions: Instrument: Thar 80preparative SFC (SFC-16); Column: ChiralPak AD, 250 x 30 mm ID, 5 μm; mobile phase: Phase A is CO ₂ and Phase B is IPA; Gradient: B 40%; Flow rate: 60 mL /min; back pressure: 100 bar; column temperature: 38 ° C; detection wavelength: 220 nm; period : ~ 18 min.

Compound 90-1a:

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.22 (s, 2H), 7.56 (d, 2H), 7.15 (d, 2H), 7.00 (s, 2H), 6.42 (d, 2H), 6.16 (t , 1H), 5.65 (dd, 1H), 4.89-4.82 (m, 1H), 3.91-3.85 (m, 1H), 3.79 (d, 2H), 3.40 (d, 3H), 1.21-1.13 (m, 9H) ).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.76.

LC-MS m/z = 450.1 [M + 1].

Compound 90-1b:

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.22 (s, 2H), 7.68-7.41 (m, 2H), 7.18 (d, 2H), 7.07-6.90 (m, 2H), 6.46 (t, 2H) , 6.16(t,1H), 5.68(dd,1H),4.89-4.82(m,1H),3.93-3.81(m,1H),3.80-3.72(m,2H),3.35(t,3H),1.23 -1.09 (m, 9H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 23.91.

LC-MS m/z = 450.1 [M + 1].

Compound 90-2a

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.59 (d, 2H), 7.41 (d, 2H), 7.01 (d, 1H), 6.88 (d, 1H), 6.82-6.64 (m, 4H), 6.52 (s, 1H), 5.68-5.46 (m, 1H), 4.89-4.82 (m, 1H), 3.89 (dd, 1H), 3.77 (d, 2H), 3.40 (s, 3H), 1.23-1.09 (m , 9H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.34.

LC-MS m/z = 450.1 [M + 1].

Compound 90-2b

_{1H NMR (400MHz, DMSO- d 6} ) δ 9.60 (s, 2H), 7.41 (d, 2H), 7.03 (d, 1H), 6.88 (d, 1H), 6.81 (s, 1H), 6.77 (d, 2H), 6.72 (s, 1H), 6.53 (d, 1H), 5.62 (dd, 1H), 4.89-4.83 (m, 1H), 3.93-3.78 (m, 1H), 3.78-3.65 (m, 2H) , 3.36 (d, 3H), 1.22-1.12 (m, 9H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.43

LC-MS m/z = 450.1 [M + 1].

Example 91

Isopropyl (2S)-2-[[methoxymethyl-[methyl-[(3R)-3-(2-methylphenoxy)-3-phenyl-propyl]amino]phosphonium Amino]propionate ( compound 91 )

Isopropyl(2S)-2-[[methoxymethyl-[methyl-[(3R)-3-(2-methylphenoxy)-3-phenyl-propyl]amino]phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.500 g, 3.07 mmol) was dissolved in 20 mL of dry dichloromethane, and then filtered, and then triethylamine (1.24 g, 12.3 mmol) was added dropwise at -30 ° C, L- A mixture of alanine isopropyl ester hydrochloride (0.514 g, 3.07 mmol) was added dropwise, and the mixture was reacted for 30 minutes, and 91A (0.895 g, 3.07 mmol) was added thereto, and the mixture was reacted at room temperature for 2 hours. Add 50 mL of water, extract with methylene chloride (100 mL×2), wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. (The solvent was methanol: dichloromethane (v/v) = 0: 100 to 1: 50) to give Compound 91 as a pale yellow oil (0.180 g, yield 12.3%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.38 (d, 2H), 7.33 (t, 2H), 7.24 (t, 1H), 7.10 (d, 1H), 6.95 (t, 1H), 6.69 (m , 2H), 5.33 (m, 1H), 4.85 (m, 1H), 4.70 (m, 1H), 3.68 (m, 1H), 3.53 (m, 2H), 3.26 (d, 3H), 3.10 (m, 2H), 2.55 (t, 3H), 2.25 (s, 3H), 2.10 (m, 1H), 2.02 (m, 1H), 1.25 (m, 3H), 1.15 (m, 6H).

LCMS m/z = 499.3 [M+23].

Example 92

Isopropyl (2S)-2-[[methoxymethyl-[methyl-[(3S)-3-(1-naphthalenyloxy)-3-(2-thienyl)propyl]amino]phosphine Mercapto]amino]propionate ( compound 92 )

Isopropyl(2S)-2-[[methoxymethyl-[methyl-[(3S)-3-(1-naphthyloxy)-3-(2-thienyl)propyl]amino]phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.500 g, 3.07 mmol) was dissolved in 10 mL of dry methylene chloride, and then evaporated, and then triethylamine (1.24 g, 12.3 mmol) was added dropwise at -30 ° C, L- A mixture of alanine isopropyl ester hydrochloride (0.514 g, 3.07 mmol) was reacted for 30 minutes after the dropwise addition, and 92A (1.02 g, 3.07 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Add 50 mL of water, extract with methylene chloride (100 mL×2), wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. (The solvent was methanol: methylene chloride (v/v) = 0: 100 to 1:50) to give Compound 92 as a pale yellow oil (0.300 g, yield 18.9%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.29-8.22 (m, 1H), 7.88-7.80 (m, 1H), 7.54-7.47 (m, 2H), 7.43 (t, 2H), 7.36-7. m,1H), 7.27-7.21 (m, 1H), 7.03 (d, 1H), 6.97 (m, 1H), 5.92 (m, 1H), 4.92-4.81 (m, 1H), 4.81-4.69 (m, 1H), 3.74-3.64 (m, 1H), 3.60-3.46 (m, 2H), 3.27 (d, 1H), 3.24 (d, 2H), 3.22-3.05 (m, 2H), 2.59 (m, 3H) , 2.43 - 2.31 (m, 1H), 2.25 - 2.09 (m, 1H), 1.22 (d, 3H), 1.20 - 1.09 (m, 6H).

LC-MS m/z = 519.2 [M+1].

Example 93

[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxoethyl]amino]-(methoxymethyl)phosphonyl]oxyphenyl]methyl 5-fluoro-2,4-dioxo-pyrimidine-1-carboxylate ( Compound 93 )

[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methyl5-fluoro-2,4-dioxo-pyrimidine-1-carboxylate

The triphosgene (0.143 g, 0.482 mmol) was dissolved in 20 mL of dry methylene chloride, and the mixture was filtered under nitrogen, and then a solution of Intermediate 4 (0.500, 1.45 mmol) in dichloromethane (5 mL) was added dropwise, and triethylamine was added dropwise under ice cooling. 5 mL of a dichloromethane solution (0.147 g, 1.45 mmol) was added dropwise, and the mixture was slowly warmed to room temperature for 1 hour. 93A (0.377 g, 2.90 mmol) and triethylamine (0.147 g, 1.45 mmol) were added to the reaction mixture, and the mixture was slowly warmed to room temperature for 2 hours. The mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (20 mL) and brine (50 mL). v) = 0: 100 to 1: 50) gave Compound 93 as a white solid (0.300 g, yield 41.3%).

LC-MS m/z = 500.0 [M-1].

Example 94

(2S)-((isopropoxycarbonyl)oxy)methyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4 ,12,14-tetrahydro-1H-pyran[3',4':6,7]pyridazine[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphonium Amino)propionate ( compound 94 )

(2S)-((isopropoxycarbonyl)oxy)methyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano [3',4':6,7]indolizino[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphoryl)amino)pr Opanoate

(Methoxymethyl)phosphonium dichloride (0.23 g, 1.42 mmol) was dissolved in dichloromethane (5 mL) and EtOAc (3.sub.4 g, 1.42 mmol) and triethylamine 0.3g, 3mmol) in dichloromethane (5mL) was a mixture, kept under stirring at this temperature for 30min, added 94A (0.28g, 0.71mmol), warmed to reflux, stirred for 30min. After cooling to room temperature, dichloromethane (20 mL) was added, and the mixture was washed successively with a saturated solution of sodium dihydrogen phosphate (10 mL×1) and saturated sodium carbonate (10 mL×3), dried over anhydrous sodium sulfate, and concentrated. Purification by chromatography (dichloromethane / methanol = (v/v) 100/1~20/1) gave Compound 94 as pale yellow solid (0.16 g,

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.25 (d, 1H), 8.00 (m, 1H), 7.69 (m, 2H), 5.75 (m, 3H), 5.29 (dd, 3H), 4.91 (m, 1H ), 4.29 (m, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.50 (dd, 3H), 3.17 (m, 2H), 1.89 (m, 2H), 1.40 (m, 6H) , 1.30 (t, 6H), 1.04 (t, 3H).

LC-MS m/z = 688.2 [M+1].

Example 95

(2S)-ethyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyridyl) Methyl [3',4':6,7]pyridazino[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphonium)amino)propionate ( compound) 95 )

(2S)-ethyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4' :6,7]indolizino[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphonium dichloride (0.83 g, 5.10 mmol) was dissolved in dichloromethane (10 mL), and then slowly added dropwise ethyl L-alanine (0.60 g, 5.10 mmol) at -30 °C A solution of a mixture of triethylamine (1.52 g, 15.03 mmol) in dichloromethane (5 mL). After stirring at this temperature for 30 min, 94A (1 g, 2.55 mmol) was then evaporated. After cooling to room temperature, dichloromethane (100 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (50 mL×1) and saturated sodium carbonate (50 mL×3), dried over anhydrous sodium sulfate, Separation and purification by hydrazine column chromatography (dichloromethane/methanol = (v/v) 100/1~20/1) afforded pale yellow solid compound 95 (0.2 g, yield 13.08%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.18 (dd, 1H), 7.98 (m, 1H), 7.68 (dd, 1H), 7.62 (t, 1H), 5.74 (d, 1H), 5.27 (m, 3H ), 4.18 (m, 3H), 3.90 (m, 3H), 3.73 (m, 1H), 3.52 (m, 3H), 3.16 (q, 2H), 1.90 (m, 2H), 1.40 (m, 3H) , 1.36 (m, 3H), 1.23 (m, 3H), 1.03 (dd, 3H).

LC-MS m/z = 598.3 [M-1]

Example 96

(2S)-Benzyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyridyl) Methyl [3',4':6,7]pyridazino[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphonium)amino)propionate Compound 96 )

(2S)-benzyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4' :6,7]indolizino[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphine dichloride (0.83 g, 5.10 mmol) was dissolved in dichloromethane (10 mL), and benzyl L-alanine (0.91 g, 5.10 mmol) was slowly added dropwise at -30 °C. A solution of a mixture of triethylamine (1.52 g, 15.03 mmol) in dichloromethane (5 mL). Stir at this temperature for 30 min, add 94A (1 g, 2.55 mmol), warm to reflux and stir for 30 min. After cooling to room temperature, dichloromethane (100 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (50 mL×1) and saturated sodium carbonate (50 mL×3), dried over anhydrous sodium sulfate, Separation and purification by hydrazine column chromatography (dichloromethane / methanol = (v/v) 100/1~20/1) gave Compound 96 (0.7 g, pale yellow solid, yield 41.49%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.18 (dd, 1H), 7.96 (m, 1H), 7.65 (m, 2H), 7.31 (m, 5H), 5.74 (d, 1H), 5.32 (m, 2H ), 5.22 (d, 2H), 5.09 (m, 2H), 4.28 (m, 1H), 3.83 (m, 3H), 3.46 (dd, 3H), 3.13 (q, 2H), 1.90 (m, 2H) , 1.37 (m, 6H), 1.03 (t, 3H).

LC-MS m/z = 662.3 [M+1].

Example 97

2-[1-[[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium) ]oxy-3-methoxy-phenyl]methoxycarbonylamino]methyl]cyclohexyl]acetic acid ( compound 97 )

2-[1-[[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-3-methoxy-phenyl]methoxycarbonylamino]methyl ]cyclohexyl]acetic acid

Intermediate 7 (0.50 g, 1.30 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; The reaction liquid 1 was obtained by stirring for 1 hour. Gabapentin (0.23 g, 1.30 mmol), N,N-dimethylformamide (10 mL), diisopropylethylamine (0.50 g, 4.00 mmol) was added to the reaction flask, and the above reaction solution 1 was added dropwise. Warm reaction for 2h. 30 mL of a saturated aqueous solution of sodium dihydrogen phosphate was added, and the mixture was evaporated. Reversed-phase preparation method: a chromatographic column prepared by using C18 with a specification of 19×250 mm, the flow rate was set to 12 mL/min; the mobile phase composition was: acetonitrile and water containing 0.1% ammonium acetate; the gradient elution method was: acetonitrile content 15%~54 %; Gradient elution retention time: 13 min. Compound 97 (0.08 g, colorless oil, yield 10.75%) was obtained.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.26 (d, 1H), 6.94 (s, 1H), 6.88 (t, 1H), 5.47 (s, 1H), 5.03 (d, 2H), 4.98 (m, 1H ), 4.06 (dd, 1H), 3.88 (m, 5H), 3.49 (d, 3H), 3.23 (d, 2H), 2.28 (s, 2H), 1.31 (m, 19H)

LC-MS m/z = 573.3 [M+1].

Example 98

Isopropyl (2S)-2-[[methoxymethyl-[2-[[4-[(3-pyridylmethoxycarbonylamino)methyl]benzylidenyl]amino]phenylamino]phosphine Mercapto]amino]propionate ( compound 98 )

Isopropyl(2S)-2-[[methoxymethyl-[2-[[4-[(3-pyridylmethoxycarbonylamino)methyl]benzoyl]amino]anilino]phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.200 g, 1.23 mmol) was dissolved in 10 mL of dry dichloromethane, and then filtered with nitrogen, triethylamine (0.373 g, 3.68 mmol) was added dropwise at -30 ° C, L- A mixture of alanine isopropyl ester hydrochloride (0.206 g, 1.23 mmol) was reacted for 30 minutes after the completion of the dropwise addition. 98A (0.462 g, 1.23 mmol) was added, and the mixture was reacted at room temperature for 2 hours, using a saturated aqueous solution of sodium dihydrogen phosphate ( Washed, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and evaporated. 1:50) Compound 98 was obtained as a pale yellow solid.

LC-MS m/z = 598.2 [M+1].

Example 99

Ethyl(2S)-2-[[[(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-2-oxo-indoline- 1-yl]-(methoxymethyl)phosphonium]amino]propionate ( Compound 99 )

Ethyl(2S)-2-[[[(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-2-oxo-indolin-1-yl]-(methoxymethyl)phosphoryl ]amino]propanoate

(Methoxymethyl)phosphonium dichloride (4.1 g, 25.2 mmol) was dissolved in 50 mL of dry dichloromethane, and then filtered, and then triethylamine (10.2 g, 101 mmol) was added dropwise at -30 ° C. A mixture of ethyl acetate (2.95 g, 25.2 mmol) was reacted for 30 min after completion of dropwise addition to obtain a reaction mixture 1. 41A (3.0 g, 12.6 mmol) was dissolved in 30 mL of tetrahydrofuran, and the mixture was filtered under nitrogen, and butyl lithium (15.75 mL, 1.6 mol/L, 25.2 mmol) was added dropwise at -78 ° C. After the completion of the reaction, the reaction mixture was obtained for 30 min. 1 reaction solution was added dropwise to the reaction solution 2, and the mixture was slowly warmed to room temperature for 2 hours. The reaction mixture was washed once with saturated aqueous sodium hydrogen sulfate (20 mL) and brine (50 mL) /1) gave Compound 99 as a yellow solid (0.6 g, yield 11%).

1.5 g of compound 99 was prepared to give two isomers 99-a (white solid 520 mg, retention time 9.848 min, ee% = 97.97%), 99-b (light yellow solid, 550 mg, retention time 24.630 min, ee% =96.92%).

Separation conditions: A chromatography column was prepared using C18 having a size of 30*150 mm. The flow rate was set to 30 mL/min. Mobile phase composition: acetonitrile and water containing 0.1% ammonium acetate. Gradient extraction method: acetonitrile content 50%~63%, gradient extraction time: 15min

Compound 99-a:

_{1H NMR (400MHz, CDCl 3)} δ 12.69 (s, 1H), 8.03-7.93 (m, 1H), 7.45 (d, 1H), 7.38 (s, 1H), 7.12 (m, 2H), 6.01 (d, 1H), 4.66 (t, 1H), 4.40-4.25 (m, 1H), 4.15 (dd, 1H), 4.07-3.87 (m, 3H), 3.48 (d, 3H), 2.39 (d, 3H), 2.34 (d, 3H), 1.50 (d, 3H), 1.01 (t, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.76.

LC-MS m/z = 446.1 [M+1].

Compound 99-b:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 12.70 (s, 1H), 8.07-7.92 (m, 1H), 7.46 (d, 1H), 7.39 (s, 1H), 7.14 (m, 2H), 6.02 (d , 1H), 4.63 (t, 1H), 4.46-4.30 (m, 1H), 4.19 (m, 3H), 4.02 (dd, 1H), 3.45 (d, 3H), 2.42 (s, 3H), 2.35 ( d, 3H), 1.37 (d, 3H), 1.33-1.20 (m, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.10

LC-MS m/z = 446.1 [M+1].

Example 100

Isopropyl (2S)-2-[[methoxymethyl(2-phenylethylsulfanyl)phosphonium]amino]propionate ( Compound 100 )

Isopropyl(2S)-2-[[methoxymethyl(2-phenylethylsulfanyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (2.4 g, 14 mmol) was dissolved in 40 mL of dry dichloromethane, and then filtered with nitrogen, and triethylamine (5.9 g, 58 mmol) was added dropwise at -30 ° C. A mixture of isopropyl acid (1.9 g, 14 mmol) was reacted for 30 min after the dropwise addition, and 100A (1.0 g, 7.2 mmol) was added and allowed to react at room temperature for 2 h. The reaction solution was washed once with a saturated aqueous solution of sodium hydrogen sulfate (20 mL) and brine (20 mL). 2/1) gave Compound 100 as a colorless oil (0.5 g, yield 19%).

_{1H NMR (400MHz, CDCl 3)} δ 7.33-7.27 (m, 2H), 7.22 (dd, 3H), 5.09-4.96 (m, 1H), 4.09 (m, 1H), 3.96-3.62 (m, 3H), 3.46 (dd, 3H), 3.19-3.04 (m, 2H), 3.04-2.88 (m, 2H), 1.42 (dd, 3H), 1.29-1.21 (m, 6H).

LC-MS m/z = 360.1 [M + 1].

Example 101

Isopropyl (2S)-2-[[[5-hydroxy-2-isopropyl-4-[4-(1-methylindol-5-yl)-5-oxo-1H-1,2 ,4-triazol-3-yl]phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 101 )

Isopropyl(2S)-2-[[[5-hydroxy-2-isopropyl-4-[4-(1-methylindol-5-yl)-5-oxo-1H-1,2,4-triazol-3-yl ]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

1C (0.700 g, 4.30 mmol) was dissolved in dry methylene chloride (10 mL), cooled to -30 ° C under nitrogen atmosphere, and a solution of Intermediate 2A in dichloromethane (0.564 g, 4.30 mmol, 3 mL) After a mixture of triethylamine (1.74 g, 17.2 mmol) was added, the reaction was continued at -30 ° C for 30 min, and 101A (0.783 g, 2.15 mmol) was added, and the mixture was allowed to warm to room temperature and the reaction was continued for 1 h. A saturated aqueous solution of sodium dihydrogen phosphate (20 mL) and dichloromethane (20 mL) was evaporated. Separation and purification (petroleum ether: ethyl acetate (v/v) = 1:1 to 1:4) gave Compound 101 as a white solid (0.200 g, yield 7.95%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 11.92 (d, 1H), 9.75 (s, 1H), 7.43-7.33 (m, 3H), 7.02 (d, 1H), 6.95-6.89 (m, 1H) , 6.80 (dd, 1H), 6.38 (d, 1H), 5.67-5.54 (m, 1H), 4.86-4.80 (m, 1H), 3.86-3.78 (m, 1H), 3.76 (s, 3H), 3.74 -3.65 (m, 2H), 3.31 (d, 3H), 3.08-3.04 (m, 1H), 1.16-1.04 (m, 9H), 0.95-0.91 (m, 6H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.37, 23.34.

LC-MS m/z = 586.2 [M + 1].

Example 102

Isopropyl (2S)-2-[[[4-(8-chloro-5,6-dihydrobenzo[1,2]cycloheptyl[3,4-b]pyridine-11-ylidene)- 1-acridinyl]-(methoxymethyl)phosphonium]amino]propionate ( Compound 102 )

Isopropyl(2S)-2-[[[4-(8-chloro-5,6-dihydrobenzo[1,2]cyclohepta[3,4-b]pyridin-11-ylidene)-1-piperidyl]-(methoxymethyl) Phosphoryl]amino]propanoate

1C (0.500 g, 3.07 mmol) was dissolved in 20 mL of dry methylene chloride, and then filtered with nitrogen, and triethylamine (4.05 g, 40 mmol) was added dropwise at -30 ° C, L-alanine isopropyl ester hydrochloride (0.514) A mixture of g, 3.07 mmol) was reacted for 30 min after the dropwise addition, and 102A (0.954 g, 3.07 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Add 50 mL of water, extract with methylene chloride (100 mL×2), wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. (The solvent was methanol: methylene chloride (v/v) = 0: 100 to 1: 50) to give Compound 102 as a yellow solid (0.430 g, yield: 26.3%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.38-8.29 (m, 1H), 7.57 (d, 1H), 7.30 (d, 1H), 7.25-7.14 (m, 2H), 7.12-7.03 (m, 1H), 4.93-4.69 (m, 2H), 3.74 (dd, 1H), 3.66-3.51 (m, 2H), 3.35-3.27 (m, 7H), 2.94-2.74 (m, 4H), 2.32-2.19 ( m, 2H), 2.14 (dd, 2H), 1.24 (d, 3H), 1.18 (m, 6H).

LC-MS m/z = 532.3 [M + 1].

Example 103

Isopropyl (2S)-2-[[[2-[(1R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenoxy](methoxymethyl) (phosphonium)amino]propionate ( compound 103 ); isopropyl (2S)-2-[[[2-[(1R)-3-(diisopropylamino)-1-phenyl-propyl]-4-methyl- Phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

1C (0.70 g, 4.30 mmol) was dissolved in dichloromethane (10 mL), EtOAc (EtOAc) 1.01 g, 10 mmol) a solution of the mixture in dichloromethane (5 mL). After stirring at this temperature for 30 min, (R)-2-(3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol (0.7 g, 2.15 mmol). The solution was warmed to room temperature and stirred for 30 min. Dichloromethane (50 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (20 mL×1) and a saturated solution of sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by column chromatography (dichloromethane / methanol = (v/v) 100/1~20/1) afforded Compound 103 (0.4 g, yield: 34.04%).

_{^{1 HNMR (400MHz, CDCl 3)}} δ 7.35 (m, 1H), 7.30-7.12 (m, 6H), 6.98-6.87 (m, 1H), 5.01-4.87 (m, 1H), 4.27 (dd, 1H), 4.06-3.72 (m, 2H), 3.58 (dd, 1H), 3.55-3.28 (m, 4H), 2.55-1.92 (m, 8H), 1.35-1.08 (m, 9H), 0.99-0.84 (m, 13H) ).

LC-MS m/z = 547.4 [M+1].

Example 104

[4-[2-[2-(Dimethylamino)-2-oxo-ethoxy]-2-oxoethyl]phenyl]4-[N-[[[(1S)-2-) Propyl-1-methyl-2-oxoethyl]amino]-(methoxymethyl)phosphonium]methyl indenyl]amino)benzoate

[4-[2-[2-(dimethylamino)-2-oxo-ethoxy]-2-oxo-ethyl]phenyl]4-[[N-[[[(1S)-2-isopropoxy-1-methyl-2 -oxo-ethyl]amino]-(methoxymethyl)phosphoryl]carbamimidoyl]amino]benzoate

1C (0.82 g, 5.02 mmol) was dissolved in dichloromethane (10 mL), EtOAc (EtOAc) A solution of 1.21 g, 12.00 mmol) in dichloromethane (5 mL). After stirring at this temperature for 30 min, 104A (1 g, 2.51 mmol). After cooling to room temperature, dichloromethane (50 mL) was added, and the mixture was washed with saturated aqueous sodium hydrogen sulfate (20 mL×1) and saturated sodium chloride (20 mL×1), dried over anhydrous sodium sulfate The residue was separated and purified by silica gel column chromatography (methylene chloride / methanol = (v / v) 100/ 1 ~ 30/1), to give compound 104 as a white solid (0.2g, yield 12.86%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.89 (s, 1H), 7.86 (s, 1H), 7.27 (d, 3H), 7.12 (t, 3H), 5.62 (s, 1H), 4.98 (s , 2H), 4.90-4.74 (m, 1H), 3.89-3.81 (m, 1H), 3.79-3.70 (m, 2H), 3.60 (s, 2H), 3.37 (dd, 3H), 2.98 (s, 3H) ), 2.84 (s, 3H), 1.19-1.14 (m, 9H).

LC-MS m/z = 620.3 [M + 1].

Example 105

[(3R)-3-[5-(Hydroxymethyl)-2-[[[(1S)-2-isopropyl-1-methyl-2-oxo-ethyl]amino]-(methoxy) Methyl)phosphonium]oxy-phenyl]-3-phenyl-propyl]-diisopropyl-ammonium hydrochloride ( Compound 105 )

[(3R)-3-[5-(hydroxymethyl)-2-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-phenyl]- 3-phenyl-propyl]-diisopropyl-ammonium chloride

1C (0.48 g, 2.93 mmol) was dissolved in dichloromethane (10 mL), EtOAc (EtOAc) A solution of 0.61 g, 6.03 mmol) in dichloromethane (5 mL). After stirring at this temperature for 30 min, the reaction was slowly added to a solution of EtOAc (1 g, 2. Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen sulfate (20 mL×1) and saturated sodium chloride (20 mL×1), dried over anhydrous sodium sulfate It was separated and purified by EtOAc (MeOH/MeOH = (v/v) 100/1~20/1) to afford white solid ( Compound 105 ) (0.4 g, yield 22.82%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.74 (d, 1H), 7.39 (dd, 3H), 7.34-7.25 (m, 3H), 7.20 (t, 1H), 7.13 (t, 1H), 5.84 -5.53(m,1H), 5.18(m,1H),4.94-4.73(m,1H),4.59-4.37(m,3H),3.99-3.69(m,3H),3.59(s,2H),3.43 (d, 3H), 3.03-2.74 (m, 2H), 1.46-1.29 (m, 1H), 1.27-1.12 (m, 21H).

LC-MS m/z = 563.3 [M + 1].

Example 106

Isopropyl (2S)-2-[[methoxymethyl-[2-methoxy-4-[[(E)-8-methylindole-6-enyl]amino]methyl]benzene Oxy]phosphonium]amino]propionate ( compound 106 )

Isopropyl(2S)-2-[[methoxymethyl-[2-methoxy-4-[[[(E)-8-methylnon-6-enoyl]amino]methyl]phenoxy]phosphoryl]amino]propanoate

1C (1.0g, 6.1mmol) was dissolved in dry dichloromethane (30mL), cooled to -30 ° C under nitrogen atmosphere, and slowly added dropwise L-alanine isopropyl ester (0.81g, 6.1mmol) A mixture of a solution of chloromethane (4 mL) and triethylamine (2.5 g, 24.4 mmol) was added dropwise, and the mixture was reacted at -30 ° C for 30 minutes. Then, 106A (0.94 g, 3.1 mmol) was added, and the reaction was allowed to continue to room temperature for 1 h. A saturated aqueous solution of sodium dihydrogen phosphate (20 mL) and dichloromethane (20 mL) was added to the mixture, and the organic layer was washed with saturated sodium hydrogen sulfate (20 mL×1) and dried over anhydrous sodium sulfate. Chromatography separation and purification (petroleum ether: ethyl acetate (v / v) = 3:1 ~ 1:1) to give compound 106 , white semi-solid (1.1 g, yield 65%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.24 (dd, 1H), 6.87 (s, 1H), 6.78 (dd, 1H), 5.87 (s, 1H), 5.42-5.27 (m, 2H), 5.04-4.92 (m, 1H), 4.46-4.31 (m, 2H), 4.16-4.02 (m, 1H), 3.93-3.76 (m, 6H), 3.53-3.38 (m, 3H), 2.25-2.16 (m, 2H) , 2.06-1.96 (m, 1H), 1.72-1.60 (m, 2H), 1.43-1.36 (m, 2H), 1.36-1.30 (m, 2H), 1.30-1.10 (m, 9H), 0.95 (d, 6H)

³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.47, 24.94.

LC-MS m/z = 527.3 [M + 1].

Example 107

Isopropyl (2S)-2-[[(11-aminocarbamimid-5,6-benzobishydro[b][1]benzazepine-5-yl)oxy-(methoxymethyl) (phosphoryl)amino)propionate ( compound 107 )

Isopropyl(2S)-2-[[(11-carbamoyl-5,6-dihydrobenzo[b][1]benzazepin-5-yl)oxy-(methoxymethyl)phosphoryl]amino]propanoate

1C (0.64 g, 3.9 mmol) was dissolved in 20 mL of dry methylene chloride, and then filtered with nitrogen, and triethylamine (1.6 g, 16 mmol) was added dropwise at -30 ° C, isopropyl L-alanine (0.52 g, 3.9 A mixture of mmol) was added dropwise and the reaction was carried out for 30 min to obtain a reaction mixture 1. 107A (0.5 g, 2.0 mmol) was dissolved in 30 mL of tetrahydrofuran, and nitrogen-protected, butyl lithium (2.4 mL, 3.9 mmol, 1.6 mol/L) was added dropwise at -78 ° C, and the mixture was allowed to react for 30 min to obtain a reaction liquid 2. 1 reaction solution was added dropwise to the reaction solution 2, and the mixture was slowly warmed to room temperature for 2 hours. Washed with a saturated aqueous solution of sodium dihydrogen phosphate (20 mL × 1), brine (20 mL × 1), dried over anhydrous sodium sulfate Compound 107 was obtained as a colorless oil (0.18 g, yield 19%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.74-7.14 (m, 8H), 6.08 (s, 1H), 5.16-4.97 (m, 1H), 4.94-4.61 (m, 2H), 4.22-3.93 (m, 1H), 3.69 (dd, 3H), 3.59-3.13 (m, 5H), 1.48-1.14 (m, 9H).

LC-MS m/z = 476.1 [M+1].

Example 108

Ethyl (2S)-2-[[[4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2) -Methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo- 5a,6,8a,9-tetrahydro-5H-isobenzofuran [5,6-f][1,3]benzoxazole-9-yl]-2,6-dimethoxy-benzene Oxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 108 )

Ethyl(2S)-2-[[[4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl -4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a,9-tetrahydro-5H -isobenzofuro[5,6-f][1,3]benzodioxo1-9-yl]-2,6-dimethoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

1C (1.15 g, 7.06 mmol) was dissolved in 20 mL of dry methylene chloride, and then filtered, and then triethylamine (2.86 g, 28.2 mmol), EtOAc (0.827 g, 7.06) Mixture of mmol), after completion of the dropwise addition, reaction was carried out for 30 min, and 108A (2.91 g, 4.94 mmol) was added and reacted at room temperature for 2 h. Washed with a saturated aqueous solution of sodium dihydrogen phosphate (20 mL × 1), brine (20 mL × 1), dried over anhydrous sodium sulfate 0) gave Compound 108 as a white solid (2.2 g, yield 39%).

^{1 H NMR (400MHz, DMSO-} d 6) δ 7.02 (s, 1H), 6.53 (d, 1H), 6.24 (d, 2H), 6.02 (s, 2H), 5.75 (s, 1H), 5.20 (dd , 3H), 4.95 (d, 1H), 4.72 (d, 1H), 4.63-4.56 (m, 2H), 4.56-4.40 (m, 1H), 4.27 (d, 2H), 4.12-3.96 (m, 7H) ), 3.81 (d, 3H), 3.63 (d, 6H), 3.50 (d, 2H), 3.34 (m,, 4H), 3.28-3.21 (m, 1H), 3.18 (d, 1H), 3.07 (m) , 1H), 2.95-2.84 (m, 1H), 1.20 (dd, 3H).

LC-MS m/z = 796.3 [M+1].

Example 109

Isopropyl (2S)-2-[[[(4R)-3-[4-[2-(dicyanomethyl)indolyl]phenyl]-4-methyl-6-oxo-4, 5-dihydrothiazol-1-yl]-(methoxymethyl)phosphonium]amino)propionate ( Compound 109 )

Isopropyl(2S)-2-[[[(4R)-3-[4-[2-(dicyanomethylene)hydrazino]phenyl]-4-methyl-6-oxo-4,5-dihydropyridazin-1-yl]-( Methoxymethyl)phosphoryl]amino]propanoate

1C (0.92 g, 5.6 mmol) was dissolved in 30 mL of dry methylene chloride, EtOAc (EtOAc m. The mixture was poured, and the reaction was carried out for 30 min to obtain a reaction liquid 1. 109A (0.79 g, 2.8 mmol) was dissolved in 20 mL of tetrahydrofuran, and nitrogen-protected, butyl lithium (6.87 mL, 11 mmol) (1.6 mol/L) was added dropwise at -78 ° C, and the mixture was allowed to react for 30 min to obtain a reaction liquid 2. 1 reaction solution was added dropwise to the reaction solution 2, and the reaction was slowly carried out to room temperature for 2 hours. The mixture was washed with saturated aqueous sodium hydrogen sulfate (20 mL×1) and brine (20 mL×1). 1) Compound 109 was obtained as a yellow solid (0.6 g, yield 21%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.10 (s, 1H), 7.89 (dd, 2H), 7.58-7.47 (m, 2H), 5.49-5.23 (m, 1H), 4.85 (m, 1H) , 4.09-3.90 (m, 3H), 3.48 (dd, 1H), 3.37 (dd, 3H), 2.81 (m, 1H), 2.39 (dd, 1H), 1.30 (d, 3H), 1.19-1.06 (m , 9H).

LC-MS m/z = 502.2 [M + 1].

Example 110

Isopropyl (2S)-2-[[[4-[[4-(4-bromo-2-fluoro-phenylamino)-6-methoxy-quinazolin-7-yl]oxymethyl] -1-Acridine]-(methoxymethyl)phosphonium]amino]propionate ( Compound 110 )

Isopropyl(2S)-2-[[[4-[[4-(4-bromo-2-fluoro-anilino)-6-methoxy-quinazolin-7-yl]oxymethyl]-1-piperidyl]-(methoxymethyl)phosphoryl ]amino]propanoate

First step: N-(4-bromo-2-fluoro-phenyl)-6-methoxy-7-(4-oxaridinylmethoxy)quinazolin-4-amine ( 110B )

N-(4-bromo-2-fluoro-phenyl)-6-methoxy-7-(4-piperidylmethoxy)quinazolin-4-amine

Compound 110A (3.0 g, 5.3 mmol) was dissolved in 1,4-dioxane (30 mL). The reaction mixture was added to 30mL of water, potassium carbonate adjusted to pH 9, extracted with dichloromethane (50mL × 2) and extracted, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, to give compound HOB, a gray solid (2.0 g of, 81% yield) .

_{1H NMR (400MHz, DMSO- d 6} ) δ 9.52 (s, 1H), 8.34 (s, 1H), 7.79 (s, 1H), 7.64 (dd, 1H), 7.53 (t, 1H), 7.46 (dd, 1H), 7.17 (s, 1H), 3.99-3.93 (m, 4H), 3.57 (s, 4H), 2.96 (d, 2H), 1.89 (d, 1H), 1.72 (d, 2H), 1.28-1.12 (m, 2H).

LC-MS m/z = 461.0 [M+1].

Second step: isopropyl (2S)-2-[[[4-[[4-(4-bromo-2-fluoro-phenylamino)-6-methoxy-quinazolin-7-yl]oxy) Methyl]-1-acridine]-(methoxymethyl)phosphonium]amino]propionate ( Compound 110 )

Isopropyl(2S)-2-[[[4-[[4-(4-bromo-2-fluoro-anilino)-6-methoxy-quinazolin-7-yl]oxymethyl]-1-piperidyl]-(methoxymethyl)phosphoryl ]amino]propanoate

1C (0.651 g, 4.0 mmol) was dissolved in 20 mL of dry methylene chloride, and then filtered and evaporated. The mixture of mmol) was reacted for 30 min after the completion of the dropwise addition to obtain a reaction liquid 1. 110B (0.922 g, 2.0 mmol) was dissolved in 20 mL of tetrahydrofuran, and the mixture was filtered under nitrogen, and butyl lithium (2.25 mL, 1.6 mol/L, 3.6 mmol) was added dropwise at -78 ° C, and the mixture was allowed to react for 30 min to obtain a reaction liquid 2. 1 reaction solution was added dropwise to the reaction solution 2, and the mixture was slowly warmed to room temperature for 2 hours. Washed successively with saturated aqueous sodium dihydrogen phosphate 20mL, 20mL saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, silica gel column chromatography (dichloromethane / methanol = 100/1 ~ 20/1) to give compound 110, Light yellow solid (0.6 g, yield 44%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.60 (s, 1H), 8.36 (s, 1H), 7.84 (s, 1H), 7.64 (d, 1H), 7.54 (t, 1H), 7.46 (dd , 1H), 7.19 (s, 1H), 4.98-4.84 (m, 1H), 4.77 (dd, 1H), 4.00 (t, 2H), 3.95 (s, 3H), 3.74 (m, 1H), 3.62 3.50 (m, 4H), 3.33 (d, 3H), 3.07 (q, 2H), 2.63 (dd, 2H), 1.98 (d, 1H), 1.76 (d, 2H), 1.26 (dd, 3H), 1.22 -1.17(m,6H).

LC-MS m/z = 682 [M + 1].

Example 111

Isopropyl (2S)-2-[[[4-[6-[(6-ethenyl-8-cyclopentyl-5-methyl-7-oxo-pyridine[2,3-d]pyrimidine) -2-yl)amino]-3-pyridyl]pyridazin-1-yl]-(methoxymethyl)phosphonium]amino]propionate ( Compound 111 )

Isopropyl(2S)-2-[[[4-[6-[(6-acetyl-8-cyclopentyl-5-methyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]- 3-pyridyl]piperazin-1-yl]-(methoxymethyl)phosphoryl]amino]propanoate

1C (0.58 g, 3.58 mmol) was dissolved in dichloromethane (20 mL), and isopropyl L-alanine (0.47 g, 3.58 mmol) and triethylamine (0.72 g, 7.16 mmol) of a solution of the mixture in dichloromethane (10 mL). After stirring at this temperature for 30 min, compound 111A (0.8 g, 1.79 mmol) was added, warmed to reflux and stirred for 30 min. The reaction solution was cooled to room temperature, and dichloromethane (50 mL) was added, and the mixture was washed successively with a saturated solution of sodium dihydrogen phosphate (50 mL×1) and a saturated solution of sodium chloride (50 mL×1). layer was concentrated and the residue was purified by silica gel column chromatography (dichloromethane / methanol = (v / v) 100/ 1 ~ 20/1), to give compound 111 as a pale yellow solid (0.18 g of, yield 15.04%) .

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.82 (s, 1H), 8.50-8.26 (m, 1H), 8.23 (d, 1H), 8.00 (dd, 1H), 7.38-7.34 (m, 1H), 6.00 -5.75 (m, 1H), 5.15-4.88 (m, 1H), 4.02 (dd, 1H), 3.72 (dd, 2H), 3.49-3.33 (m, 8H), 3.12 (dd, 4H), 2.55 (s , 3H), 2.43-2.31 (m, 5H), 2.12-2.02 (m, 2H), 1.94-1.84 (m, 2H), 1.70 (dd, 2H), 1.47-1.40 (m, 3H), 1.29-1.24 (m, 6H).

LC-MS m/z = 669.4 [M+1].

Example 112

Isopropyl (2S)-2-[[[(5R)-7-chloro-5-methyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-( Methoxymethyl)phosphonium]amino]propionate ( Compound 112 )

Isopropyl(2S)-2-[[[(5R)-7-chloro-5-methyl-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-(methoxymethyl)phosphoryl]amino]propanoate

Dichloromethane 1C (1.52g, 9.33mmol) was dissolved in dichloromethane (20mL), the at -5 deg.] C, was added a mixture of compound 112A (1g, 4.31mmol) and triethylamine (2.18g, 21.60mmol) of (10 mL)) The solution was stirred at room temperature for 30 min then EtOAc &lt;RTI ID=0.0&gt;&gt; Dichloromethane (30 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (30 mL×1) and saturated sodium chloride (30 mL×1), dried over anhydrous sodium sulfate Separation and purification by hydrazine column chromatography (dichloromethane/methanol = (v/v) 100/1~30/1) gave Compound 112 as a yellow oil (0.4 g, yield 22.26%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.17-7.05 (m, 2H), 7.05-6.94 (m, 1H), 5.07-4.99 (m, 1H), 4.05-3.70 (m, 1H), 3.69-3.49 ( m, 2H), 3.48-3.11 (m, 7H), 3.10-2.75 (m, 4H), 1.43-1.29 (m, 6H), 1.28-1.22 (m, 6H).

LC-MS m/z = 417.2 [M + 1].

Example 113

Isopropyl (2S)-2-[[[4-[4-[[5-chloro-4-(2-isopropylsulfonylanilinyl)pyrimidin-2-yl]amino]-5-isopropoxy 2-methyl-phenyl]-1-pyrazinyl]-(methoxymethyl)phosphonium]amino]propionate ( Compound 113 )

Isopropyl(2S)-2-[[[4-[4-[[5-chloro-4-(2-isopropylsulfonylanilino)pyrimidin-2-yl]amino]-5-isopropoxy-2-methyl-phenyl]-1- Piperidyl]-(methoxymethyl)phosphoryl]amino]propanoate

1C (0.58 g, 3.58 mmol) was dissolved in dichloromethane (20 mL), and isopropyl L-alanine (0.47 g, 3.58 mmol) and triethylamine (0.72 g, 7.16 mmol) of a solution of the mixture in dichloromethane (10 mL). After maintaining this temperature for 30 min, compound 113A (1 g, 1.79 mmol) was added, warmed to reflux and stirred for 30 min. The reaction solution was cooled to room temperature, and dichloromethane (50 mL) was added, and the mixture was washed successively with a saturated solution of sodium dihydrogen phosphate (50 mL×1) and a saturated solution of sodium chloride (50 mL×1). layer was concentrated and purified by silica gel column chromatography separation (dichloromethane / methanol = (v / v) 100/ 1 ~ 20/1), to give compound 113 residue, a pale yellow solid (0.25 g, yield 17.92%) .

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.55 (s, 1H), 8.57 (d, 1H), 8.14 (s, 1H), 8.05-7.89 (m, 2H), 7.61 (t, 2H), 7.28 (d ,1H),6.73(s,1H),5.14-4.94(m,1H),4.58-4.52(m,1H),4.09-3.95(m,1H),3.87-3.64(m,4H),3.45(t , 3H), 3.40-3.21 (m, 2H), 2.93-2.70 (m, 3H), 2.16 (d, 3H), 1.71-1.47 (m, 4H), 1.43 (dd, 3H), 1.37 (d, 6H) ), 1.32 (d, 6H), 1.28-1.24 (m, 6H).

LC-MS m/z =779.3 [M+1].

Example 114

Isopropyl (2S)-2-[[[(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluoro) Phenyl)-1-acridinyl]-(methoxymethyl)phosphonium]amino]propionate ( Compound 114 )

Isopropyl(2S)-2-[[[(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)-1-piperidyl]-(methoxymethyl)phosphoryl]amino] Propanoate

Compound 1C (1.138 g, 6.982 mmol) was dissolved in dry methylene chloride (10 mL), cooled to -30 ° C under nitrogen atmosphere, and then isopropyl L-alanine (0.9159 g, 6.982 mmol) was slowly added dropwise. A mixture of dichloromethane solution (5 mL) and triethylamine (2.826 g, 27.93 mmol) was stirred at -30 ° C for 30 min after completion of the addition of compound 114A (1.150 g, 3.491 mmol), and then warmed to room temperature and then heated. The reaction was refluxed for 1 h. A saturated aqueous solution of sodium dihydrogen phosphate (20 mL) and dichloromethane (20 mL) were added to the mixture and the mixture was evaporated. Separation and purification (petroleum ether: ethyl acetate (v/v) = 1:1 to 1:4) gave Compound 114 as a yellow oil (0.160 g, yield 8.32%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.18-7.10 (m, 2H), 6.98 (t, 2H), 6.62 (d, 1H), 6.36-6.30 (m, 1H), 6.12 (dd, 1H), 5.87 (s, 2H), 5.10-4.99 (m, 1H), 4.08-3.88 (m, 2H), 3.84-3.68 (m, 3H), 3.60-3.54 (m, 1H), 3.50-3.33 (m, 5H) , 2.88-2.73 (m, 2H), 2.70-2.60 (m, 1H), 1.86-1.64 (m, 2H), 1.42 (d, 2H), 1.30-1.22 (m, 8H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -114.16, -114.18.

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.61, 24.06.

LC-MS m/z = 551.3 [M + 1].

Example 115

(2S)-2-((((9,13b-dihydroxy-1H-dibenzo[c,f]imidazo[1,5-a]azepin-3-yl)amino) (methoxy) Isopropylphosphonium)amino)propionic acid isopropyl ester ( Compound 115 )

(2S)-isopropyl-2-(((9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepin-3-yl)amino)(methoxymethyl)phosphoryl)amino)propanoate

1C (1 g, 6.13 mmol) was dissolved in dichloromethane (20 mL), EtOAc (EtOAc, EtOAc (EtOAc) A solution of the mixture in dichloromethane (10 mL)). After stirring to room temperature for 10 min, 115A (1.22 g, 4.3 mmol) was added and the mixture was reacted at room temperature for 30 min. Dichloromethane (30 mL) was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfate (50 mL×1) and a saturated sodium chloride solution (30 mL×1), dried over anhydrous sodium sulfate, filtered and evaporated. Separation and purification by column chromatography (dichloromethane/methanol = (v/v) 100/1~20/1) gave the above compound (2S)-2-(((9,13b-dihydroxy-1H-diphenyl) And [c,f]imidazo[1,5-a]azepin-3-yl)amino)(methoxymethyl)phosphonium)amino)propionic acid isopropyl ester ( Compound 115 ), colorless Liquid (0.31 g, yield 10.76%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.57-7.39 (m, 1H), 7.37-7.35 (m, 1H), 7.20-7.15 (m, 6H), 5.04 (m, 1H), 4.91-4.79 ( m,1H), 4.41(t,1H),4.21-4.04(m,2H),3.84-3.63(m,2H), 3.48-3.45(m,1H), 3.40-3.32(m,3H), 3.28- 3.27 (m, 2H) 3.21 (d, 1H), 1.29-1.06 (m, 9H).

LCMS m/z = 471.2 [M + 1].

Example 116

Isopropyl (2S)-2-[[[(5R)-7-chloro-1-[2-methyl-4-[(2-methylbenzomethyl)amino]benzylidene]-2 ,3,4,5-tetrahydro-1-benzazepine-5-yl]oxy-(methoxymethyl)phosphonium]amino]propionate ( Compound 116 ); isopropyl(2S)- 2-[[[(5R)-7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-2,3,4,5-tetrahydro-1-benzazepin-5-yl ]oxy-(methoxymethyl)phosphoryl]amino]propanoate

1C (0.73 g, 4.46 mmol) was dissolved in dichloromethane (10 mL), isopropyl L-alanine (0.59 g, 4.46 mmol) and triethylamine (1.01 g, A 10 mmol solution of the mixture in dichloromethane (10 mL) was stirred at this temp. In a separate three-necked flask, compound 116A (1 g, 2.23 mmol) was dissolved in tetrahydrofuran (20 mL), and n-butyllithium solution (1.39 mL, 1.6 mol/L) was added dropwise at -78 ° C, and stirred at this temperature for 30 min. . The mixture 1 was slowly added to the reaction solution, slowly warmed to room temperature, and dichloromethane (50 mL) was added thereto, and the mixture was washed successively with a saturated solution of sodium dihydrogen phosphate (30 mL×1) and a saturated sodium chloride solution (30 mL×1). The organic layer was dried (MgSO4) 2-[[[(5R)-7-chloro-1-[2-methyl-4-[(2-methylbenzomethyl)amino]benzylidene]-2,3,4,5- Tetrahydro-1-benzazepine-5-yl]oxy-(methoxymethyl)phosphonium]amino]propionate ( Compound 116 ), pale yellow solid (0.24 g, yield 16.06%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 10.19 (d, 1H), 7.81-6.69 (m, 10H), 5.58 (d, 2H), 5.00-4.57 (m, 2H), 3.91 (d, 1H) , 3.84-3.60 (m, 2H), 3.35 (d, 3H), 2.74 (s, 1H), 2.42-2.16 (m, 7H), 1.99 (s, 1H), 1.72 (dd, 2H), 1.33 (dd , 3H), 1.24-1.11 (m, 6H).

LC-MS m/z = 670.2 [M+1].

Example 117

Ethyl (2S)-2-[[methoxymethyl-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl)phenoxy] (phosphonium)amino]propionate ( compound 117 )

Ethyl(2S)-2-[[methoxymethyl-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxypheny l)vinyl]phenoxy]phosphoryl]amino]propanoate

1C (1.2g, 7.1mmol) was dissolved in 30mL dry dichloromethane, nitrogen, -30 deg.] C was added dropwise triethylamine (1.9g, 19mmol) and the mixture of compound 54A (1.5g, 4.7mmol) is dropwise After reacting for 30 min, L-alanine ethyl ester (1.7 g, 14 mmol) was added, and the mixture was reacted at room temperature for 2 h. The reaction solution was washed with saturated aqueous sodium hydrogen sulfate (20 mL) and brine (20 mL). 1), the aforementioned compound ethyl (2S)-2-[[methoxymethyl-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)] Vinyl)phenoxy]phosphonium]amino]propionate ( Compound 117 ), colorless oil (1.2 g, yield 46%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 (m, 1H), 7.06 (d, 1H), 6.78 (d, 1H), 6.49 (s, 2H), 6.44 (d, 2H), 4.21-4.06 (m) , 3H), 3.95-3.76 (m, 9H), 3.69 (d, 6H), 3.48 (dd, 3H), 1.37-1.25 (m, 3H), 1.25-1.19 (m, 3H).

LC-MS m/z = 524.3 [M + 1].

Example 118

Benzyl (2S)-2-[[methoxymethyl-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl)phenoxy] (phosphonium)amino]propionate ( compound 118 )

Benzyl (2S)-2-[[methoxymethyl-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)vinyl]phenoxy]phosphoryl]amino]propanoate

1C (1.2g, 7.1mmol) was dissolved in 30mL dry dichloromethane, nitrogen was added dropwise triethylamine -30 ℃ (1.9g, 19mmol) and a mixture of 54A (1.5g, 4.7mmol) and dropwise, After reacting for 30 min, L-alanine benzyl ester (2.5 g, 14 mmol) was added, and the reaction was continued at room temperature for 2 h. The reaction solution was washed with saturated aqueous sodium hydrogen sulfate (20 mL) and brine (20 mL). 1), the aforementioned compound benzyl (2S)-2-[[methoxymethyl-[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)] Vinyl)phenoxy]phosphonium]amino]propionate ( Compound 118 ), colorless oil (1.0 g, yield 35%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.39-7.27 (m, 5H), 7.24 (dd, 1H), 7.06 (d, 1H), 6.76 (d, 1H), 6.48 (s, 2H), 6.44 (d , 2H), 5.10 (m, 2H), 4.30-4.11 (m, 1H), 3.87-3.73 (m, 9H), 3.69 (s, 6H), 3.43 (dd, 3H), 1.39-1.17 (m, 3H) ).

LC-MS m/z = 586.3 [M + 1].

Example 119

S-isopropyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]thiopropionate ( Compound 119 )

S-isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanethioate

1C (5.0 g, 30.69 mmol) was dissolved in 50 mL of dichloromethane, and propofol (5.47 g, 30.69 mmol) and triethylamine (12.42 g, 122.74 mmol) were added dropwise at 0 ° C under N2. The mixed solution in 50 mL of dichloromethane was added dropwise and allowed to react at room temperature for 1 h. At this temperature, L-alanine isopropyl sulfide trifluoroacetate (16.02 g, 61.37 mmol) was added, and the reaction was carried out according to Example 1 of WO 2015197006, and the reaction was continued for 2 h at room temperature. The reaction solution was washed with a saturated aqueous solution of saturated sodium dihydrochloride (100 mL), and then evaporated. :1~1:1), the above compound S-isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino group is obtained. Thiopropionate ( Compound 119 ), yellow oil (5.0 g, yield 39.22%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (d, 3H), 4.23-4.11 (m, 1H), 3.98-3.74 (m, 2H), 3.69-3.26 (m, 7H), 1.37-1.11 (m, 21H).

LC-MS m/z = 416.2 [M+1].

Example 120

Isopropyloxycarbonyloxymethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]-2-methyl-propionate ( Compound 120 )

Isopropoxycarbonyloxymethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]-2-methyl-propanoate

First step: isopropoxycarbonyloxymethyl 2-(t-butoxycarbonylamino)-2-methyl-propionate ( 120B )

Isopropoxycarbonyloxymethyl 2-(tert-butoxycarbonylamino)-2-methyl-propanoate

N-Tertiyloxycarbonyl-2-methylalanine ( 120A ) (20 g, 98.5 mmol) was suspended in N,N-dimethylformamide (60 mL), and potassium carbonate (27.17 g, 197 mmol) ), isopropyl chloromethyl carbonate (22.54 g, 147.75 mmol) was slowly added dropwise at 0 ° C, and the reaction was carried out overnight at room temperature. The reaction mixture was washed with EtOAc EtOAc (EtOAc) Ethyl acetate (v/v) = 25:1 to 4:1) to give the above compound isopropoxycarbonyloxymethyl 2-(t-butoxycarbonylamino)-2-methyl-propionate ( 120B ) , white solid (23 g, yield 73.20%).

LC-MS m/z = 342.1 [M+23].

Second step: isopropoxycarbonyloxymethyl 2-amino-2-methyl-propionate hydrochloride ( 120C )

Isopropoxycarbonyloxymethyl 2-amino-2-methyl-propanoate hydrochloride

The compound 120B (20 g, 62.7 mmol) was dissolved in ethyl acetate (60 mL), and then evaporated to dry hydrogen chloride gas for 4 hr at room temperature, and the reaction mixture was concentrated under reduced pressure to give the compound isopropyloxycarbonyloxymethyl 2- Amino-2-methyl-propionate hydrochloride ( 120C ), white solid (8.1 g, yield 58.99%).

LC-MS (m/z) = 220.1 [M+1].

The third step: isopropoxycarbonyloxymethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]-2-methyl-propionate ( Compound 120 )

Isopropoxycarbonyloxymethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]-2-methyl-propanoate

1C (8g, 49.08mmol) was dissolved in dichloromethane (80 mL), EtOAc (9.6 g, 54.0 mmol) and triethylamine (19.86 g, 196. A solution of dichloromethane (60 mL) was added dropwise and allowed to react at room temperature for 1 h. Compound 120C (8.1 g, 36.98 mmol) was added at this temperature and the reaction was continued at room temperature for 2 h. The reaction mixture was washed with EtOAc EtOAc EtOAc (EtOAc) 10:1~1:1), the above compound isopropoxycarbonyloxymethyl 2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]- 2-Methyl-propionate ( Compound 120 ), colorless liquid (1.8 g, yield 7.53%).

LC-MS m/z = 488.2 [M+1].

Compound 120 (1.8 g) was separated and separated to give two optical isomer compound 120-a (retention time: 3.54 min, 771.39 mg, colorless liquid, ee% = 99.3%), compound 120-b (retention time: 5.29 min, 698.48 mg, colorless liquid, ee% = 97.3%).

Preparation conditions: Equipment: Thar 350 preparative SFC (SFC-6); Column: Pheno Lux Cellulose-4, 300 × 50 mm ID, 10 μm; mobile phase: Phase A is CO ₂ and Phase B is isopropanol; Gradient: B 20% ; flow rate: 200mL / min; back pressure: 100bar; column temperature: 38 ℃; wavelength: 220nm; cycle time: ~ 3min; sample preparation: compound was dissolved in ~ 100mL methanol; injection: 3mL / per injection Work up:. After separation, the fraction was obtained by rotary distillation at 40 ° C bath temperature to obtain the desired isomer.

Compound 120-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.77-5.71 (m, 2H), 4.92-4.89 (m, 1H), 3.85 (d, 2H), 3.73 (d, 1H), 3.58 -3.54 (m, 2H), 3.47 (d, 3H), 1.51 (s, 3H), 1.40 (s, 3H), 1.30 (d, 6H), 1.22-1.20 (m, 12H).

LC-MS m/z = 488.2 [M+1].

³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.49.

Compound 120-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 5.77-5.71 (m, 2H), 4.94-4.87 (m, 1H), 3.85 (d, 2H), 3.73 (d, 1H), 3.58 -3.54 (m, 2H), 3.47 (d, 3H), 1.51 (s, 3H), 1.40 (s, 3H), 1.30 (d, 6H), 1.22-1.20 (m, 12H).

LC-MS m/z = 488.2 [M+1].

³¹ P NMR (162 MHz, CDCl ₃ ) δ 21.50.

Example 121

Ethyl (2S)-2-[[(2,6-diisopropoxyphenoxy)methoxy-(methoxymethyl)phosphonium]amino]propionate (Compound 121 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)methoxy-(methoxymethyl)phosphoryl]amino]propanoate

First step: 2-(chloromethoxy)-1,3-diisopropylbenzene ( 121A )

2-(chloromethoxy)-1,3-diisopropylbenzene( 121A )

Dispute propofol (1.00 g, 5.6 mmol) and bromochloromethane (7.25 g, 56.04 mmol) in tetrahydrofuran (10 mL), add solid sodium hydroxide (0.45 g, 11.25 mmol), warm to 50 ° C, stir for 5 h . Added ethyl acetate (50mL) extracted with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the compound 121A, as a yellow oil (1.00g, 78.7%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.16 (d, 3H), 5.92 (s, 2H), 3.35-3.24 (m, 1H), 1.28-1.05 (m, 13H).

Second step: ethyl (2S)-2-(((2,6-diisopropoxyphenyl)methoxy)(methoxymethyl)phosphonium)amino)propionate

Ethyl(2S)-2-(((2,6-diisopropylphenoxy)methoxy)(methoxymethyl)phosphoryl)amino)propanoate

Compound 121A (1.3 g, 5.73 mmol) and Intermediate 5 (1.8 g, 5.52 mmol) were dissolved in N,N-dimethylformamide (10 mL), and then potassium carbonate (1. Sodium iodide (0.1 g, 0.67 mmol) was heated to 50 ° C under nitrogen atmosphere and stirred for 2 h. The reaction mixture was cooled to EtOAc (EtOAc) (EtOAc m. Ethyl acetate/petroleum ether = (v/v) 1/20 to 1/1) to give the title compound 121 as a colorless transparent oil (0.90 g, yield 37.8%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.16-7.06 (m, 3H), 5.54 (dd, 1H), 5.48-5.40 (m, 1H), 4.22-4.01 (m, 3H), 3.72 (dd, 2H) , 3.51-3.19 (m, 6H), 1.36 (dd, 3H), 1.27-1.18 (m, 15H).

LC-MS m/z (ESI): 416.2 [M+1].

Example 122

Isopropyl (2S)-2-[[[5-[(3,5-dimethylphenoxy)methyl]-2-oxa-oxazolin-3-yl]-(methoxymethyl) Phosphonium]amino]propionate

Isopropyl(2S)-2-[[[5-[(3,5-dimethylphenoxy)methyl]-2-oxo-oxazolidin-3-yl]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.162 g, 1.00 mmol) was dissolved in 4 mL of dry dichloromethane, and then filtered, and then, then, then, then, then,,,,,,,,,,,,,, Methylene chloride solution (1 mL), 1 h after the dropwise addition, triethylamine (0.402 g, 4.00 mmol) and 122A (0.110 g, 0.50 mmol) were added, and the mixture was warmed to room temperature and then heated to 40 ° C for 3 h. . Washed with saturated sodium dihydrogen phosphate solution and once with 5mL, 10 mL water, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, Purification by column chromatography (petroleum ether / ethyl acetate = 1: 1), to give the compound 122 , off-white solid (0.12 g, yield 56.4%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.64 (d, 1H), 6.53 (d, 2H), 4.97 (m, 2H), 4.04 (m, 8H), 3.48 (m, 3H), 2.28 (m, 6H ), 1.43 (m, 3H), 1.22 (m, 6H).

LC-MS m/z (ESL) = 443.1 [M + 1].

Example 123

2-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium]oxybenzoic acid ( Compound 123 )

2-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxybenzoic acid

Under the protection of anhydrous nitrogen, the compound (methoxymethyl)phosphine dichloride (0.615 g, 3.77 mmol) and dichloromethane 5 mL were added to the reaction flask, and salicylic acid (0.521 g, 3.77 mmol) was slowly added at -30 °C. And a mixed solution of triethylamine (1.53 g, 15.1 mmol), after the addition, the reaction was carried out at -30 ° C to 0 ° C for 30 min. A solution of L-alanine isopropyl ester (0.632 g, 3.77 mmol) in dichloromethane was added under ice-cooling, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated, purification by column chromatography (dichloromethane / methanol = 70: 1) to give the compound 123 as a colorless oil (0.50g, 40.0%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.65 (m, 1H), 8.48 (d, 1H), 7.63 (d, 1H), 7.48 (m, 1H), 7.40 (d, 1H), 7.24 (t , 1H), 4.93 (m, 1H), 4.39 (m, 1H), 3.81 (d, 2H), 3.35 (d, 3H), 1.38 (t, 3H), 1.19 (m, 6H).

LC-MS m/z (ESI) = 360.2 [M+1];

Example 124

Ethyl (2S)-2-[[[[5-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]phenylamino]quinazolin-6-yl]-2- Furanyl]methyl-(2-methylsulfonylethyl)amino]-(methoxymethyl)phosphonium]amino]propionate ( Compound 124 )

Ethyl(2S)-2-[[[[5-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-2-furyl]methyl-(2-methylsulfonylethyl )amino]-(methoxymethyl)phosphoryl]amino]propanoate

Under a nitrogen atmosphere, (methoxymethyl)phosphine dichloride (0.33 g, 2.00 mmol) and tetrahydrofuran 5 mL were added to a reaction flask, and under cooling with ice, 124A (0.58 g, 1.00 mmol), triethylamine ( A mixed solution of 0.50 g, 5.00 mmol) and tetrahydrofuran (5 mL) was added to the reaction flask, and the mixture was heated to 45 ° C for 20 min. Add a solution of L-alanine ethyl ester in dichloromethane (1.55 mL, 2 g/10 mL) under ice-cooling, and then react at room temperature for 2 h, add 10 mL of methanol, stir for 5 min. 40mL, saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, purification by column chromatography (dichloromethane / methanol = 30: 1) to give compound 124 as a yellow solid (0.25g , yield 30.0%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.76 (d, 1H), 8.67 (s, 1H), 8.53 (dd, 1H), 7.97-7.80 (m, 3H), 7.74 (m, 1H), 7.35 (m , 1H), 7.24 (dd, 2H), 7.08-6.93 (m, 2H), 6.76-6.63 (m, 1H), 6.42 (dd, 1H), 5.14 (d, 2H), 4.39-4.04 (m, 5H) ), 3.85-3.61 (m, 5H), 3.44-3.24 (m, 5H), 2.94 (s, 3H), 2.03 (d, 1H), 1.48 (d, 1H), 1.42 (d, 1H), 1.25- 1.17 (m, 3H).

LC-MS m/z = 788.2 [M+1].

Example 125

Isopropyl (2S)-2-[[[[5-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]phenylamino]quinazolin-6-yl]-2 -furanyl]methyl-(2-methylsulfonylethyl)amino]-(methoxymethyl)phosphonium]amino]propionate ( Compound 125 )

Isopropyl(2S)-2-[[[[5-[4-[3-chloro-4-[(3-fluorophenyl)methoxy]anilino]quinazolin-6-yl]-2-furyl]methyl-(2-methylsulfonylethyl )amino]-(methoxymethyl)p Hosphoryl]amino]propanoate

Under a nitrogen atmosphere, (methoxymethyl)phosphine dichloride (0.33 g, 2.00 mmol) and tetrahydrofuran 5 mL were added to a reaction flask, and 124A (0.58 g, 1.00 mmol) and triethylamine ( 124A ) A mixed solution of 0.50 g, 5.00 mmol) and tetrahydrofuran (5 mL) was added to the reaction flask, and the reaction was carried out at 45 ° C for 20 min; and a solution of L-alanine isopropyl ester in dichloromethane (1.65 mL, 2 g / After 10 hours), the mixture was stirred at room temperature for 2 h, and then added with EtOAc (EtOAc). Purification by column chromatography (dichloromethane / methanol = 30/1) afforded Compound 125 as a yellow solid (0.25 g, yield: 31.0%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.86-8.65 (m, 2H), 8.61-8.51 (m, 1H), 7.97-7.82 (m, 3H), 7.36 (m, 1H), 7.30-7.17 (m, 3H), 7.09-6.95 (m, 2H), 6.80-6.65 (m, 1H), 6.43 (dd, 1H), 5.16 (s, 2H), 4.99 (m, 1H), 4.36 (d, 1H), 4.27 (dd, 1H), 4.09-4.00 (m, 1H), 3.85-3.70 (m, 4H), 3.69-3.55 (m, 1H), 3.43 (d, 3H), 3.33 (m, 2H), 2.94 (d , 3H), 1.48 (s, 1H), 1.41 (d, 1H), 1.28-1.14 (m, 7H).

LC-MS m/z = 802.3 [M + 1].

Example 126

3-[3-[(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-pyrazole-4-ylidene] 肼]-2- [[[(1S)-Isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium]oxy-phenyl]benzoic acid ( Compound 126 )

3-[3-[(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-pyrazo1-4-ylidene]hydrazino]-2-[[[(1S)-2 -isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-phenyl]benzoic acid

(Methoxymethyl)phosphonium dichloride (0.979 g, 6.01 mmol) was dissolved in 40 mL of dry dichloromethane, and then evaporated, and then triethylamine (2.43 g, 24 mmol) was added dropwise at -30 ° C, L- A mixture of isopropyl alanate (0.789 g, 6.01 mmol) was reacted for 30 min after the dropwise addition, and 126A (1.33 g, 3.01 mmol) was added and allowed to react at room temperature for 2 h. Wash once with 20 mL of a saturated aqueous solution of sodium dihydrogen phosphate, and wash once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and evaporated. Compound 126 , yellow solid (0.70 g, yield 40.0%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.55 (d, 1H), 13.02 (s, 1H), 8.09 (d, 1H), 8.03-7.98 (m, 1H), 7.87-7.76 (m, 2H) , 7.72 (d, 1H), 7.62 (m, 2H), 7.43 (t, 1H), 7.31 (d, 1H), 7.21 (dd, 1H), 5.28-4.71 (m, 2H), 3.68 (d, 1H) ), 3.47 (dd, 1H), 3.39-3.31 (m, 1H), 3.13 (d, 3H), 2.33 (d, 3H), 2.27 (s, 3H), 2.23 (s, 3H), 1.19-1.02 ( m, 9H).

Example 127

Isopropyl (2S)-2-[[[4-fluoro-2-[2-oxo-1-(1-oxoisoindol-2-yl)-2-(thiazol-2-ylamino) Ethyl]phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 127 )

Isopropyl(2S)-2-[[[4-fluoro-2-[2-oxo-1-(1-oxoisoindolin-2-yl)-2-(thiazol-2-ylamino)ethyl]phenoxy]-(methoxymethyl) Phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.51 g, 3.0 mmol) was dissolved in 20 mL of dry dichloromethane, and then filtered, and then triethylamine (1.3 g, 13 mmol) was added dropwise at -30 ° C, L- A mixture of isopropyl alanate (0.41 g, 3.0 mmol) was reacted for 30 min after the dropwise addition, and 127A (0.6 g, 1.6 mmol) was added, and the mixture was reacted at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure, and then purified by column chromatography (dichloromethane / methanol = 100/1~20 / l) Compound 127 , white solid (0.50 g, yield 50.0%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 12.52 (s, 1H), 7.75 (dd, 1H), 7.72-7.46 (m, 5H), 7.43-7.23 (m, 2H), 7.23-7.06 (m, 1H), 6.54-6.39 (m, 1H), 5.76 (d, 1H), 4.95-4.59 (m, 2H), 4.28-4.07 (m, 1H), 4.07-3.57 (m, 3H), 3.39-3.07 ( m, 3H), 1.29-1.15 (m, 3H), 1.15 - 1.02 (m, 6H).

LC-MS m/z = 605.2 [M + 1].

Example 128

Isopropyl (2S)-2-[[[4-[(E)-2-(3,5-dimethoxyphenyl)vinyl]phenoxy]-(methoxymethyl)phosphonium Amino]propionate ( compound 128 )

Isopropyl(2S)-2-[[[4-[(E)-2-(3,5-dimethoxyphenyl)vinyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (1.27 g, 7.80 mmol) was dissolved in 20 mL of dry dichloromethane, and then filtered, and then triethylamine (3.16 g, 31.2 mmol) was added dropwise at -30 °C. A mixture of L-alanine isopropyl ester (1.02 g, 7.80 mmol) was reacted for 30 min after the dropwise addition, and rosewood (1.0 g, 3.9 mmol) was added and allowed to react at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether = 1/10~2/1). Compound 128 was obtained as a white solid (0.60 g, yield 30.0%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.45 (d, 2H), 7.25 (dd, 2H), 6.97 (t, 2H), 6.65 (d, 2H), 6.40 (t, 1H), 5.12-4.88 (m , 1H), 4.23-3.99 (m, 1H), 3.92-3.69 (m, 8H), 3.56 (t, 1H), 3.46 (dd, 3H), 1.32 (d, 3H), 1.261.20 (m, 6H) ).

LC-MS m/z = 478.3 [M+1].

Example 129

Isopropyl (2S)-2-((((3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1 H -pyridine [2, 1-a]isoquinolin-2-yl)oxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 129 )

isopropyl (2S) -2 - (( ((3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1 H -pyrido [2,1-a] isoquinolin-2- Yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate

First step: 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyridine [2,1-a]isoquinoline-2- Alcohol ( 129B )

3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-o1

129A (1.00g, 3.15mmol) was dissolved in anhydrous methanol (20mL), sodium borohydride (0.18g, 4.76mmol) was slowly added at room temperature, stirring was continued for 2h, ethyl acetate (50mL) was added, followed by saturated chlorination The aqueous ammonium solution (20 mL x 1) and saturated brine (20 mL x 1) were washed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 129B, a light yellow solid (1.00 g of, 99.0% yield).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.66 (d, 1H), 6.58 (s, 1H), 3.84 (d, 6H), 3.52-3.31 (m, 1H), 3.04 (s, 3H), 2.73-2.42 (m, 3H), 2.01 (s, 1H), 1.78-1.43 (m, 5H), 1.07 (s, 1H), 0.99-0.82 (m, 6H).

The second step: (2S)-isopropyl 2-((((3-(isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyridine) [2,1-a]isoquinolin-2-yl)oxy)(methoxy)phosphonium)amino)propionate ( Compound 129 )

(2S)-isopropyl 2-(((((((((((((((((((((((((((((((((((((((((((((( Oxy)(methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphonium dichloride (1.52 g, 9.33 mmol) was dissolved in dichloromethane (20 mL), EtOAc (1 g, 3.13 mmol) and triethylamine (2.18 g, 21.60 mmol) in dichloromethane (10 mL). After warming to room temperature and stirring for 30 min, isopropyl L-alanine (2.45 g, 18.66 mmol) was added and stirring was continued for 30 min. Dichloromethane (30 mL) was added and washed with a saturated solution of sodium dihydrogen phosphate (30 mL×1) and a saturated sodium chloride solution (30 mL×1), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by column chromatography (dichloromethane / methanol = (v/v) 100/1~20/1) afforded Compound 129 as a yellow oil (0.25 g, yield 14.7%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.86-6.62 (m, 1H), 6.57 (d, 1H), 5.11-4.82 (m, 1H), 4.37-4.18 (m, 1H), 4.18-3.96 (m, 1H), 3.86 (dd, 6H), 3.76-3.64 (m, 2H), 3.50-3.41 (m, 3H), 3.40-2.57 (m, 7H), 2.46 (s, 1H), 2.15-2.02 (m, 1H), 1.78-1.48 (m, 3H), 1.42 (m, 3H), 1.31-1.17 (m, 6H), 1.13-1.00 (m, 2H), 0.98-0.84 (m, 6H).

LC-MS m/z = 541.3 [M+1].

Example 130

Isopropyl (2R)-2-[[[4-[[(2R,3R,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-4,4-difluoro- 3-hydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxymethyl]phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( Compound 130 )

Isopropyl(2R)-2-[[[4-[[(2R,3R,5R)-5-(4-amino-2-oxo-pyrimidin-1-yl)-4,4-difluoro-3-hydroxy- Tetrahydrofuran-2-yl]methoxycarbonyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

130A (2.0g, 5.79mmol) was dissolved in 10mL of dry tetrahydrofuran, protected with nitrogen, cooled to 0 ° C, added phosgene (0.860g, 2.9mmol), then slowly added diisopropylethylamine (0.749g) , 5.79 mmol), continue to react at 0 ° C for 30 minutes after the addition. In addition, 130B (2.36g, 5.79mmol) was suspended in 20mL of dry dichloromethane, protected with nitrogen, cooled to 0 ° C, pyridine (3mL) was added, and the prepared tetrahydrofuran solution was slowly added, and then heated naturally after the addition. The reaction was carried out for 3 hours at room temperature. 30 mL of water and 100 mL of ethyl acetate were added, and the organic layer was washed once with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate and evaporated. v/v) = 1:1 to 3:7) gave Compound 130 as a white solid (0.10 g, yield 2.7%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.26 (d, 1H), 7.41 (d, 2H), 7.23-7.15 (m, 2H), 7.09 (d, 1H), 6.15 (t, 1H), 5.72 -5.62(m,2H), 5.16(s,2H),4.87-4.81(m,1H), 4.29-4.15(m,1H),3.92-3.82(m,2H),3.83-3.72(m,3H) , 3.68-3.64 (m, 1H), 3.37 (dd, 3H), 1.19-1.11 (m, 9H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.89, 24.01.

LC-MS m/z = 635.3 [M + 1].

Example 131

[4-[[(1S)-2-Isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonyl]oxyphenyl]methyl 5-(4-chlorophenyl)-3-[2,6-difluoro-3-(propanesulfonylamino)benzylidene]pyrrolo[2,3-b]pyridine-1-carboxylate ( Compound 131 )

[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methyl 5-(4-chlorophenyl)-3-[2,6- Difluoro-3-(propylsulfonylamino)benzoyl]pyrrolo[2,3-b]pyridine-1-carboxylate

The triphosgene (0.172 g, 0.579 mmol) was dissolved in 20 mL of dry dichloromethane, and the mixture was filtered under nitrogen. A solution of Intermediate 4 (0.500, 1.45 mmol) in dichloromethane (5 mL) was added dropwise. 5 mL of a solution of methyl ethylamine (0.187 g, 1.45 mmol) in dichloromethane. After the dropwise addition, the mixture was slowly warmed to room temperature for 1 hour, and 131A (1.06 g, 2.17 mmol) and diisopropylethylamine (0.187 g, 1.45) were added. Methyl), slowly rose to room temperature for 2 hours. Add 50 mL of water, extract with methylene chloride (100 mL×2), wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 50 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. (dichloromethane/methanol v/v) = 0: 100 to 1: 50) to give compound 131 as a white solid (0.50 g, yield 40.1%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.04 (s, 1H), 8.67 (d, 2H), 7.85 (d, 4H), 7.57 (d, 2H), 7.49-7.06 (m, 4H), 5.69 (d, 1H), 5.25 (s, 2H), 4.82 (s, 1H), 3.78 (s, 5H), 2.51 (s, 4H), 1.82 (s, 2H), 1.18 (m, 12H).

Example 132

Isopropyl (2S)-2-((((4'-hydroxy-3,3',5,5'-tetraisopropyl-[1,1'-biphenyl]-4-yl)oxy) Methoxymethyl)phosphonium)amino)propionate ( compound 132 )

Isopropyl(2S)-2-(((4'-hydroxy-3,3',5,5'-tetraisopropyl-[1,1'-biphenyl]-4-yl)oxy)methoxymethyl)phosphoryl)amino)propanoate

(Methoxymethyl)phosphonium dichloride (3.45 g, 21.16 mmol) was dissolved in 50 mL of dichloromethane, and then, under the protection of -10 ° C, 132A (5.0 g, 14.10 mmol) and triethylamine (5.7) were added dropwise. A solution of g, 56.42 mmol) in dichloromethane (50 mL) was stirred at room temperature for 1 hour. And L-alanine isopropyl ester (5.55 g, 42.31 mmol) was added at this temperature. The reaction was carried out for two hours at room temperature. Washed with 100 mL of a saturated solution of sodium dihydrogen phosphate, separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography ( petroleum ether: ethyl acetate (v/v) = 10:1 to 1:1) Compound 132 was obtained as a yellow oil (0.40 g, yield 4.9%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.23 (d, 2H), 7.18 (d, 2H), 5.08-4.89 (m, 1H), 4.18-4.06 (m, 1H), 3.99-3.78 (m, 2H) , 3.66-3.42 (m, 6H), 3.24 - 3.17 (m, 2H), 1.40-1.18 (m, 33H).

Example 133

Compound 133-1: isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-4-[3-[(1R)-1-cyclopropylethyl) ]-4-hydroxy-5-isopropyl-phenyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-4-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]-6- Isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Compound 133-2: isopropyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-4-[3-[(1R)-1-cyclopropylethyl) ]-4-hydroxy-5-isopropyl-phenyl]-6-isopropyl-phenoxy]-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-4-[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenyl]-6- Isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

1C (1.22 g, 7.5 mmol) was dissolved in 20 mL of dry methylene chloride, EtOAc (EtOAc m. Mixture of mmol), after the completion of the dropwise addition, for 30 min, 133A (2.03 g, 5 mmol) was added and the mixture was reacted at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure, column chromatography, eluting with ethyl acetate / petroleum ether = 1/1 to 1/0 Agent. Compound 133-1 was obtained as a yellow solid (0.7 g, yield 22.3%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.40-7.37 (m, 1H), 7.28-7.20 (m, 3H), 5.04-4.92 (m, 1H), 4.09-4.05 (m, 1H), 3.90-3.77 ( m, 2H), 3.62-3.44 (m, 5H), 3.25-3.18 (m, 1H), 2.83-2.74 (m, 1H), 2.59-2.51 (m, 1H), 1.36-1.17 (m, 28H), 1.01-0.86 (m, 2H), 0.60-0.23 (m, 8H).

Compound 133-2 was obtained as a yellow solid (0.5 g, yield 11.8%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.40-7.37 (m, 2H), 7.28-7.24 (m, 2H), 5.05-4.92 (m, 2H), 4.09-4.05 (m, 1H), 3.93-3.77 ( m,3H), 3.60-3.42 (m, 10H), 2.83-2.77 (m, 2H), 2.57-2.52 (m, 2H), 1.32-1.17 (m, 36H), 1.01-0.86 (m, 2H), 0.57-0.03 (m, 8H).

Example 134

Isopropyl (2S)-2-[[(N-[4-amino-5-bromo-6-(4-cyano-2,6-dimethyl-phenyloxy)pyrimidin-2-yl] -4-cyano-phenylamino)-(methoxymethyl)phosphonium]amino]propionic acid isopropyl ester ( Compound 134 )

Isopropyl(2S)-2-[[(N-[4-amino-5-bromo-6-(4-cyano-2,6-dimethyl-phenoxy)pyrimidin-2-yl]-4-cyano-anilino)- (methoxymethyl)phosphoryl]amino]propanoate

1C (0.25 g, 1.5 mmol) and 5 mL of dichloromethane were added to the reaction flask under anhydrous nitrogen, and etravirine (0.63 g, 1.4 mmol) and triethylamine (0.62 g) were slowly added at -30 ° C under cooling. 6.1 mmol) of a mixture of dichloromethane (5 mL), after the addition was completed, reacted at 40 ° C for 30 min; and added L-alanine isopropyl ester hydrochloride (0.26 g, 1.5 mmol) of dichloromethane The solution was added to the room temperature for 2 h.

LC-MS m/z = 656.1 [M + 1].

Example 135

Isopropyl (2S)-2-[[2-[4-(5,7-dimethoxy-4-oxo-3H-quinazolin-2-yl)-2,6-dimethyl-benzene Oxy]ethoxy-(methoxymethyl)phosphonium]amino]propionate ( Compound 135 )

Isopropyl(2S)-2-[[2-[4-(5,7-dimethoxy-4-oxo-3H-quinazolin-2-yl)-2,6-dimethyl-phenoxy]ethoxy-(methoxymethyl)phosphoryl]amino Propanoate

Dichloromethane (3.6 mL) was added to the reaction flask, protected with nitrogen, cooled to -30 ° C, (methoxymethyl)phosphonium dichloride (2.00 g, 12.3 mmol) was added, and L-alanine was added dropwise. A solution of propyl ester (0.3 g, 2 mmol) and triethylamine (0.8 g, 8 mmol) in dichloromethane (3 mL) was stirred for 1 h, 135A (0.40 g, 1 mmol) and triethylamine (0.2 g, 2 mmol) A solution of dichloromethane (3 mL) was reacted at room temperature for 2 h. After cooling with ice water, a saturated sodium dihydrogen phosphate solution (50 mL) was added, and extracted with dichloromethane (60 mL × 3). The organic phase was combined and washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate dryness and the residue was purified by silica gel chromatography (DCM / MeOH = 40/1 ) to give compound 135 as a yellow solid (0.1g, 20%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.76 (br, 1H), 7.72 (s, 2H), 6.83 (d, 1H), 6.46 (d, 1H), 5.12-4.90 (m, 1H), 4.51-4.30 (m, 2H), 4.16-4.00 (m, 3H), 3.97 (s, 3H), 3.93 (s, 3H), 3.81-3.71 (m, 2H), 3.45 (dd, 3H), 2.38 (d, 6H) ), 1.41 (dd, 3H), 1.28-1.22 (m, 6H).

LC-MS m/z = 592.2 [M + 1];

Example 136

2-[1-[[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphinyl] Oxyphenyl]methoxycarbonylamino]methyl]cyclohexyl]acetic acid ( compound 136 )

2-[1-[[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methoxycarbonylamino]methyl]cyclohexyl]acetic acid

First step: isopropyl ((4-(hydroxymethyl)phenoxy) (methoxymethyl)phosphonium)-L-alanine ester (470 mg, 1.36 mmol), triphosgene (0.16) g, 0.52 mmol) was dissolved in dichloromethane (5 mL), cooled to EtOAc EtOAc EtOAc.

Gabapentin (0.23 g, 1.36 mmol) was dissolved in DMF (5 mL), DIPEA (0.18 g, 1.4 mmol) was added, and the mixture was cooled in an ice water bath, and the previous reaction was dropped into it, and the mixture was warmed to room temperature and stirred for 2 hours. The ice water was cooled, ethyl acetate (100 mL) was added and the organic phase was washed once with diluted hydrochloric acid (4%, 150 mL). Drying, filtration, spin-drying, Prep-HPLC to give compound 136 as a colorless oil (0.05 g, yield 7%).

Preparation conditions: instrument: preparation of liquid phase; chromatography column: C18 preparative chromatography column; 19 * 250mm; mobile phase: acetonitrile and water containing 0.1% TFA; gradient: acetonitrile content 30% to 55%; flow rate: 12mL / min Back pressure: 1800 psi; column temperature: 30 ° C; detection wavelength: 210 nm; period: ~ 21 min.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.41-7.28 (m, 2H), 7.22 (t, 2H), 5.41-5.29 (m, 1H), 5.06 (s, 2H), 5.03-4.94 (m, 1H) , 4.17-4.09 (m, 1H), 3.91-3.70 (m, 2H), 3.45 (d, 3H), 3.23 (d, 2H), 2.30 (s, 2H), 1.57-1.18 (m, 19H).

LC-MS m/z = 543.3 [M+l];

Example 137

Ethyl (2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methoxy-(methoxymethyl)phosphonium Amino]propionate ( compound 137 )

Ethyl(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methoxy-(methoxymethyl)phosphoryl]amino]propanoate

First step: triethylamine (S)-N-(1-ethoxy-1-oxopropyl-2-yl)-p-(methoxymethyl)phosphoniumamine

Triethylamine(S)-N-(1-ethoxy-1-oxopropan-2-yl)-P-(methoxymethyl)phosphonamidate

Intermediate 5B (0.5 g, 1.59 mmol) and triethylamine (0.16 g, 1.59 mmol) were dissolved in anhydrous methanol (20 mL), and 0.5 g of palladium carbon was added, and reacted under a hydrogen atmosphere at room temperature for 4 hours, and palladium was filtered off. Carbon, concentrated to give compound intermediate 5 as a colorless liquid (0.52 g, yield 100%). Used directly in the next step.

LC-MS m/z = 226.2 [M + 1].

The second step: ethyl-(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methoxy-(methoxy) Phosphonic]amino]propionate

Ethyl-(2S)-2-[[[2-[(1R)-1-cyclopropylethyl]-6-isopropyl-phenoxy]methoxy-(methoxymethyl)phosphoryl]amino]propanoate

Intermediate 5 (0.52 g, 1.59 mmol) and potassium carbonate (0.44 g, 3.17 mmol) were dissolved in N,N-dimethylformamide (20 mL) and (R)-2-(chloromethoxy) 1-(1-cyclopropyl)-3-isopropylbenzene (0.40 g, 1.59 mmol) was heated to 50 ° C for 5 hours and cooled to room temperature. 100 mL of water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (50 mL×3). The organic phase was combined, and the organic phase was washed with water (50 mL×2), dried over anhydrous sodium sulfate and evaporated. Purification (petroleum ether: ethyl acetate (v/v) = 0:1 to 20:1) gave Compound 137 as a colorless liquid (0.50 g, yield 25.51%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.23 (dd, 1H), 7.18-7.10 (m, 2H), 5.52-5.45 (m, 1H), 5.41-5.37 (m, 1H), 4.24-4.12 (m, 2H), 4.1-4.03 (m, 1H), 3.78-3.63 (m, 2H), 3.48-3.21 (m, 5H), 2.56-2.51 (m, 1H), 1.38-1.33 (m, 3H), 1.29- 1.20 (m, 12H), 0.98-0.88 (m, 1H), 0.62-0.48 (m, 1H), 0.38-0.32 (m, 1H), 0.30-0.18 (m, 1H), 0.18-0.12 (m, 1H) ).

LC-MS m/z = 442.3 [M + 1].

Example 138

Isopropyl (2S)-2-[[(3,5-bis-tert-butyl-4-hydroxy-phenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 138 )

Isopropyl(2S)-2-[[(3,5-ditert-butyl-4-hydroxy-phenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

First step: 2,6-di-t-butyl-1,4-benzoquinone ( 138B )

2,6-ditert-butyl-1,4-benzoquinone

138A (2.0g, 9.7mmol) was dissolved in 100mL of methanol, 30% hydrogen peroxide (18mL) was added, heated to 35 ° C, slowly added dropwise iodine (4.9g, 19mmol) in methanol (30mL), after the addition The reaction was continued at 35 ° C for 1 hour. The reaction solution was added dropwise to a saturated aqueous solution of sodium sulfite (200 mL), which was cooled in ice-cooled, and ethyl acetate (100 mL) was added, and the mixture was separated, and the organic layer was washed with saturated sodium chloride (30 mL). The crude product was purified by EtOAc (EtOAc:EtOAc)

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.50 (s, 2H), 1.28 (s, 18H).

LC-MS m/z = 221.3 [M + 1].

Second step: 2,6-di-t-butylbenzene-1,4-diol ( 138C )

2,6-ditert-butylbenzene-1,4-diol

The compound 2,6-di-t-butyl-1,4-benzoquinone ( 138B ) (1.20 g, 5.45 mmol) was suspended in 18 mL of glacial acetic acid, and zinc powder (1.43 g, 21.8 mmol) was added and heated. The reaction was carried out at 30 ° C for 1 hour. The celite was filtered, and the filter cake was washed with 50 mL of ethyl acetate. The filtrate was combined, and the mixture was combined with EtOAc EtOAc. The product was separated and purified by silica gel column chromatography (purification: petroleum ether / ethyl acetate (v / v) = 1:0 to 19:1) to obtain the above compound 2,6-di-t-butylbenzene-1,4 -diol ( 138C ), white solid (0.600g, yield 49.6%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.67 (s, 2H), 4.72 (s, 1H), 4.29 (s, 1H), 1.41 (s, 18H).

LC-MS m/z = 245.1 [M+23].

Third step: isopropyl (2S)-2-[[(3,5-bis-tert-butyl-4-hydroxy-phenoxy)-(methoxymethyl)phosphonium]amino]propionate ( compound 138 )

Isopropyl(2S)-2-[[(3,5-ditert-butyl-4-hydroxy-phenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.147 g, 0.900 mmol) was dissolved in 3 mL of dry dichloromethane, cooled to -30 ° C under nitrogen atmosphere, and isopropyl L-alanine (0.118 g) was added dropwise. , 0.900 mmol) of a mixed solution of 1 mL of a dichloromethane solution and triethylamine (0.182 g, 1.80 mmol). After the addition, the reaction was continued at -30 ° C for 1 hour, and 2,6-di-t-butylbenzene-1 was added. 4-diol ( 138C ) (0.100 g, 0.450 mmol) was naturally warmed to room temperature for 1 hour. The mixture was washed with saturated sodium dihydrogen phosphate (5 mL×2), dried over anhydrous sodium sulfate and evaporated. :1) Compound 138 was obtained as a colorless oil (30 mg, yield 15%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.02 (dd, 2H), 5.08-4.96 (m, 2H), 4.15-4.08 (m, 1H), 3.84-3.69 (m, 2H), 3.57-3.49 (m, 1H), 3.45 (d, 3H), 1.41 (s, 18H), 1.36-1.30 (m, 3H), 1.28-1.18 (m, 6H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.71, 22.74.

LC-MS m/z = 444.3 [M + 1].

Example 139

(2S)-Isopropyl 2-((((10-methoxy-6,8,13,13a-tetrahydro-5H-[1,3]dioxo[4,5-g]isoquinoline And [3,2-a]isoquinolin-9-yl)oxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 139 )

(2S)-isopropyl 2-((((10-methoxy-6,8,13,13a-tetrahydro-5H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin- 9-yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate

First step tetrahydroberberine ( 139B )

Red Tetrahydroberberine

The berberine hydrochloride 139A (2.00 g, 5.59 mmol) was dissolved in 30 mL of methanol, and the mixture was filtered under nitrogen, and then sodium borohydride (0.634, 16.8 mmol) was added portionwise, and the mixture was slowly warmed to room temperature for 2 hours. The organic phase was extracted with dichloromethane (100×3), dried over anhydrous sodium sulfate and evaporated. ~1:50) gave compound 139B as a pale yellow solid (1.20 g, yield 66.0%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.53 (s, 1H), 6.91 (s, 1H), 6.78 (d, 1H), 6.66 (s, 1H), 6.57 (d, 1H), 5.94 (d , 2H), 4.01 (d, 1H), 3.76 (s, 3H), 3.37 (d, 1H), 3.28 (d, 1H), 3.24 (d, 1H), 3.11-3.03 (m, 1H), 2.96- 2.85 (m, 1H), 2.64-2.52 (m, 2H), 2.44 (dd, 1H).

LC-MS m/z = 326.2 [M + 1].

The second step (2S)-isopropyl 2-((((10-methoxy-6,8,13,13a-tetrahydro-5H-[1,3]dioxo[4,5-g]] Isoquino[3,2-a]isoquinolin-9-yl)oxy)(methoxymethyl)phosphonium)amino)propionate ( Compound 139 )

(2S)-isopropyl 2-((((10-methoxy-6,8,13,13a-tetrahydro-5H-[1,3]dioxolo[4,5-g]isoquinolino[3,2-a]isoquinolin- 9-yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate

1C (0.500 g, 3.07 mmol) was dissolved in 20 mL of dry methylene chloride, and then filtered, and then triethylamine (1.24 g, 12.3 mmol), isopropyl ester A mixture of 0.514 g, 3.07 mmol) was reacted for 30 minutes after the dropwise addition, and 139B (0.999 g, 3.07 mmol) was added thereto, and the mixture was reacted at room temperature for 2 hours. Add 50 mL of water, extract with methylene chloride (100 mL×2), wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. (The solvent is methanol: dichloromethane (v/v) = 0:100 to 1:50) to give compound 139 , yellow solid (1.00 g, yield 59.6%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 6.96-6.88 (m, 3H), 6.66 (s, 1H), 5.95 (d, 2H), 5.32-5.13 (m, 1H), 4.95-4.84 (m, 1H), 4.19 (m, 1H), 4.02-3.80 (m, 3H), 3.78 (s, 3H), 3.50-3.42 (m, 1H), 3.41 (dd, 2H), 3.38 (dd, 2H), 3.36 -3.31(m,1H),3.05(s,1H),2.92(dd,1H),2.68-2.53(m,2H),2.45(d,1H),1.31-1.26(m,1H),1.25-1.21 (m, 2H), 1.21-1.15 (m, 6H).

LC-MS m/z = 547.2 [M+1].

Example 140

Ethyl (2S)-2-[[(N-[4-[(2,3-dimethylcarbazol-6-yl)-methyl-amino]pyrimidin-2-yl]-4-methyl- 3-Aminosulfonyl-(methoxymethyl)phosphonium]amino]propionate ethyl ester ( Compound 140 )

Ethyl(2S)-2-[[(N-[4-[(2,3-dimethylindazol-6-yl)-methyl-amino]pyrimidin-2-yl]-4-methyl-3-sulfamoyl-anilino)- (methoxymethyl)phosphoryl]amino]propanoate

The starting material 1C (0.976 g, 5.99 mmol) was dissolved in 50 mL of dry methylene chloride, and then filtered, and then, then, then, then, then, then,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Mixture of mmol), after the completion of the dropwise addition, the reaction solution was carried out for 30 min to obtain a reaction solution 1. The starting material pazopanib 89A (1.31 g, 2.99 mmol) was dissolved in 50 mL of tetrahydrofuran, and the mixture was filtered under nitrogen, and butyl lithium (3.74 mL) was added dropwise at -78 °C. 1.6 mol/L, 5.99 mmol), the reaction was carried out for 30 min after the completion of the dropwise addition to obtain a reaction liquid 2, and the reaction liquid 1 was added dropwise to the reaction liquid 2, and the mixture was slowly warmed to room temperature for 2 hours. Wash once with 20 mL of saturated aqueous solution of sodium dihydrogen phosphate, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure, and column chromatography, using dichloromethane / methanol = 100/1~20/1 as a solvent . Compound 140 was obtained as a white solid (0.6 g, yield 31%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.69 (d, 1H), 8.45 (s, 1H), 7.83-7.70 (m, 2H), 7.49 (dd, 1H), 7.39 (dd, 1H), 7.04 (d, 1H), 6.88 (dd, 1H), 5.80 (dd, 1H), 4.23-3.95 (m, 6H), 3.87 (s, 1H), 3.52 (t, 3H), 3.45 (dd, 2H), 3.21 (d, 3H), 2.67-2.61 (m, 3H), 2.52 (d, 3H), 1.18 (m, 6H).

LC-MS m/z = 645.2 [M+1].

Example 141

Benzyl (2S)-2-[[[4-[[(3R,4R)-4-[(3,4-dimethoxyphenyl)methyl]-2-oxo-tetrahydrofuran-3-yl ]methyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphonium]amino]propionate compound ( compound 141 )

Benzyl(2S)-2-[[[4-[[(3R,4R)-4-[(3,4-dimethoxyphenyl)methyl]-2-oxo-tetrahydrofuran-3-yl]methyl]-2-methoxy- Phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

The starting material 1C (1.31 g, 8.06 mmol) was dissolved in 30 mL of dry methylene chloride, and the mixture was stirred under nitrogen, and a mixture of triethylamine (2.17 g, 21.5 mmol), 47A (2.0 g, 5.37 mmol) was added dropwise at -30 ° C. After completion of the reaction for 30 min, L-alanine benzyl ester (2.89 g, 16.1 mmol) was added and allowed to react at room temperature for 2 h. Wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and then concentrated under reduced pressure, column chromatography, ethyl acetate / petroleum ether = 1/10~1 The compound 141 was obtained as a colorless oil (1.0 g, yield 25%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.40-7.25 (m, 5H), 7.23 (m, 1H), 6.76 (d, 2H), 6.63 (m, 1H), 6.59-6.45 (m, 2H), 5.09 (m, 2H), 4.28-4.04 (m, 2H), 4.01-3.60 (m, 13H), 3.44 (dd, 3H), 2.94 (dd, 2H), 2.70-2.37 (m, 4H), 1.38-1.15 (m, 3H).

LC-MS m/z = 642.3 [M+1].

Example 142

Isopropyl (2S)-2-[[methoxymethyl-[2-methoxy-4-[[[(E)-8-methylindole-6-enyl]amino]methyl]benzene Ethyl]phosphonium]amino]propionic acid ethyl ester ( compound 142 )

Isopropyl(2S)-2-[[methoxymethyl-[2-methoxy-4-[[[(E)-8-methylnon-6-enoyl]amino]methyl]phenoxy]phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (1.0 g, 6.lmmol) was dissolved in dry dichloromethane (30 mL), cooled to -30 ° C under nitrogen atmosphere, and the material L-alanine was slowly added dropwise. A mixture of ethyl acetate in dichloromethane (4 mL, 0.72 g, 6.1 mmol) and triethylamine (2.5 g, 24.4 mmol), and the reaction was continued at -30 ° C for 30 minutes after the completion of the addition of 106 A (0.94 g, 3.1 mmol). ), naturally heated to room temperature for 1 hour. Add 20 mL of saturated aqueous sodium dihydrogen phosphate solution, 20 mL of dichloromethane, and separate the mixture. The organic layer was washed with saturated aqueous sodium dihydrochloride (20 mL), dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography ( petroleum ether: ethyl acetate Ester (v/v) = 3:1 to 1:1) gave compound 142 , white semi-solid (0.36 g, yield 22%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.24 (dd, 1H), 6.87 (s, 1H), 6.81-6.76 (m, 1H), 5.90 (s, 1H), 5.41-5.27 (m, 2H), 4.45 -4.33(m,2H),4.23-4.04(m,3H),3.93-3.80(m,4H),3.47(d,3H), 2.24-2.20(m,3H),2.06-1.96(m,2H) , 1.70 - 1.62 (m, 2H), 1.44-1.32 (m, 4H), 1.32-1.21 (m, 6H), 0.95 (d, 6H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.50, 24.93.

LC-MS m/z = 513.3 [M + 1].

Example 143

Isopropyl (2S)-2-[[[3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methyl-propyl]phenoxy](methoxy) Methyl)phosphonium]amino]propionic acid ( compound 143 )

Isopropyl(2S)-2-[[[3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methyl-propyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

The starting material 1C (0.200 g, 1.23 mmol) was dissolved in 10 mL of dry methylene chloride, and then filtered, and then, triethylamine (0.373 g, 3.68 mmol) was added dropwise at -30 ° C, L-alanine isopropyl ester hydrochloride A mixture of (0.206 g, 1.23 mmol) was reacted for 30 minutes after the dropwise addition, and 143A (0.272 g, 1.23 mmol) was added, and the mixture was reacted at room temperature for 2 hours. Add 50 mL of water, extract with methylene chloride (100 mL×2), wash once with 20 mL of saturated aqueous sodium dihydrogen phosphate solution, wash once with 20 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. (The solvent was methanol: dichloromethane (v/v) = 0: 100 to 1: 50) to give Compound 143 as a yellow oil (0.100 g, yield: 18.4%).

LC-MS m/z = 443.2 [M + 1].

Example 144

Isopropyl (2S)-2-[methoxymethyl-(4-methylthiophenoxy)phosphonium]amino]propionate ( Compound 144 )

Isopropyl(2S)-2-[[methoxymethyl-(4-methylsulfanylphenoxy)phosphoryl]amino]propanoate

The starting material (methoxymethyl)phosphonium dichloride (1.300 g, 8.00 mmol) was dissolved in 20 mL of dry dichloromethane, and nitrogen-protected, and isopropyl L-alanine (1.050 g) was added dropwise at -30 °C. 8.00 mmol) of a dichloromethane solution (5 mL), 1 h after the dropwise addition, triethylamine (3.240 g, 32.00 mmol) and 4-methylthio-phenol (0.561 g, 4.00 mmol), and allowed to warm to room temperature. After heating to 40 ° C for 4 h. Water (30 mL) was added, and the aqueous layer was separated with methylene chloride (20 mL×2). ). Compound 144 was obtained as a white solid (0.635 g, yield 43.9%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.27-7.15 (m, 4H), 5.05-4.94 (m, 1H), 4.15-4.03 (m, 1H), 3.85-3.72 (m, 2H), 3.56-3.51 (m, 1H), 3.48-3.43 (m, 3H), 2.46 (s, 3H), 1.32 (d, 3H), 1.24-1.21 (m, 6H).

LC-MS m/z = 362.1 [M + 1].

Example 145

Isopropyl (2S)-2-[methoxymethyl-(3-cyanophenoxy)phosphonium]amino]propionate ( Compound 145 )

Isopropyl(2S)-2-[[methoxymethyl-(3-cyanophenoxy)phosphoryl]amino]propanoate

The starting material (methoxymethyl)phosphonium dichloride (1.900 g, 12.00 mmol) was dissolved in 20 mL of dry dichloromethane, and nitrogen-protected, and isopropyl ester of L-alanine (1.600 g) was added dropwise at -30 °C. 12.00 mmol) of a dichloromethane solution (5 mL), after 1 hour of completion, 1 h, triethylamine (4.800 g, 48.00 mmol) and 3-cyano-phenol (0.710 g, 6.00 mmol) were added and allowed to warm to room temperature. Heat to 40 ° C for 4 h. Water (30 mL) was added, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjj Compound 145 was obtained as a pale yellow liquid (0.366 g, yield 18%)

_{^{1 H NMR (400MHz, CDCl 3}} ): δ 7.54-7.42 (m, 4H), 5.05-4.96 (m, 1H), 4.15-4.03 (m, 1H), 4.15-4.04 (m, 1H), 3.85-3.77 (m, 1H), 3.67-3.62 (m, 1H), 3.50-3.46 (m, 3H), 1.36-1.32 (m, 3H), 1.24-1.21 (m, 6H).

LC-MS m/z = 341.1 [M + 1].

Example 146

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxoethyl]amino]-(methoxymethyl)phosphinyl]oxyphenyl) ]methyl]O1-methyl(E)-2-butenoic acid diester ( compound 146 )

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methyl]O1-methyl(E)-but-2- Edidioate

First step: methyl (E)-4-chloro-4-carbonyl-but-2-enoate ( 146B )

Methyl(E)-4-chloro-4-oxo-but-2-enoate

Monomethyl fumarate 146A (0.260 g, 2.00 mmol) was dissolved in dichloromethane (10 mL), and two portions of N,N-dimethylformamide and hydrazine chloride (1 mL) were added and stirred for 1 hour. , concentrated under reduced pressure to remove excess oxalyl acyl chloride to give a brown compound 146B, was used directly without further purification in the second step ^{reaction; 1 H NMR (400MHz, CDCl} 3) δ 6.92 (dd, 2H), 5.81 (s, 2H) , 3.83 (s, 3H).

Second step; O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium) ]oxyphenyl]methyl]O1-methyl(E)-2-butenoic acid diester ( compound 146 )

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methyl]O1-methyl(E)-but-2- Edidioate

Compound 146B was dissolved in dry dichloromethane (10 mL), and then filtered, and then &lt;RTI ID=0.0&gt;&gt; Isopropyl ester ( Intermediate 4 ) (0.740 g, 2.00 mmol) and triethylamine (0.404 g, 4.40 mmol). Diluted with water (20 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (20 mL×2), and the organic phase was combined, washed with brine (40 mL), dried over anhydrous sodium sulfate Ether: ethyl acetate (v/v) = 1:1) was purified. Compound 146 was obtained as a pale yellow oil (0.415 g, yield: 45.4%)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.22 (m, 4H), 6.92-6.88 (m, 2H), 5.19 (br, 2H), 5.03-4.94 (m, 1H), 4.16-4.06 (m, 1H), 3.85-3.74 (m, 5H), 3.59-3.53 (m, 1H), 3.49-3.43 (m, 3H), 1.32 (d, 3H), 1.24-1.21 (m, 6H).

LC-MS m/z = 458.1 [M+1].

Example 147

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonyl]oxy]- 3-methoxy-phenyl]methyl]O1-methyl(E)-2-butenoic acid diester ( compound 147 )

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-3-methoxy-phenyl]methyl]O1-methyl(E )-but-2-enedioate

First step: methyl (E)-4-chloro-4-carbonyl-but-2-enoate ( 146B )

Methyl(E)-4-chloro-4-oxo-but-2-enoate

Monomethyl fumarate 146A (0.260 g, 2.00 mmol) was dissolved in dichloromethane (10 mL), and two portions of N,N-dimethylformamide and hydrazine chloride (1 mL) were added and stirred for 1 hour. , concentrated under reduced pressure to remove excess oxalyl acyl chloride to give a brown compound 146B, was used directly without further purification in the second step ^{reaction; 1 H NMR (400MHz, CDCl} 3) δ 6.92 (dd, 2H), 5.81 (s, 2H) , 3.83 (s, 3H).

Second step: O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium) ]oxy-3-methoxy-phenyl]methyl]O1-methyl(E)-2-butenoic acid diester ( compound 147 )

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-3-methoxy-phenyl]methyl]O1-methyl(E )-but-2-enedioate

The above chlorohydrazine 146A was dissolved in dry dichloromethane (10 mL), and then filtered, and (2S)-2-[[4-(hydroxymethyl)-2-methoxy-phenoxy]-(methoxy) Methyl)phosphoniumamino]propionic acid isopropyl ester ( Intermediate 7 ) (0.750 g, 2.00 mmol) and triethylamine (0.404 g, 4.40 mmol). Diluted with water (20 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (20 mL×2), and the organic phase was combined, washed with brine (40 mL), dried over anhydrous sodium sulfate Ether: ethyl acetate (v/v) = 1:1) was purified. The title compound 147 was obtained as a brown oil (0.200 g, yield: 20.5%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.33-7.30 (m, 2H), 6.93-6.88 (m, 4H), 5.17 (d, 2H), 5.02-4.93 (m, 1H), 4.14-4.03 (m, 1H), 3.94-3.84 (m, 5H), 3.82 (s, 3H), 3.52-3.49 (m, 3H), 1.33-1.19 (m, 9H).

LC-MS m/z = 488.1 [M+1].

Example 148

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonyl]oxy]- 3,5-dimethoxy-phenyl]methyl]O1-methyl(E)-2-butenoic acid diester ( compound 148 )

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-3,5-dimethoxy-phenyl]methyl]O1-methyl (E)-but-2-enedioate

First step: methyl (E)-4-chloro-4-carbonyl-but-2-enoate ( 146B )

Methyl(E)-4-chloro-4-oxo-but-2-enoate

Monomethyl fumarate 146A (0.260 g, 2.00 mmol) was dissolved in dichloromethane (10 mL), and two portions of N,N-dimethylformamide and hydrazine chloride (1 mL) were added and stirred for 1 hour. , concentrated under reduced pressure to remove excess oxalyl acyl chloride to give a brown compound 146B, was used directly without further purification in the second step ^{reaction; 1 H NMR (400MHz, CDCl} 3) δ 6.92 (dd, 2H), 5.81 (s, 2H) , 3.83 (s, 3H).

Second step; O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium) ]oxy-3,5-dimethoxy-phenyl]methyl]O1-methyl(E)-2-butenoic acid diester ( compound 148 )

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-3,5-dimethoxy-phenyl]methyl]O1-methyl (E)-but-2-enedioate

The above chlorohydrazine 146B was dissolved in dry dichloromethane (10 mL), and then protected with nitrogen, (2S)-2-[[4-(hydroxymethyl)-2,6-dimethoxy-phenoxy]- ( Methoxymethyl)phosphoniumamino]propionic acid isopropyl ester ( Intermediate 8 ) (0.810 g, 2.00 mmol) and triethylamine (0.404 g, 4.00 mmol) were stirred at room temperature for 4 hr. Diluted with water (20 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (20 mL×2), and the organic phase was combined, washed with brine (40 mL), dried over anhydrous sodium sulfate Ether: ethyl acetate (v/v) = 1:1) was purified. Compound 148 was obtained as a brown oil (0.435 g, yield 42.1%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.89 (dd, 2H), 6.61 (d, 2H), 5.15 (d, 2H), 5.06-4.98 (m, 1H), 4.16-4.09 (m, 1H), 4.02 -3.89 (m, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.81 (d, 3H), 3.52-3.51 (m, 3H), 1.43-1.33 (m, 3H), 1.26-1.22 (m, 6H).

LC-MS m/z = 518.2 [M+1].

Example 149

[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphinyl]oxyphenyl]- Furfuran-2-carboxylate ( compound 149 )

[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methylfuran-2-carboxylate

First step: furan-2-carboxamidine chloride ( compound 149B )

Furan-2-carbonyl chloride

Compound 149A (0.336 g, 3.00 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; Excess grassy chlorine gave brown chlorochloride compound 149B which was used in the second step without further purification;

Second step; [4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphinyl]oxy Phenyl]methylfuran-2-carboxylate ( compound 149 )

[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methyl furan-2-carboxylate

The above ruthenium chloride was dissolved in dry dichloromethane (10 mL), protected with nitrogen, and (2S)-2-[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphinylamino] Isopropyl propionate ( Intermediate 4 ) (0.520 g, 1.00 mmol) and triethylamine (0.44 g, 4.40 mmol). Diluted with water (20 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (20 mL×2), and the organic phase was combined, washed with brine (40 mL), dried over anhydrous sodium sulfate Ether: ethyl acetate (v/v) = 1:1). Compound 149 was obtained as a pale yellow oil (0.211 g, yield 31.9%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.58-7.57 (m, 1H), 7.40-7.31 (m, 3H), 7.23-7.19 (m, 3H), 5.30 (br, 2H), 5.02-4.97 (m, 1H), 4.13-4.08 (m, 1H), 3.86-3.74 (m, 2H), 3.64-3.59 (m, 1H), 3.43 (s, 3H), 1.32 (d, 3H), 1.24-1.21 (m, 6H).

LC-MS m/z = 462.1 [M+23].

Example 150

Isopropyl (2S)-2-[[(4-acetamidophenoxy)-(methoxymethyl)phosphonium]amino]propionate ( Compound 150 )

Isopropyl(2S)-2-[[(4-acetamidophenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

Under the protection of anhydrous nitrogen, compound 1C (1.21 g, 7.41 mmol) and dichloromethane (5 mL) were placed in a reaction flask, and acetaminophen 150A (1.12 g, 7.41 mmol) and triethylamine (s) were slowly added at -30 ° C under cooling. 3.0g, 29.6mmol) of the mixed solution, after the addition, -30 ° C naturally rose to 0 ° C reaction for 30 min; ice-cooled under the addition of L-alanine isopropyl ester hydrochloride (1.24 g, 7.41 mmol) of two The methyl chloride solution (5 mL) was reacted at room temperature for 2 hours. After concentration under reduced pressure, it was purified by column chromatography (dichloromethane/methanol (v/v) = 100:1). Compound 150 was obtained as a colorless oil (0.4 g, yield 14.5%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.68 (s, 1H), 7.42 (dd, 2H), 7.07 (dd, 2H), 5.04-4.96 (m, 1H), 4.10-4.02 (m, 1H), 3.83 -3.69 (m, 3H), 3.45 (d, 3H), 2.12 (s, 3H), 1.32 (d, 3H), 1.24-1.21 (m, 6H).

LC-MS m/z = 373.1 [M + 1].

Example 151

Isopropyl (2S)-2-[[methoxymethyl-[4-[[(1S)-3-(4-phenoxyphenyl)-1-(1-prop-2-enyl) -3-Acridine)pyrazolo[3,4-d]pyrimidin-4-yl]carbamomethoxymethyl]phenoxy]phosphonium]amino]propionate ( Compound 151 )

Isopropyl(2S)-2-[[methoxymethyl-[4-[[(1S)-3-(4-phenoxyphenyl)-1-(1-prop-2-enoyl-3-piperidyl)pyrazolo[3,4-d ]pyrimidin-4-yl]carbamoyloxymethyl]phenoxy]phosphoryl]amino]propanoate

Intermediate 4 (0.500 g, 1.45 mmol) was dissolved in 5 mL of dry tetrahydrofuran, cooled to 0 ° C under ice-cooling, and added to phosgene (0.215 g, 0.724 mmol). The amine (0.281 g, 2.17 mmol) was added to the reaction mixture at 0 ° C for 30 minutes to obtain a solution of the compound 151A in tetrahydrofuran. Further, Ibrutinib (0.319 g, 0.724 mmol) was dissolved in 5 mL of dry tetrahydrofuran, diisopropylethylamine (0.281 g, 2.17 mmol) was added, and then slowly added to the above prepared 151A tetrahydrofuran solution. After the addition, the reaction was carried out in a microwave reactor at 70 ° C for 30 minutes. 30 mL of water and 50 mL of dichloromethane were added, and the organic layer was washed once with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate and evaporated. v) = 0: 100 ~ 3 : 97) to give compound 151 as a white solid (0.080 g, 6.8% yield).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.99 (m, 1H), 7.92-7.86 (m, 3H), 7.38-7.33 (m, 4H), 7.26 (s, 2H), 7.14-7.11 (m, 1H) , 7.06-7.03 (m, 4H), 6.60 (dd, 1H), 6.31 (dd, 1H), 5.76-5.68 (m, 1H), 5.30-5.20 (m, 2H), 4.04-4.96 (m, 1H) , 4.74 (s, 1H), 4.42 (m, 0.5H), 3.97-3.92 (m, 0.5H), 3.82-3.74 (m, 2H), 3.62-3.60 (m, 1H), 3.46 (d, 3H) , 3.12 (s, 2H), 2.35-2.20 (m, 2H), 2.00-1.86 (m, 2H), 1.62-1.50 (m, 2H), 1.32 (d, 3H), 1.23 (m, 6H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.35, 23.42.

LC-MS m/z = 405.5 [1/2M + 1]

Example 152

Isopropyl (2S)-2-[[[4-[[1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl ]-2-oxo-pyrimidin-4-yl]carbamomethoxymethyl]phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( compound 152 )

Isopropyl(2S)-2-[[[4-[[1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-oxo -pyrimidin-4-yl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

First step: 4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-trimethylformamoxy-5-(trimethylformamoxymethyl)tetrahydrofuran -2-yl]pyrimidin-2-one ( 152B )

4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-trimethylsilyloxy-5-(trimethylsilyloxymethyl)tetrahydrofuran-2-yl]pyrimidin-2-one

Compound 152A (4.60 g, 15.4 mmol) was added to 1,4-dioxane (20 mL), followed by hexamethyldiazepine (10 mL, 48.4 mmol) and trimethylsulfonium trifluoromethanesulfonate. The ester (0.129 g, 0.768 mmol) was heated to 90 ° C for 2 hours after the addition. Was added 20mL of water, ethyl acetate, 50mL, liquid separation, the organic layer was washed once with 20mL saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product of compound 152B as a white solid (6.0 g of, 96% yield) Used directly in the next step.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.74 (d, 1H), 6.33-6.30 (m, 1H), 5.81 (d, 1H), 4.29-4.22 (m, 1H), 3.93-3.90 (m, 2H) , 3.77-3.71 (m, 1H), 0.17 (s, 18H).

LC-MS (m/z) = 408.2 [M+1].

The second step: isopropyl (2S)-2-[[[4-[[1-[(2R,4R,5R)-3,3-difluoro-4-trimethylformamoxy-5- (Trimethylformamoxymethyl)tetrahydrofuran-2-yl]-2-oxo-pyrimidin-4-yl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphorus Mercapto]amino]propionate ( compound 152C )

Isopropyl(2S)-2-[[[4-[[1-[(2R,4R,5R)-3,3-difluoro-4-trimethylsilyloxy-5-(trimethylsilyloxymethyl)tetrahydrofuran-2-yl]-2-oxo -pyrimidin-4-yl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Intermediate 4 (2.0 g, 5.79 mmol) was dissolved in 10 mL of dry tetrahydrofuran, cooled to 0 ° C under ice-cooling, and added to phosgene (0.860 g, 2.9 mmol). The amine (0.749 g, 5.79 mmol) was added to the reaction mixture at 0 ° C for 30 minutes to obtain a solution of the compound 151A in tetrahydrofuran. Further, Compound 152B (2.36 g, 5.79 mmol) was dissolved in 10 mL of dry tetrahydrofuran, cooled to 0 ° C under nitrogen atmosphere, and then 4-dimethylaminopyridine (0.706 g, 5.79 mmol) was added, and the above was added slowly. The 151A tetrahydrofuran solution was naturally warmed to room temperature for 3 hours after the addition. 30 mL of water and 100 mL of ethyl acetate were added, and the organic layer was washed once with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate and evaporated. /v) = 1:1 to 3: 7) Compound 152C was obtained as white solid (1.0 g, yield 27.2%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 10.84 (s, 1H), 7.99 (d, 1H), 7.26 (d, 2H), 7.09-7.01 (m, 2H), 6.97 (d, 1H), 6.05 (t, 1H), 5.55-5.47 (m, 1H), 5.02 (s, 2H), 4.72-4.66 (m, 1H), 4.25-4.17 (m, 1H), 3.86-3.80 (m, 1H), 3.80 -3.66 (m, 2H), 3.66-3.56 (m, 3H), 3.23 (d, 3H), 1.04-0.99 (m, 9H), -0.01 (s, 18H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.82, 24.00.

The third step: isopropyl (2S)-2-[[[4-[[1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran -2-yl]-2-oxo-pyrimidin-4-yl]carbamomethoxymethyl]phenoxy]-(methoxymethyl)phosphonium]amino]propionate ( compound 152 )

Isopropyl(2S)-2-[[[4-[[1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-2-oxo -pyrimidin-4-yl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Compound 152C (0.400 g, 0.514 mmol) was dissolved in 5 mL of tetrahydrofuran, and 1 mL of an aqueous solution of ammonium fluoride (0.400 g, 10.8 mmol) was added thereto, and the mixture was reacted at room temperature for 1 hour. 10 mL of water and 20 mL of dichloromethane were added, and the aqueous layer was separated and extracted with 10 mL of methylene chloride. The organic layer was combined and washed twice with saturated sodium chloride (20 mL) and dried over anhydrous sodium sulfate. Separation and purification (petroleum ether: ethyl acetate (v/v) = 1 : 4 - methanol: methylene chloride (v/v) = 19: 19) Compound 152 as white solid (0.094 g, yield 28.8%) .

^{1 H NMR (400MHz, DMSO- d} 6) δ 10.95 (s, 1H), 8.22 (d, 1H), 7.41 (d, 2H), 7.24-7.15 (m, 2H), 7.10 (d, 1H), 6.29 (d,1H), 6.16(t,1H), 5.72-5.61(m,1H), 5.27(t,1H), 5.17(s,2H),4.87-4.81(m,1H), 4.27-4.12(m , 1H), 3.92-3.73 (m, 5H), 3.68-3.62 (m, 1H), 3.37 (dd, 3H), 1.19-1.14 (m, 9H).

¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ-114.81.

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.83, 24.01.

LC-MS m/z = 635.3 [M + 1].

Example 153

Ethyl (2R,4S)-4-[[4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-) Oxymethyl)phosphinyl]oxyphenyl]methoxy]-4-oxo-butanyl]amino]-2-methyl-5-(4-phenylphenyl)pentanoate ( Compound 153 )

Ethyl(2R,4S)-4-[[4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methoxy] -4-oxo-butanoyl]amino]-2-methyl-5-(4-phenylphenyl)pentanoate

Starting material 153A (0.500 g, 1.22 mmol) was dissolved in dichloromethane (20 mL). Intermediate 4 (0.420 g, 1.22 mmol), triethylamine (0.246 g, 2.43 mmol) and 2-(7- Nitrobenzotriazole)-tetramethylurea hexafluorophosphate (HATU) (0.693 g, 1.82 mmol) was stirred at room temperature for 2 hours. 30 mL of water and 100 mL of ethyl acetate were added, and the organic layer was washed with sodium dihydrogen phosphate (20 mL × 3), and then washed once with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate and evaporated. Purification by chromatography (petroleum ether: ethyl acetate (v/v) = 1:1 to 2:3) gave Compound 153 as colorless oil (0.200 g, yield: 22.3%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.57 (d, 2H), 7.51 (d, 2H), 7.42 (t, 2H), 7.37-7.17 (m, 7H), 5.62 (t, 1H), 5.05 (s , 2H), 5.03-4.97 (m, 1H), 4.27-4.21 (m, 1H), 4.17-4.05 (m, 3H), 3.87-3.72 (m, 2H), 3.60-3.52 (m, 1H), 3.44 (d, 3H), 2.89-2.78 (m, 2H), 2.65 (t, 2H), 2.57-2.53 (m, 1H), 2.41 (t, 2H), 1.96-1.90 (m, 1H), 1.55-1.48 (m, 1H), 1.31 (d, 3H), 1.27-1.19 (m, 9H), 1.16 (d, 3H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.18, 23.25.

Example 154

Isopropyl (2S)-2-[[[4-[1-[3-(cyanomethyl)-1-ethylsulfonyl-azetidin-3-yl]pyrazole-4- Pyrrolo[2,3-d]pyrimidin-7-yl]methoxy-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[4-[1-[3-(cyanomethyl)-1-ethylsulfonyl-azetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidin-7- Yl]methoxy-(methoxymethyl)phosphoryl]amino]propanoate

First step: 2-[1-ethylsulfonyl-3-[4-[7-(hydroxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl] Azetidin-3-yl]cyanomethane

2-[1-ethylsulfonyl-3-[4-[7-(hydr.oxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl]azetidin-3-yl]acetonitrile

154A (2g, 5.4mmol) was dissolved in 20mL of aqueous formaldehyde solution, and reacted at 70 ° C for 30 minutes, 100mL of water was added, and extracted with dichloromethane (50ml X2), the organic phase was dried over anhydrous sodium sulfate and concentrated to give the above compound 154B , white solid (2.0 g, yield 95.2%) was used in the next step without purification.

LC-MS m/z = 402.1 [M + 1].

The second step: isopropyl (2S)-2-[[[4-[1-[3-(cyanomethyl)-1-ethylsulfonyl-azetidin-3-yl]pyridinium Zin-4-yl]pyrrolo[2,3-d]pyrimidin-7-yl]methoxy-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[4-[1-[3-(cyanomethyl)-1-ethylsulfonyl-azetidin-3-yl]pyrazol-4-yl]pyrrolo[2,3-d]pyrimidin-7- Yl]methoxy-(methoxymethyl)phosphoryl]amino]propanoate

154B (2 g, 5.0 mmol) was dissolved in tetrahydrofuran (20 mL). At the same time, 1 C (1.62 g, 9.9 mmol) of a solution of 20 mL of dichloromethane was added, and at -30 ° C, L-alanine isopropyl ester (1.30 g, 9.9 mmol) and triethylamine (4.0 g, 39.6 mmol) were added. And, at this temperature, the reaction was carried out for 1 h, and the reaction liquid was further added to the reaction liquid of 154B , and reacted at 50 ° C for 3 h. Add 50 mL of water, and extract with dichloromethane (50 mL×2). The organic phase is dried over anhydrous sodium sulfate. The residue is purified and purified by silica gel chromatography (dichloromethane/methanol (v/v)=100:1~10:1) Compound 154 was obtained as a white solid (0.5 g, yield 16.1%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.97 (s, 1H), 8.81 (s, 1H), 8.51 (s, 1H), 7.77 (dd, 1H), 7.23 (dd, 1H), 6.15-6.06 (m, 2H), 5.51-5.39 (m, 1H), 4.99-4.74 (m, 1H), 4.60 (d, 2H), 4.25 (d, 2H), 3.95-3.77 (m, 1H), 3.68 (d) , 2H), 3.61-3.57 (m, 2H), 3.28-3.20 (m, 5H), 1.32-1.12 (m, 12H).

LC-MS m/z = 623.2 [M + 1].

Example 155

Isopropyl (2S)-2-[[[2-[(5-chloro-2,1,3-benzothiadiazol-4-yl)amino]-4,5-dihydroimidazol-1-yl ]-(Methoxymethyl)phosphonium]amino]propionate ( Compound 155 )

Isopropyl(2S)-2-[[[2-[(5-chloro-2,1,3-benzothiadiazol-4-yl)amino]-4,5-dihydroimidazol-1-yl]-(methoxymethyl)phosphoryl]amino Propanoate

Under a nitrogen atmosphere, 1 C (0.25 g, 1.50 mmol) and 5 mL of tetrahydrofuran were added to the reaction flask, and tizanidine 155A (0.39 g, 1.50 mmol), triethylamine (0.62 g, 6.10 mmol) was added under cooling with ice water. A mixed solution of 5 mL of tetrahydrofuran was added to the reaction flask. After the addition, the oil bath was heated to 45 ° C for 20 minutes, and a solution of L-alanine isopropyl ester hydrochloride in dichloromethane (1.30 mL, 2 g) was added under ice cooling. /10 mL), adding the reaction at room temperature for 2 hours, adding 10 mL of methanol, stirring for 5 minutes, concentrating under reduced pressure, the residue was added ethyl acetate 40 mL, washed with saturated aqueous sodium chloride (50 mL×1) and dried over anhydrous sodium sulfate , filtered and concentrated to dryness under reduced pressure; the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 50/ 1), to give compound 155 as a pale yellow solid (0.025 g, yield: 3.4%).

LC-MS m/z = 475.2 [M+1].

Example 156

Isopropyl (2S)-2-[[[3-[2(dimethylamino)ethyl]1H-indol-4-yl]oxy-(methoxymethyl)phosphonium]amino]propyl Acid ester ( compound 156 )

Isopropyl(2S)-2-[[[3-[2-(dimethylamino)ethyl]-1H-indol-4-yl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

Under the protection of nitrogen, (methoxymethyl)phosphine dichloride 1C (0.33g, 2.00mmol) and tetrahydrofuran 5mL were added to the reaction flask, cooled to about -30 °C, 3-[2-(dimethylamino) a mixed solution of ethyl]-1H-indol-4-ol 156A (0.41 g, 2.00 mmol), triethylamine (0.81 g, 8.00 mmol) and tetrahydrofuran 5 mL was added to the reaction flask, and the cooling was carried out after the addition. The reaction was carried out for 20 minutes; cooled to about -30 ° C, and a solution of L-alanine isopropyl ester hydrochloride in dichloromethane (1.70 mL, 2 g/10 mL) was added, and the mixture was stirred at room temperature for 2 hours, and 10 mL of methanol was added and stirred. 5 minutes, concentrated under reduced pressure, the residue was purified by column chromatography (dichloromethane / methanol (v / v) = 20/ 1), compound 156, a gray oil (0.31 g, yield: 37%).

_{^{1 H NMR (400MHz, CD 3}} OD) δ 7.20-7.18 (m, 2H), 7.10-6.99 (m, 2H), 4.93-4.88 (m, 1H), 3.99-3.96 (m, 1H), 3.48 (d , 1H), 3.42 (d, 1H), 3.42-3.34 (m, 7H), 2.86 (s, 6H), 1.30-1.16 (m, 9H).

LC-MS m/z = 426.3 [M + 1].

Example 157

Isopropyl (2S)-2-[[[8-(2-acetamidoethyl)-2-naphthyl]oxy-(methoxymethyl)-phosphonium]amino]propionate ( Compound 157 )

Isopropyl(2S)-2-[[[8-(2-acetamidoethyl)-2-naphthyl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

First step: N-[2-(7-hydroxy-1-naphthalenyl)ethyl]acetamide ( compound 157B )

N-[2-(7-hydroxy-1-naphthyl)ethyl]acetamide

Under the protection of nitrogen, Agomelatine 157A (1.95g, 8.00mmol) and 40mL of dichloromethane were added to the reaction flask, and the solution of boron tribromide in dichloromethane (1mol/L, 16mL) was slowly added dropwise under ice cooling. After the addition, the reaction was carried out under ice cooling for 2 hours, and 10 mL of methanol was added dropwise thereto, and the mixture was stirred for 5 minutes, concentrated under reduced pressure, and purified by column chromatography (dichloromethane/methanol (v/v) = 30:1). Compound 157B , off-white solid (1.51 g, yield: 82.2%).

LC-MS (m/z) = 230.1 [M+1].

Second step: isopropyl (2S)-2-[[[8-(2-acetamidoethyl)-2-naphthyl]oxy-(methoxymethyl)-phosphino]amino] Propionate ( compound 157 )

Isopropyl(2S)-2-[[[8-(2-acetamidoethyl)-2-naphthyl]oxy-(methoxymethyl)phosphoryl]amino]propanoate

Under a nitrogen atmosphere, (methoxymethyl)phosphine dichloride 1C (0.33 g, 2.00 mmol) and tetrahydrofuran 5 mL were added to a reaction flask, and cooled to about -30 ° C to give a compound 157A (0.46 g, 2.00 mmol). A mixed solution of triethylamine (0.81 g, 8.00 mmol) and tetrahydrofuran (5 mL) was added to the reaction flask, and after cooling, the reaction was allowed to warm up for 20 minutes; cooled to -30 ° C, and L-alanine isopropyl ester hydrochloride was added. The dichloromethane solution (1.70 mL, 2 g/10 mL) was added to the mixture at room temperature for 2 hours, 10 mL of methanol was added, and the mixture was stirred for 5 minutes, concentrated under reduced pressure, and then purified by column chromatography (dichloromethane/methanol (v/) v) = 20/1) gave the title compound 157 as a white oil (0.16 g, yield: 19%).

LC-MS (m/z) = 451.3 [M+1].

Example 158

2-[1-[[1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphonium]oxy] Ethoxycarbonylamino]methyl]cyclohexyl]acetic acid ( compound 158 )

2-[1-[[1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyethoxycarbonylamino]methyl]cyclohexyl]acetic acid

First step: benzyl 2-[1-(aminomethyl)cyclohexyl] acetate 4-methylbenzenesulfonate ( compound 158A )

Benzyl 2-[1-(aminomethyl)cyclohexyl]acetate; 4-methylbenzenesulfonic acid

Gabapentin 97A (1.0 g, 5.84 mmol) was dissolved in benzyl alcohol (9 mL), p-toluenesulfonic acid monohydrate (1.22 g, 6.42 mmol) was added, stirred and dissolved, cyclohexane (300 mL) was added, and the mixture was refluxed with water. hour. After cooling, it was beaten twice with methyl tert-butyl ether (300 mL × 2), and the solid was dried under reduced pressure to give the compound 158A as a white solid (2.5 g, yield: 99%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.77 (d, 3H), 7.41-7.21 (m, 4H), 7.11 (d, 2H), 5.01 (s, 2H), 3.09-2.86 (m, 2H), 2.50 (s, 2H), 2.32 (s, 3H), 1.53-1.13 (m, 10H).

Step Two: Benzyl 2- [1 - [(1-chloro-ethoxycarbonyl) methyl] cyclohexyl] acetate (Compound 158B)

Benzyl 2-[1-[(1-chloroethoxycarbonylamino)methyl]cyclohexyl]acetate

Compound 158A (0.8 g, 1.85 mmol) was dissolved in dichloromethane <RTI ID=0.0>(</RTI><RTIID=0.0></RTI></RTI><RTIgt; , 4.1 mmol), naturally warmed to room temperature and stirred for 2 hours. The temperature was lowered to 0 ° C, water (50 mL) was added dropwise, and the pH was adjusted to about 4 with 2 mol/L hydrochloric acid. It was extracted with dichloromethane (50 mL × 2), filtered, and concentrated under reduced pressure to give the compound 158B (yield: yield: 100%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.46-7.28 (m, 5H), 6.55 (q, 1H), 5.50 (br, 1H), 5.12 (s, 2H), 3.20 (d, 2H), 2.35 (s , 2H), 1.77 (d, 3H), 1.61-1.28 (m, 10H).

The third step: isopropyl (2S)-2-[[1-[[1-(2-benzyloxy-2-oxo-ethyl)cyclohexyl]methylcarbamethoxy]ethoxy- (methoxymethyl)phosphonium]amino]propionate ( compound 158C )

Isopropyl(2S)-2-[[1-[[1-(2-benzyloxy-2-oxo-ethyl)cyclohexyl]methylcarbamoyloxy]ethoxy-(methoxymethyl)phosphoryl]amino]propanoate

Isopropyl ((benzyloxy)(methoxymethyl)phosphonium) -L -alanine ester ( Intermediate 6A ) (0.40 g, 1.3 mmol) was dissolved in dry THF (5 mL) Triethylamine (0.13 g, 1.3 mmol) and Pd/C (10%, 80 mg) were stirred at room temperature for 2 hr.

Compound 158B (223mg, 0.6mmol) was dissolved in chloroform (10 mL), injected into the above filtrate was added _{Ag 2 CO 3 (0.334g, 1.21mmol} ), stirred at room temperature for 5 hours. Suction pads diatomaceous earth, and the filtrate was rotary evaporation, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1: 1), to give the compound 158C, a pale yellow oil (40mg, yield : 11.6%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.44-7.28 (m, 5H), 6.79-6.30 (m, 1H), 5.44 (br, 1H), 5.11 (s, 2H), 5.03 (m, 1H), 4.18 -3.98(m,1H),3.84-3.59(m,2H),3.44-3.31(m,3H),3.31-2.99(m,2H),2.35(s,2H),1.60-1.31(m,13H) , 1.30-1.04 (m, 9H).

LC-MS (m/z) = 593.2 [M+23]

Fourth step: 2-[1-[[1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphine Mercapto]oxyethoxycarbonylamino]methyl]cyclohexyl]acetic acid ( compound 158 )

2-[1-[[1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyethoxycarbonylamino]methyl]cyclohexyl]acetic acid

Compound 158C (40 mg, 0.7 mmol) was dissolved in THF (5 mL). Filtered off with suction, the filtrate by rotary evaporation, was purified by column chromatography (DCM: MeOH (v / v ) = 15: 1), to give the compound 158 (9mg, yield: 2.7%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.64-6.33 (m, 1H), 5.50-5.28 (m, 1H), 5.10 - 4.93 (m, 1H), 4.16 - 3.90 (m, 1H), 3.86 - 3.61 ( m, 2H), 3.50-3.31 (m, 4H), 3.21-2.92 (m, 1H), 2.42-2.16 (m, 2H), 1.59-1.32 (m, 13H), 1.31-1.16 (m, 9H).

LC-MS (m/z) = 503.1 [M+23].

Example 159

Isopropyl (2S)-2-[[[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenoxy]-(methoxymethyl) Phosphonium]amino]propionate ( compound 159 )

Isopropyl(2S)-2-[[[3-[(1R)-1-cyclopropylethyl]-4-hydroxy-5-isopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

1C (1.60 g, 9.82 mmol) was dissolved in 20 mL of dry dichloromethane, and then filtered with nitrogen, and triethylamine (1.5 g, 14.75 mmol) and isopropyl L-alanine (1.30 g) were added dropwise at -30 °C. 9.91 mmol) of the mixture was reacted for 30 min after the completion of the dropwise addition, and the starting material 159A (1.50 g, 6.8 lmmol) was added and reacted at room temperature for 2 h. The reaction solution was washed once with 20 mL of a saturated aqueous solution of sodium hydrogen sulfate, and then washed twice with 20 mL of brine. Compound 159, yellow oil (0.6 g, 20.0%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.80 (s, 1H), 6.90-6.88 (m, 1H), 6.80-6.88 (m, 1H), 5.48-5.44 (m, 1H), 4.90-4.83 ( m, 1H), 3.90-3.80 (m, 1H), 3.72-3.68 (m, 2H), 3.36 (d, 3H), 3.30-3.23 (m, 1H), 1.19-1.11 (m, 19H), 1.01 0.91 (m, 1H), 0.51-0.47 (m, 1H), 0.34-0.28 (m, 1H), 0.17-0.05 (m, 2H).

Example 160

(2S)-Benzyl 2-(((methoxymethyl)(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H) -3,12-epoxy[1,2]dioxan[4,3-i]isobenzopyran-10-yl)oxy)phosphonium)amino)propionate ( Compound 160 )

(2S)-benzyl 2-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-3H-3,12-epoxy[1, 2]dioxepino[4,3-i]isochromen-10-yl)oxy)phosphoryl)amino)propanoate

1C (1.15 g, 7.06 mmol) was dissolved in dichloromethane (20 mL), EtOAc (EtOAc, EtOAc, EtOAc. A solution of the mixture in dichloromethane (10 mL). After stirring at this temperature for 20 min, 160A (1 g, 3.52 mmol Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen sulfate (30 mL×1) and a saturated sodium chloride solution (30 mL×1), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Separation and purification by hydrazine column chromatography (ethyl acetate / petroleum ether = 1 / 5 / 2 / 1) gave Compound 160 as a yellow oil (0.05 g, yield: 2.57%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.44-7.28 (m, 5H), 5.40-5.05 (m, 4H), 4.19 (m, 1H), 3.90-3.81 (m, 1H), 3.70 (dd, 1H) , 3.51-3.34 (m, 3H), 2.41-2.22 (m, 1H), 2.17 - 17.79 (m, 4H), 1.78-1.65 (m, 2H), 1.56-1.19 (m, 12H), 0.97-0.86 ( m, 6H).

LC-MS m/z (ESI) = 576.3 [M+23].

Example 161

(2S)-cyclopropyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H- Pyran[3',4':6,7]indole[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphonium)amino)propionate ( compound) 161 )

(2S)-cyclopropyl 2-((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4' :6,7]indolizino[1,2-b]quinolin-9-yl)oxy)(methoxymethyl)phosphoryl)amino)propanoate

The 1C (1g, 6.13mmol) was dissolved in dichloromethane (25mL), a minus 30 ℃, under nitrogen, was added dropwise 75B (0.8g, 6.13mmol) and triethylamine (2.48g, 24.53mmol) in methylene A solution of methane (10 mL) was added dropwise and allowed to react at room temperature for 1 hour. At this temperature, 49A (1.92 g, 4.9 mmol) was added, and the reaction was carried out at 50 ° C for 1 hour after the addition. The reaction mixture was washed with aq. EtOAc (EtOAc) (EtOAc) 30:1) Compound 161 was obtained as a pale yellow solid (0.31 g, yield 8.38%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.18 (dd, 1H), 7.97-7.94 (m, 1H), 7.71-7.63 (m, 1H), 7.62 (d, 1H), 5.72 (d, 1H), 5.30 (d,1H), 5.24 (dd, 2H), 4.19-4.11 (m, 2H), 3.92-3.86 (m, 3H), 3.74-3.72 (m, 1H), 3.54-3.50 (m, 3H), 3.18 -3.15 (m, 2H), 1.91-1.86 (m, 2H), 1.41-1.33 (m, 6H), 1.02 (t, 3H), 0.77-0.57 (m, 4H).

LC-MS m/z (ESI) = 612.2 [M+1].

Example 162

Isopropyl (2S)-2-[[[4-[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxy) Methyl)phosphonium]oxy-3,5-diisopropyl-phenyl]-2,6-diisopropyl-phenoxy]-(methoxymethyl)phosphonium]amino Propionate ( compound 162 )

Isopropyl(2S)-2-[[[4-[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxy-3,5- Diisopropyl-phenyl]-2,6-diisopropyl-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

The 1C (0.91g, 5.64mmol) was dissolved in 20mL of dichloromethane, at minus 10 ℃, nitrogen, a solution of 132A (1.0g, 2.82mmol) and triethylamine (1.14g, 11.28mmol) in methylene A solution of methane (20 mL) was added dropwise and allowed to react at room temperature for 1 hour. At this temperature, isopropyl L-alanine (1.11 g, 8.46 mmol) was added, and the mixture was reacted at room temperature for 4 hours. 50 mL of a saturated aqueous solution of sodium dihydrogen phosphate was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The residue was purified and purified by gel column chromatography ( petroleum ether: acetic acid Ethyl ester = 10:1 to 1:1) gave compound 162 as a white solid (0.3 g, 13.33%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.22 (m, 4H), 5.05-5.94 (m, 2H), 4.16-4.09 (m, 2H), 4.01-3.79 (m, 4H), 3.69-3.44 (m, 12H), 1.41-1.18 (m, 42H).

Example 163

[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxoethyl]amino]-(methoxymethyl)phosphonyl]oxyphenyl]methyl (4R)-4-[(3R,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3 ,4,5,67,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yl]pentanoic acid ethyl ester ( compound 163 )

[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)ph Osphoryl]oxyphenyl]methyl(4R)-4-[(3R,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2, 3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate

163A (0.80 g, 1.90 mmol) was dissolved in 10 mL of dry N,N-dimethylformamide, and intermediate 4 (0.99 g, 2.85 mmol) and 2-(1H-benzotrisazo -1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.92 g, 2.85 mmol), followed by dropwise addition of diisopropylethylamine (0.37 g, 2.85 mmol) After the addition, the reaction was carried out overnight at room temperature. 100 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and evaporated. Ether = 0:1 to 1:1) Compound 163 was obtained as pale yellow solid (0.080 g, 10.5%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.31 (d, 2H), 7.22 (d, 2H), 5.05 (m, 2H), 4.98 (dd, 1H), 4.11 (dd, 1H), 3.80 (m, 2H ), 3.70 (s, 1H), 3.54 (s, 1H), 3.46 (dd, 3H), 3.39 (m, 1H), 2.39 (m, 1H), 2.26 (m, 1H), 1.95 (m, 1H) , 1.82 (m, 6H), 1.62 (m, 4H), 1.44 (m, 10H), 1.32 (m, 7H), 1.23 (m, 7H), 1.14 (m,, 3H), 1.00 (m, 1H) , 0.91 (m, 9H).

³¹ P NMR (162 MHz, CDCl ₃ ): δ 24.12, 23.18.

Example 164

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(hydroxymethyl)phosphonium]amino]propionate ( Compound 164 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(hydroxymethyl)phosphoryl]amino]propanoate

First step: diethoxyphosphonium methoxymethylbenzene ( 164B )

Diethoxyphosphorylmethoxymethylbenzene

164A (37.7 g, 240.7 mmol) and triethyl phosphite (40.0 g, 240.7 mmol) were placed in a 500 mL single-mouth flask and reacted at 130 °C for 3 hours. It was cooled to room temperature and purified by silica gel column chromatography (ethyl ether (ethyl acetate) (v/v) = 10:1 to 1:1) to afford compound 164B as colorless oil (30 g, yield 48.25%).

LCMS m/z = 259.1 [M + 1].

The second step: dichlorophosphonium methoxymethylbenzene ( 164C )

Dichlorophosphorylmethoxymethylbenzene

164B (30 g, 116.1 mmol) was dissolved in 200 mL of acetonitrile, and trimethylbromodecane (53.3 g, 348.5 mmol) was added at room temperature, and reacted at 50 ° C for 3 hours. Concentrated to remove acetonitrile, the crude product was dissolved in 200 mL of dichloromethane, and 2 mL of N,N-dimethylformamide was added under ice-cooling and nitrogen atmosphere, and chlorobenzene (44.2 g) was added dropwise at this temperature. 348.5 mmol). After the reaction was carried out for 4 hours at room temperature, the reaction mixture was concentrated to give 164 C , which was used directly for the next reaction (28 g, yellow oil, yield 100%)

The third step: ethyl (2S)-2-[[benzyloxymethyl-(2,6-diisopropylphenoxy)phosphonium]amino]propionate ( 164D )

Ethyl(2S)-2-[[benzyloxymethyl-(2,6-diisopropylphenoxy)phosphoryl]amino]propanoate

164C (18.0 g, 117.1 mmol) was dissolved in 400 mL of dichloromethane, and propofol (20.8 g, 117.1 mmol) and triethylamine (47.4 g, 468.5 mmol) were added dropwise at -10 °C under nitrogen. A solution of dichloromethane (100 mL) was added dropwise and allowed to react at room temperature for 1 hour. At this temperature, 100 mL of a solution of L-alanine ethyl ester (27.4 g, 234.2 mmol) in dichloromethane was added. The reaction was carried out for two hours at room temperature. The reaction solution was washed with a saturated aqueous solution of saturated sodium dihydrochloride (500 mL), and then evaporated. 10:1~1:1) 164D (20g, yellow oil, yield 37%)

LCMS m/z = 460.2 [M-1].

Fourth step: ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(hydroxymethyl)phosphonium]amino]propionate ( compound 164 )

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(hydroxymethyl)phosphoryl]amino]propanoate

164D (15.0 g, 32.5 mmol) was dissolved in 100 mL of dichloromethane and 100 mL of ethyl acetate, and 10 g of palladium carbon was added thereto, and hydrogenation was carried out under normal pressure for 8 hours. The palladium on carbon was removed by filtration and concentrated to give compound 164 (yield: 6g, yield: 66.2%).

LCMS m/z = 372.2 [M + 1].

Compound 164 (5.5 g) was used for separation, separation conditions: instrument: MG II preparative SFC (SFC-15); column: ChiralPak AD, 250 x 30 mm ID, 5 μm; mobile phase: phase A was CO ₂ and phase B Isopropanol; Gradient: B 40%; Flow rate : 50 mL/min; Back pressure: 100 bar; Column temperature: 38 ° C; Wavelength : 220 nm; Cycle time : ~7 min; Sample preparation: Dissolve the compound in ~100 mL of methanol; : 3 mL / each injection; Work up: After separation, the fraction was dried by a rotary distillation at a bath temperature of 40 ° C to obtain the desired isomer.

Two optical isomer compounds 164-a were obtained (3.3 g, retention time 3.98 min, white solid, ee% = 100%), 164-b (1.55 g, retention time 5.01 min, white solid, ee% = 100% )

Compound 164-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.13 (s, 3H), 4.19 (m, 3H), 4.04 (m, 2H), 3.50 (m, 2H), 3.18 (t, 1H), 1.29 (m, 6H ), 1.23 (d, 12H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 26.32

LCMS m/z = 372.2 [M + 1].

Compound 164-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.12 (s, 3H), 4.08 (m, 5H), 3.64 (t, 1H), 3.41 (m, 2H), 1.42 (d, 3H), 1.23 (m, 15H ).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.16

LCMS m/z = 372.2 [M + 1].

Example 165

Isopropyl (2S)-2-[[[4-(1-hydroxyethyl)phenoxy]-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[4-(1-hydroxyethyl)phenoxy]-(methoxymethyl)phosphoryl]amino-]propanoate

First step: 4-(1-hydroxyethyl)phenol ( 165B )

4-(1-hydroxyethyl)phenol

165A (30.0g, 246mmol), 1L of dry tetrahydrofuran was added to a dry three-necked flask, cooled to 0 ° C under nitrogen atmosphere, and a solution of methylmagnesium bromide in tetrahydrofuran (246 mL, 3.0 mol/L, 737 mmol) was slowly added dropwise with stirring. After the addition, the temperature was raised to 40 ° C for 3 hours. After completion of the reaction, the mixture was cooled to -10 ° C, and a saturated aqueous solution of ammonium chloride (300 mL) was slowly added dropwise. After the addition, ethyl acetate was extracted (200 mL×2), washed once with 150 mL of saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. To the residue, 200 mL of dichloromethane was added and the mixture was stirred for 30 minutes, filtered, and then filtered, and then, then, and then, and then the mixture was stirred for 30 minutes, and the mixture was filtered and dried to give Compound 165B, white solid (20.0 g, 58.9%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.14 (s, 1H), 7.11 (d, 2H), 6.72-6.61 (m, 2H), 4.88 (d, 1H), 4.60 (m, 1H), 1.27 (d, 3H).

LC-MS m/z (ESI) = 121.1 [M-17]

Second step: isopropyl (2S)-2-[[[4-(1-hydroxyethyl)phenoxy]-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[4-(1-hydroxyethyl)phenoxy]-(methoxymethyl)phosphoryl]amino-]propanoate

1C (10.0 g, 61.4 mmol) was dissolved in 100 mL of dry dichloromethane, and then filtered, and then, triethylamine (24.8 g, 246 mmol) and L-alanine isopropyl ester hydrochloride (10. A mixture of g, 61.4 mmol) was reacted for 30 minutes after the completion of the dropwise addition. 165B (12.7 g, 92.1 mmol) was added to the reaction mixture, and the mixture was reacted at room temperature for 3 hours. 150 mL of water was added, and the mixture was extracted with dichloromethane (200 mL×2). The organic layer was washed once with 150 mL of saturated aqueous sodium dihydrogen phosphate solution, and once with 150 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was isolated and purified (methanol: methylene chloride = 0: 100 to 1: 50) to afford compound 165 as pale yellow oil (10.0 g, 45.3%).

^{1 H NMR (400MHz, DMSO- d} 6): δ 7.30 (d, 2H), 7.10 (t, 2H), 5.59 (m, 1H), 5.11 (d, 1H), 4.89-4.81 (m, 1H), 4.69 (m, 1H), 3.92-3.80 (m, 1H), 3.79-3.69 (m, 2H), 3.38 (d, 2H), 3.29 (s, 1H), 1.30 (d, 3H), 1.17 (m, 9H).

LC-MS m/z (ESI) = 360.2 [M+1].

Example 166

Isopropyl (2S)-2-[[[4-[(5aR,8aR)-4-[[(4aR,6S,7R,8R,8aS)-7,8-dihydroxy-2-(2-thiophene) -4,4a,6,7,8,8a-hexahydropyranyl[3,2-d][1,3]dioxen-6-yl]oxy]-8-oxo-5a ,6,8a,9-tetrahydro-5H-isobenzofuran [5,6-f][1,3]benzodioxolan-10-yl]-2,6-dimethoxy-benzene Oxy]-(methoxymethyl)phosphonium)amino)propionate ( Compound 166 )

Isopropyl(2S)-2-[[[4-[(5aR,8aR)-4-[[(4aR,6S,7R,8R,8aS)-7,8-dihydroxy-2-(2-thienyl)-4 ,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a,9-tetrahydro-5H-isobenzofuro [5,6-f][1,3]benzodioxol-10-yl]-2,6-dimethoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

1C (0.164g, 1mmol) and 10mL of dichloromethane were added to the reaction flask under nitrogen, and L-alanine isopropyl ester hydrochloride (0.167mg, 1mmol) of dichloromethane was slowly added at -30 °C. (8 mL) solution, after the addition, the reaction was carried out at -30 ° C to 0 ° C for 1 hour; 166A (0.33 g, 0.5 mmol) and triethylamine (0.407 g, 4 mmol) were added under ice cooling, and the reaction was carried out for 3 hours at room temperature. . After adding 20 mL of a saturated aqueous solution of sodium dihydrogen phosphate, and extracting with dichloromethane (20 mL × 2), the organic phase was dried over anhydrous sodium sulfate and evaporated. :1~0:100) gave Compound 166 as a white solid (0.136g, 37%).

LC-MS m/z (ESI) = 878.2 [M+1].

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.33 (dd, 1H), 7.18 (d, 1H,), 7.00 (m, 1H), 6.84 (d, 1H), 6.52 (d, 1H), 6.26 (d, 2H), 6.00 (dd, 1H), 5.98 (s, 1H), 5.81 (s, 1H), 5.04-4.97 (m, 1H), 4.92 (d, 1H), 4.67 (d, 1H), 4.61 (d) , 1H), 4.44-4.10 (m, 1H), 4.36-4.32 (m, 1H), 4.25-4.19 (m, 1H), 4.12-4.06 (m, 1H), 3.96-3.76 (m, 5H), 3.72 (d, 6H), 3.57-3.45 (m, 6H), 3.30 (dd, 1H), 2.87-2.81 (m, 1H), 1.40 (d, 2H), 1.27-1.22 (m, 9H).

³¹ P NMR (162 MHz, CDCl ₃ ): δ 26.07, 26.01.

Example 167

Isopropyl (2S)-2-[[methoxymethyl-[(2S,4S)-4-[4-(5-methyl-2-phenyl-pyrazol-3-yl)pyridazine- 1-yl]-2-(tetrahydrothiazole-3-carbonyl)pyrrolidin-1-yl]phosphonium]amino)propionate ( compound 167 )

Isopropyl(2S)-2-[[methoxymethyl-[(2S,4S)-4-[4-(5-methyl-2-phenyl-pyrazol-3-yl)piperazin-1-yl]-2-(thiazolidine- 3-carbonyl)pyrrolidin-1-yl]phosphoryl]amino]propanoate

1C (0.164g, 1mmol) and 10mL of dichloromethane were added to the reaction flask under nitrogen, and L-alanine isopropyl ester hydrochloride (0.167mg, 1mmol) of dichloromethane was slowly added at -30 °C. (8 mL) solution, after the addition, the reaction was carried out at -30 ° C to 0 ° C for 1 hour; 167A (0.33 g, 0.5 mmol) and triethylamine (0.407 g, 4 mmol) were added under ice-cooling, and the mixture was reacted at room temperature for 3 h. 20 mL of a saturated aqueous solution of sodium dihydrogen phosphate was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and evaporated. = 1:1 to 0: 100) gave Compound 167 as a colorless liquid (0.03 g, 9%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.74-7.71 (m, 2H), 7.41-7.35 (m, 2H), 7.25-7.21 (m, 1H), 5.65 (s, 1H), 5.28 (s, 2H) , 5.06-4.96 (m, 1H), 4.57-4.52 (m, 2H), 3.93-3.87 (m, 2H), 3.76-3.56 (m, 5H), 3.42 (s, 3H), 3.08-2.94 (m, 3H), 2.85-2.80 (m, 4H), 2.54-2.41 (m, 5H), 2.02 (s, 3H), 1.76-1.64 (m, 1H), 1.30-1.20 (m, 9H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.03, 22.44.

LC-MS m/z (ESI) = 648.3 [M+1].

Example 168

Isopropyl (2S)-2-[[[4-[[2-(5,6-dimethyl-9-oxo-oxaindole-4-yl)ethyl)oxymethyl]phenoxy Base]-(methoxymethyl)phosphonium]amino]propionate ( compound 168 )

Isopropyl(2S)-2-[[[4-[[2-(5,6-dimethyl-9-oxo-xanthen-4-yl)acetyl]oxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

First step: 2-(5,6-dimethyl-9-oxo-oxaindole-4-yl)acetamidine

2-(5,6-dimethyl-9-oxo-xanthen-4-yl)acetyl chloride

168A (0.564g, 2mmol) was dissolved in 10mL of dry dichloromethane, and the mixture was stirred and cooled in an ice bath. Dichloromethane (2mL) was added dropwise, and the reaction was stirred at room temperature for 1 hour to stop the reaction. The solvent was concentrated under reduced pressure to give 168B. (0.6g, 100%).

The second step: isopropyl (2S)-2-[[[4-[[2-(5,6-dimethyl-9-oxo-oxaindole-4-yl)ethyl)]oxy Phenoxy]-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[[4-[[2-(5,6-dimethyl-9-oxo-xanthen-4-yl)acetyl]oxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Intermediate 4 (0.5g, 1.45mmol) was dissolved in dry dichloromethane (6 mL), stirred and cooled in an ice bath, was added 168B (0.48g, 1.59mmol) in dichloromethane (4 mL), was added dropwise triethylamine ( 0.30 g, 2.9 mmol), slowly warmed to room temperature for 2 h, and the reaction was stopped. The reaction solution was concentrated, the residue was purified by silica gel column chromatography (100% ethyl acetate) to give compound 168, as a colorless liquid (0.16g, 18%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.28 (dd, 1H), 8.08 (d, 1H), 7.62 (dd, 1H), 7.33 (t, 1H), 7.20 (t, 3H), 7.12 (t , 2H), 5.11 (s, 2H), 5.03-4.96 (m, 1H), 4.12-4.04 (m, 1H), 4.02 (s, 2H), 3.80-3.72 (m, 2H), 3.47-3.42 (m , 3H), 2.43 (s, 3H), 2.32 (s, 3H), 1.72 (s, 1H), 1.30 (d, 3H), 1.24-1.20 (m, 6H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 24.14, 23.17.

LC-MS m/z = 610.2 [M + 1].

Example 169

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphinyl]oxyphenyl ]methoxymethyl]O1-methyl(E)-but-2-enoic acid diester ( compound 169 )

O4-[[4-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]oxyphenyl]methoxymethyl]O1-methyl(E)-but-2- Edidioate

Monomethyl fumarate ( 146A ) (6.500 g, 50.00 mmol) was dissolved in dichloromethane/water (100 mL / 100 mL) and tetrabutylammonium sulfate (1.696 g, 5.00 mmol) and sodium bicarbonate (16. , 200.00 mmol), stirring for 30 min, adding chloromethyl chlorosulfonate (12.375 g, 75.00 mmol), stirring at room temperature for 24 h; separating the organic phase, the aqueous phase is extracted with dichloromethane (100 mL×2), over sodium sulfate, and separated and purified by silica gel column chromatography was concentrated under reduced pressure (ethyl acetate: petroleum ether = 1: 5) to give 169A, as a colorless liquid (6.364g, yield 71.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.92 (dd, 2H), 5.81 (s, 2H), 3.83 (s, 3H).

The above product ( 169A ) (0.715 g, 4.00 mmol) was dissolved in dry N,N-dimethylformamide (15 mL), and (2S)-2-[[4-(hydroxymethyl)benzene Oxy]-(methoxymethyl)phosphoniumamino]propionic acid isopropyl ester (0.691 g, 2.00 mmol), potassium carbonate (0.553 g, 4.00 mmol) and potassium iodide (0.122 g, 0.15 mmol), 50 ° C Stir for 8 h. Diluted with water (20 mL), the organic phase was separated, the aqueous phase was extracted with methylene chloride (20 mL×2), and the organic phase was combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate Separation and purification (petroleum ether: ethyl acetate = 1 : 2) gave the title compound 169 as pale yellow oil (0.120 g, yield: 7.4%).

LC-MS = 488.1 [M+1].

Example 170

Ethyl(2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphoryl]amino]propanoate

Ethyl (2S)-2-[[(2,6-diisopropylphenoxy)-(methoxymethyl)phosphonium]amino]propionate

( Intermediate 3 ) (0.80 g, 2.6 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (0.5 g, 4.9 mmol) and ethylamine Methyl acetate solution 10 mL. The reaction was carried out for 3 hours at room temperature. 20 mL of a saturated aqueous solution of sodium dihydrogen phosphate was added to the reaction mixture, and the mixture was extracted with (20 mL × 2) dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. Ethyl ester (v/v) = 10:1 to 1:1) gave the above compound 7 as a yellow oil (0.3 g, yield 29.7%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.11 (d, 3H), 4.30-3.98 (m, 3H), 4.02-3.70 (m, 2H), 3.67-3.21 (m, 6H), 1.43-1.00 (m, 18H).

LCMS m/z = 386.2 [M + 1].

Example 171

Isopropyl (2S)-2-[[(2,6-diisopropoxyphenoxy)methoxy-(methoxymethyl)phosphonium]amino]propionate

Isopropyl(2S)-2-[[(2,6-diisopropylphenoxy)methoxy-(methoxymethyl)phosphoryl]amino]propanoate

Compound 121A (2 g, 8.85 mmol) and Intermediate 6 (2.2 g, 9.20 mmol) were dissolved in N,N-dimethylformamide (10 mL), and then potassium carbonate (2.4 g, 17.39 Sodium (0.1 g, 0.67 mmol) was heated to 50 ° C under nitrogen atmosphere and stirred for 2 h. The reaction mixture was cooled to EtOAc (EtOAc) (EtOAc m. Ethyl acetate/petroleum ether = (v/v) 1/20 to 1/1) gave Compound 171 as a colorless transparent oil (2 g, yield 52.64%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.20-7.04 (m, 3H), 5.61-5.39 (m, 2H), 5.04-4.99 (m, 1H), 4.10-3.98 (m, 1H), 3.71-3.67 ( m, 2H), 3.48-3.23 (m, 6H), 1.34 (dd, 3H), 1.26-1.19 (m, 18H).

LC-MS m/z = 430.2 [M + 1].

Compound 171 (1 g) was used for separation, and the separation conditions were as follows: Apparatus: MG II preparative SFC (SFC-1); Column: ChiralPak AS, 250 × 30 mm ID, 5 μm; Mobile phase: Phase A was CO ₂ and B The phase was methanol; gradient: B20%; flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 ° C; wavelength: 220 nm; period: ~3 min; sample preparation: dissolved in ~30 mL of methanol; injection: 1 mL/ Every injection.

Two optical isomer compounds 171-a (0.46 g, retention time 4.03 min, colorless transparent liquid, ee% = 100%) and compound 171-b (0.42 g, retention time 5.05 min, colorless transparent liquid, ee%) were obtained. =100%)

Compound 171-a

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.19-7.04 (m, 3H), 5.53 (dd, 1H), 5.45 (dd, 1H), 5.11-4.88 (m, 1H), 4.05 (d, 1H), 3.73 (d, 2H), 3.50-3.42 (m, 4H), 3.36-3.32 (m, 2H), 1.34 (d, 3H), 1.25-1.18 (m, 18H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.86.

LC-MS m/z = 430.2 [M + 1].

Compound 171-b

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.19-6.98 (m, 3H), 5.53 (dd, 1H), 5.47 (dd, 1H), 5.05-4.99 (m, 1H), 4.11-3.95 (m, 1H) , 3.80-3.59 (m, 2H), 3.50-3.44 (m, 1H), 3.42 (d, 3H), 3.40-3.34 (m, 2H), 1.35 (d, 3H), 1.25-1.21 (m, 18H) .

³¹ P NMR (162 MHz, CDCl ₃ ) δ 25.10.

LC-MS m/z = 430.2 [M + 1].

Example 172

Isopropyl (2S)-2-[[[2-[(1R)-3-(diisopropylamino)-1-phenyl-propyl]-4-(hydroxymethyl)phenoxy]- (Methoxymethyl)phosphonium]amino]propionate ( Compound 172 ).

Isopropyl(2S)-2-[[[2-[(1R)-3-(diisopropylamino)-1-phenyl-propyl]-4-(hydr·oxymethyl)phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate

Compound 105 (0.5 g, 8.35 mmol) was dissolved in water (20 mL) and the pH was adjusted to about 9 with saturated sodium hydrogen carbonate. (50mL) and extracted with dichloromethane, the solvent was removed under reduced pressure to give compound 172, colorless liquid (0.3 g of, yield 63.85%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 7.37-7.22 (m, 6H), 7.14 (t, 1H), 7.07 (dd, 1H), 5.73-5.27 (m, 1H), 5.12 (t, 1H) , 4.89-4.82 (m, 1H), 4.52-4.30 (m, 3H), 3.84-3.60 (m, 3H), 3.39 (d, 3H), 3.02-2.82 (m, 2H), 2.31 (t, 2H) , 2.1-1.94 (m, 2H), 1.20 - 1.07 (m, 9H), 0.89-086 (m, 12H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.01, 22.81.

LC-MS m/z = 563.4 [M + 1].

Example 173

Ethyl-5-[(Z)-[5-fluoro-1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxy) Methyl)phosphonium]-2-oxo-indoline-3-ylidene]methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate ( compound 173 )

Ethyl5-[(Z)-[5-fluoro-1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]-2-oxo-indolin- 3-ylidene]methyl]-2,4-dimethyl-1H-pyr·r·ole-3-carboxylate

First step: ethyl 5-[(Z)-(5-fluoro-2-oxo-indoline-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3 -formate

Ethyl 5-[(Z)-(5-fluoro-2-oxo-indolin-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate

5-Fluoroindoline-2-one 173A (5.0 g, 33 mmol), ethyl 5-carbamimido-2,4-dimethyl-1H-pyrrole-3-carboxylate 173B (7.1 g, 36 mmol) Dissolved in 200 mL of ethanol, acridine (5.6 g, 66 mmol), and heated to 90 ° C for 2 h. A large amount of solid precipitated during the reaction, and the solid was filtered to give 173 C ( yel .

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.91 (s, 1H), 10.93 (s, 1H), 7.84-7.69 (m, 2H), 6.98-6.89 (m, 1H), 6.85 (dd, 1H) , 4.22 (q, 2H), 2.54 (s, 3H), 2.51 (s, 3H), 1.30 (t, 3H).

LC-MS m/z = 329.2 [M+1].

The second step: ethyl 5-[(Z)-[5-fluoro-1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]- (Methoxymethyl)phosphonium]-2-oxo-indoline-3-ylidene]methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate ( compound) 173 )

Ethyl 5-[(Z)-[5-fluoro-1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]-2-oxo-indolin -3-ylidene]methyl]-2,4-dimethyl-1H-pyrrole- 3-carboxylate

(Methoxymethyl)phosphonium dichloride (2.0 g, 12 mmol) was dissolved in 40 mL of dry dichloromethane, and then filtered with nitrogen, and triethylamine (4.9 g, 49 mmol) was added dropwise at -30 ° C. A mixture of isopropyl acid (1.6 g, 12 mmol) was reacted for 30 min after completion of the dropwise addition to obtain a reaction liquid 1. 173C (2.0 g, 6.1 mmol) was dissolved in 40 mL of tetrahydrofuran, and the mixture was filtered under nitrogen, and butyl lithium (7.5 mL, 1.6 mol/L, 12 mmol) was added dropwise at -78 ° C. After the completion of the reaction, the reaction mixture was obtained for 30 min. 1 reaction solution was added dropwise to the reaction solution 2, and the mixture was slowly warmed to room temperature for 2 hours. Washed with 20mL of saturated sodium dihydrogen phosphate solution and once with 50mL saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the residue was purified by reverse phase preparative to give two isomers, compound 173-a (0.40g, retention time 11.809 min, yellow solid, yield 10%, ee% = 100%), Compound 173-b (0.40 g, </ RTI></RTI></RTI> 11.992 min, yellow solid, yield 10%, ee% = 100%).

Inverting preparation method: a chromatography column was prepared using C18 having a size of 30*150 mm. The flow rate was set to 30 mL/min. Mobile phase composition: acetonitrile and water containing 0.1% ammonium acetate. Gradient extraction method: acetonitrile content 55% to 70%, gradient extraction time: 15min.

Compound 173-a

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.16 (s, 1H), 8.00-7.65 (m, 3H), 6.99 (t, 1H), 6.04-5.77 (m, 1H), 5.06-4.66 (m, 1H), 4.45-4.09 (m, 3H), 4.13-3.82 (m, 2H), 3.33 (d, 3H), 2.56 (d, 6H), 1.43-1.22 (m, 6H), 1.22-1.05 (m, 6H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.23.

¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ-118.33.

LC-MS m/z = 550.3 [M + 1].

Compound 173-b

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.25 (s, 1H), 7.94-7.84 (m, 2H), 7.82 (s, 1H), 6.98 (m, 1H), 6.14 (dd, 1H), 4.63 -4.52(m,1H),4.32-4.15(m,3H),3.97(dd,2H),3.36(s,3H),2.56(d,6H),1.34-1.25(m,6H),0.85(d , 3H), 0.78 (d, 3H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 23.74.

¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ-118.62.

LC-MS m/z = 550.3 [M + 1].

Example 174

Ethyl-5-[(Z)-[1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl) Phosphonium]-2-oxo-indoline-3-ylidene]methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate ( compound 174 )

Ethyl 5-[(Z)-[1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]-2-oxo-indolin-3-ylidene ]methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate

First step: ethyl-2,4-dimethyl-5-[(Z)-(2-oxoindoline-3-ylidene)methyl]-1H-pyrrole-3-carboxylate

Ethyl 2,4-dimethyl-5-[(Z)-(2-oxoindolin-3-ylidene)methyl]-1H-pyrrole-3-carboxylate

Indoline-2-one 174A (5.0 g, 38 mmol), ethyl 5-methylindenyl-2,4-dimethyl-1H-pyrrole-3-carboxylate 173B (8.1 g, 41 mmol) was dissolved in 200 mL Acetone (6.4 g, 75 mmol) was added to ethanol, and the mixture was heated to 90 ° C for 2 h. A large amount of solid precipitated during the reaction, and the solid was filtered to give 174B as a yellow solid (10 g, yield 86%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.88 (s, 1H), 10.94 (s, 1H), 7.80 (d, 1H), 7.66 (s, 1H), 7.14 (d, 1H), 7.01 (d , 1H), 6.89 (d, 1H), 4.21 (t, 2H), 2.54 (s, 3H), 2.50 (s, 3H), 1.30 (t, 3H).

LC-MS = 311.1 [M + 1].

The second step: ethyl-5-[(Z)-[1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxy) Methyl)phosphonium]-2-oxo-indoline-3-ylidene]methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate ( compound 174 )

Ethyl 5-[(Z)-[1-[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(methoxymethyl)phosphoryl]-2-oxo-indolin-3-ylidene ]methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylate

The starting material (methoxymethyl)phosphonium dichloride (2.1 g, 13 mmol) was dissolved in 40 mL of dry dichloromethane, and the mixture was filtered under nitrogen, and triethylamine (5.2 g, 52 mmol) was added dropwise at -30 ° C. A mixture of isopropyl isopropyl ester (1.7 g, 13 mmol) was reacted for 30 min after completion of dropwise addition to obtain a reaction mixture 1. 174B (2.0 g, 6.4 mmol) was dissolved in 40 mL of tetrahydrofuran, and then filtered under nitrogen, and butyl lithium (8.12 mL, 1.6 mol/L, 13 mmol) was added dropwise at -78 ° C. 1 reaction solution was added dropwise to the reaction solution 2, and the mixture was slowly warmed to room temperature for 2 hours. Washed with 20mL of saturated sodium dihydrogen phosphate solution and once with 50mL saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the residue was purified by reverse phase preparative to give two isomers, compound 174-a (0.50g, retention time 10.896 min, yellow solid, yield 10%, ee% = 99.66%), Compound 174-b (0.50 g, </ RTI></RTI></RTI></RTI> 12.011 min, yellow solid, yield 10%, ee% = 100%).

Inverted preparation method: a chromatography column was prepared using C18 having a size of 19*250 mm. The flow rate was set to 12 mL/min. Mobile phase composition: acetonitrile and water containing 0.1% ammonium acetate. Gradient extraction method is: acetonitrile content 60% to 90%, gradient extraction time: 15min.

Compound 174-a

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.11 (s, 1H), 7.90 (dd, 2H), 7.74 (s, 1H), 7.15 (m, 2H), 5.86 (dd, 1H), 4.95-4.72 (m, 1H), 4.38-4.16 (m, 3H), 4.06-3.89 (m, 2H), 3.36 (d, 3H), 2.57 (s, 3H), 2.53 (s, 3H), 1.34-1.23 (m , 6H), 1.13 (dd, 6H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 24.14.

LC-MS = 532.2 [M + 1].

Compound 174-b

^{1 H NMR (400MHz, DMSO- d} 6) δ 13.21 (s, 1H), 7.89 (dd, 2H), 7.74 (s, 1H), 7.13 (m, 2H), 6.09 (dd, 1H), 4.68-4.49 (m, 1H), 4.26 (m, 3H), 4.08-3.90 (m, 2H), 3.37 (s, 3H), 2.54 (t, 6H), 1.31 (dd, 6H), 0.84 (d, 3H), 0.78 (d, 3H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 23.63.

LC-MS = 532.3 [M + 1].

Example 175

Isopropyl (2S)-2-[[[5-[2-[4-(1,2-benzothiazol-3-yl)pyridazin-1-yl]ethyl]-6-chloro-2- Oxo-indol-1-yl-(methoxymethyl)phosphonium]amino]propionate ( compound 175 )

Isopropyl(2S)-2-[[[5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-2-oxo-indolin-1- Yl]-(methoxymethyl)phosphoryl]amino]propanoate

(Methoxymethyl)phosphonium dichloride (0.65 g, 3.99 mmol) was dissolved in 20 mL of dry methylene chloride, EtOAc (EtOAc) A mixture of isopropyl isopropyl ester (0.524 g, 3.99 mmol) was reacted for 30 min after completion of dropwise addition to obtain a reaction mixture 1. 175A (0.824 g, 2.0 mmol) was dissolved in 40 mL of tetrahydrofuran, and the mixture was filtered under nitrogen, and butyl lithium (1.25 mL, 1.6 mol/L, 2 mmol) was added dropwise at -78 ° C. After the completion of the reaction, the reaction mixture was obtained for 30 min. 1 reaction solution was added dropwise to the reaction solution 2, and the mixture was slowly warmed to room temperature for 2 hours. It was washed once with 20 mL of a saturated aqueous solution of sodium dihydrogen phosphate, and once with 50 mL of brine, dried over anhydrous sodium sulfate and evaporated. /1~20/1) Column chromatography gave the title compound 175 as a colorless oil (0.4 g, yield 30%)

^{1 H NMR (400MHz, DMSO- d} 6) δ 8.05 (dd, 2H), 7.86 (d, 1H), 7.56 (dd, 1H), 7.43 (t, 1H), 7.30 (d, 1H), 6.07-5.81 (m, 1H), 4.71 (dd, 1H), 4.21-4.07 (m, 1H), 4.05-3.82 (m, 2H), 3.77-3.53 (m, 2H), 3.47 (s, 4H), 3.36 (s) , 3H), 2.93-2.81 (m, 2H), 2.70 (s, 4H), 2.63-2.52 (m, 2H), 1.37-0.79 (m, 9H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 23.22, 23.06.

LC-MS = 634.2 [M + 1].

Example 176

Isopropyl (2S)-2-[[2-[4-[6-[[5-[(2-chloro-6-methyl-phenyl)carbamoyl]thiazol-2-yl]amino] -2-methyl-pyrimidin-4-yl]pyridazin-1-yl]ethoxy-(methoxymethyl)phosphonium]amino]propionate ( compound 176 ).

Isopropyl(2S)-2-[[2-[4-[6-[[5-[(2-chloro-6-methyl-phenyl)carbamoyl]thiazol-2-yl]amino]-2-methyl-pyrimidin- 4-yl]piperazin-1-yl]ethoxy-(methoxymethyl)phosphoryl]amino]propanoate.

In a three-necked flask, isopropyl L-alanine (1.56 g, 11.89 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (484 mg, 11.90 mmol, 60%) Stirring was continued for 20 min to obtain a solution of L-alanine isopropyl ester sodium salt. In another three-neck flask, Compound 1C (0.97g, 5.95mmol) was dissolved in dichloromethane (20mL), the at -5 deg.] C, was added 176A (2g, 4.10mmol) and triethylamine (1g, 9.89mmol A solution of the mixture in dichloromethane (10 mL). After warming to room temperature and stirring for 10 min, L-alanine isopropyl ester sodium salt solution was added, and stirring was continued for 30 min. Dichloromethane (50 mL) was added and washed with a saturated solution of sodium dihydrogen phosphate (30 mL×1) and a saturated sodium chloride solution (30 mL×1), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by column chromatography (dichloromethane / methanol = (v/v) 100/1~20/1) afforded Compound 176 as white powder solid (0.06 g, yield: 2.06%).

^{1 H NMR (400MHz, DMSO- d} 6) δ 11.44 (s, 1H), 9.85 (s, 1H), 8.21 (s, 1H), 7.40-7.25 (m, 3H), 6.06 (s, 1H), 5.15 (d, 1H), 5.01-4.76 (m, 1H), 4.02 (s, 2H), 3.81 (s, 1H), 3.67-3.45 (m, 6H), 3.38-3.28 (m, 7H), 2.61 (d) , 2H), 2.41 (s, 3H), 2.24 (s, 3H), 1.26-1.19 (m, 9H).

³¹ P NMR (162 MHz, DMSO- d ₆ ) δ 26.26, 25.77.

LC-MS m/z = 709.2 [M+1].

Example 177

Isopropyl (2S)-2-[[[4-[6-[[7-cyclopentyl-6-(dimethylaminomethylmethyl)pyrrolo[2,3-d]pyrimidin-2-yl) Amino]-3-pyridyl]pyridazin-1-yl]-(methoxymethyl)phosphonium]amino]propionate ( Compound 177 ); isopropyl(2S)-2-[[[4- [6-[[7-cyclopentyl-6-(dimethylcarbamoyl)pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-1-yl]-(methoxymethyl)phosphoryl]amino]propanoate .

Dichloro Compound 1C (0.37g, 2.27mmol) was dissolved in dichloromethane (10 mL), the at -5 deg.] C, was added 177A (0.5g, 1.15mmol) and triethylamine (0.75g, 7.42mmol) in a mixture of Methane (10 mL) solution. After warming to room temperature and stirring for 10 min, isopropyl L-alanine (0.65 g, 4.96 mmol) was added and stirring was continued for 30 min. Dichloromethane (30 mL) was added and washed with a saturated solution of sodium dihydrogen phosphate (30 mL×1) and a saturated sodium chloride solution (30 mL×1), dried over anhydrous sodium sulfate, and the organic layer was concentrated. Purification by column chromatography (dichloromethane / methanol = (v/v) 100/1~20/1) gave Compound 177 as pale yellow solid (0.09 g, yield 11.93%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.69 (s, 1H), 8.40 (d, 1H), 8.19 (s, 1H), 7.35 (d, 1H), 6.44 (s, 1H), 5.13-4.98 (m , 1H), 4.79 (d, 1H), 4.13 - 3.89 (m, 1H), 3.82-3.62 (m, 2H), 3.56-3.30 (m, 8H), 3.15 (s, 6H), 3.10-3.06 (m , 4H), 2.56 (s, 2H), 2.13-2.00 (m, 4H), 1.72 (d, 2H), 1.47-1.39 (m, 3H), 1.29-1.22 (m, 6H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 23.90, 23.27.

LC-MS m/z = 656.3 [M+1].

Example 178 (refer to the following method A-D synthesis)

Method A: (Methoxymethyl)phosphine dichloride (1.0 eq) and dry dichloromethane were added to the reaction flask under nitrogen. At -30 ° C, the amino acid ester (1.0 eq, such as L-) was slowly added. a mixed solution of alanine isopropyl ester hydrochloride or L-alanine benzyl ester hydrochloride) and an organic base (such as triethylamine, diisopropylethylamine, 4.0 eq), added, -30 ° C The reaction was carried out at ~0 ° C for 30 min. Add the fragment compound (1.0 eq) to the reaction solution under ice-cooling conditions (you can also dissolve it in DCM or DMF first. If necessary, add a base such as triethylamine or diisopropylethylamine). The reaction was carried out at room temperature (or 40 ° C) for 2 h, and detected by LC-MS.

Method B: (Methoxymethyl)phosphine dichloride (1.0 eq) and dry dichloromethane were added to the reaction flask under nitrogen atmosphere, and the fragment compound (1.0 eq) was added under cooling at -30 ° C (may also be Dissolve in DCM or DMF, add, -30 ° C ~ 0 ° C reaction for 30 min, then slowly add amino acid ester (1.0 eq, such as L-alanine isopropyl ester or L-alanine benzyl ester salt a mixed solution of an acid salt and an organic base (such as triethylamine, diisopropylethylamine, 4.0 eq). Add the fragment compound (1.0 eq) to the reaction solution under ice-cooling (or dissolve in DCM) Or DMF, add room temperature (or 40 ° C) reaction for 2h, LC-MS detection.

Method C: isopropyl (2S)-2-[[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphonium]amino]propionate (1.0 eq), three-light The gas (0.5 eq) was dissolved in dichloromethane (5 mL), cooled to 0 ° C, and diisopropylethylamine (1.1 eq) was added dropwise and stirred for 1 h. The title compound (1.0 eq) was dissolved in DMF (5 mL), then diisopropylethylamine (1.1 eq. Ethyl acetate (100 mL) was added and the organic phase was washed once with diluted hydrochloric acid (4%, 150 mL). Dry, filter, concentrated under reduced pressure, and sent to prepare, LC-MS detection.

Method D: To a solution of the fragment compound (1 eq) in THF, NaH (1 eq) (or n-BuLi, 1 eq), the mixture was warmed to room temperature and stirred for 20 min to obtain a sodium salt (or lithium salt) solution of the starting material. In a separate three-necked bottle, (methoxymethyl)phosphine dichloride (2 eq) was dissolved in dichloromethane, and L-alanine ethyl ester (2.0 eq) and three were slowly added dropwise at -30 °C. A solution of ethylamine (4 eq) in dichloromethane was stirred at this temperature for 30 min to obtain a monophosphorus chloride intermediate, which was then added to the above sodium salt (or lithium salt) solution at room temperature, stirring was continued for 30 min, and LC-MS was detected. .

Biological test

1. Mouse righting reflex experiment

The anesthetic efficacy of the test compound was tested using a mouse righting reflex test (Ratnakumari Lingamaneni et al. (2001). Anesthesiology, 2001, 94, 1050-7).

Test animals: ICR mice, 6-8 weeks old, 18-22 g, male and female, provided by Chengdu Dashuo Experimental Animal Co., Ltd., animal production license number SCXK (chuan) 2015-030. Animals were kept in SPF environment at a temperature of 20-22 ° C, relative humidity: 51-55%, 12h/12h light and dark light, free diet and drinking water, and the test was started after 3 days of adaptive observation.

Drug preparation: Accurately weigh a certain amount of test compound, dissolve in DMSO, add solutol HS-15 to solubilize, then add physiological saline, shake and mix. The final concentration of DMSO is 10-20%, and the final concentration of solutol HS-15 is 10%. All test compounds were freshly prepared prior to use.

One day before the test, the animals were fasted for 12 hours and were randomly divided according to their body weight, 6 rats/group. A single test compound was administered orally at a dose of 50-750 mg/kg (converted to the dose of the prototype drug) at a dose of 20 mL/kg. Record the disappearance time of the righting reflection and the recovery time of the righting reflection. The time from the administration to the disappearance of righting reflex is the induction time of anesthesia, the time when the righting reflex disappears until the recovery of righting reflex is the duration of anesthesia, and the anesthesia effect is evaluated by the anesthesia induction time, the anesthesia maintenance time, and the righting reflex disappearance rate. .

The righting reflex disappearance time: the righting reflex disappears, so that it is in the supine position and can last for 60s; the righting reflex recovery time: the righting reflex ability is restored, so that the supine position correction time is less than 2s.

The experimental results are shown in Table 3:

Conclusion: Propofol is a marketed intravenous anesthetic, (R)-2-(1-cyclopropylmethyl)-6-isopropylphenol, 2,6-di((R)-1-cyclopropylethyl Phenol is a novel intravenous anesthetic (WO2014180305). After a single oral administration of the compound of the present invention in the above table, the mouse has an obvious anesthetic effect and has a quick onset of action. The compounds of the invention are shown to have good oral absorption characteristics.

2, mouse sedative hypnosis test

2.1 Test materials

Test animal

ICR mice, 6-8 weeks old, 18-22 g, female half, a total of 200, the supplier is Victoria Lihua, the license number is SCXK (Beijing) 2012-0001.

Test drug

Compound 7-b was administered at a dose of 55 mg/kg, 65 mg/kg, and 75 mg/kg in three doses (a dose converted to propofol). The drug was administered by intragastric administration at a dose of 20 ml/kg.

2.2 Test methods

Pentobarbital sodium dose test

The supra- and sub-threshold doses of sodium pentobarbital were determined prior to the formal trial. One day before the experiment, the animals were fasted and could not help but stay overnight.

Supreme dose of pentobarbital sodium: The dose of pentobarbital sodium that makes the animal 100% fall asleep, but does not make the sleep time too long, that is, the dose that makes the animal all fall asleep, and the dose is used for the formal test.

In this test, the experimental value of this test system was 40 mg/kg, and it was administered intraperitoneally, and the administration volume was 20 ml/kg.

Prolonging the sleep time test of sodium pentobarbital in mice

One day before the experiment, the animals were fasted and could not help but stay overnight. They were randomly divided into 4 groups, 10 in each group, half male and half female. They were blank control group, compound 7-b 55 mg/kg, 65 mg/kg, 75 mg/kg dose group (converted to propofol dose). Each group was given a solvent and a different concentration of compound 7-b, and then the supramidose dose of pentobarbital sodium was administered separately, and the sleep time was recorded. Differences between the drug-administered group and the control group were compared, and the difference was significant by t test. Prolonged sleep time (P < 0.5), indicating that the dose of the test drug has a central sedative and hypnotic effect. (Pentabarbital sodium was given 10-15 min before the peak of the test drug)

Re-sleep test

Animals given a sleep dose of sodium pentobarbital were given a test drug immediately after waking up to see if the animal went to sleep again. If there is a positive result and is significantly different from the control group, it indicates that the test drug has a central sedative and hypnotic effect.

Evaluation index

Prolongs the sleep time of sodium pentobarbital and allows the animals awake from sodium pentobarbital to sleep again.

Conclusion: The above data indicate that the compound 7-b of the present invention can significantly prolong the sleep time of sodium pentobarbital, and can make the animals waking up by sodium pentobarbital sleep again, indicating that it has oral central sedative and hypnotic effects.

3. Pharmacokinetic testing

3.1 Rat pharmacokinetics

The compound of the present invention is orally administered to a rat, and the concentration of the prototype drug in the plasma is detected. The universality of the invention of the prodrug technology for the modification of different functional groups of drugs.

Test animals: SD rats, 6-8 weeks old, 180-220 g, male. Provided by Chengdu Dashuo Experimental Animal Co., Ltd., the production license number is SCXK (chuan) 2015-030. Animals were kept in SPF environment at a temperature of 20-22 ° C, relative humidity: 51-55%, 12h/12h light and dark light, free diet and drinking water, and the test was started after 3 days of adaptive observation.

Drug preparation: Accurately weigh a certain amount of test compound, dissolve in DMSO, add solutol HS-15 to solubilize, then add physiological saline, shake and mix. The final concentration of DMSO was 10% and the final concentration of solutol HS-15 was 10%. All test compounds were freshly prepared immediately before use.

Before oral administration, the rats were fasted for 12 hours and returned to food 4 hours after the drug. On the day of the experiment, rats were randomly divided into groups/groups according to their body weight. Rats were orally administered with different test compounds at a dose of 10 mL/kg. Before the administration and 5min, 10min, 15min (±2min), 30min, 1h (±5min), 1.5h, and 2h (±5min), 4h, 6h, 8h, some time points before and after administration Blood was collected from venous plexus 0.3 mL, heparin was anticoagulated, 3500 rpm, centrifuged for 10 min, and plasma was collected. All plasma samples were stored at -80 °C prior to analysis. The prototype drug in the plasma sample was detected by HPLC-MS/MS, and the results are shown in the following table: Remarks: BLOQ: Below the test line; after oral administration of the compound of the invention, the concentration of the prototype drug in the plasma is measured.

Conclusion: The compound of the present invention listed in the table can be clearly detected in plasma after intragastric administration in rats, indicating that the compound of the present invention has oral absorption properties and can be converted into a prototype drug in rats. The prodrug technology of the invention can be applied to drugs containing different functional groups, has universal applicability, has broad application prospects in the fields of medicinal chemistry and drug design, and provides a novel prodrug design scheme for those who are generally in the field.

3.2 Compound 49 Rat Pharmacokinetic Test

experimental method:

3.2.1 Test materials

(1) Test animals: SD rats, male, 180-220 g, 6-8 weeks old.

(2) Test compound:

Compound 49: A certain amount of the compound was accurately weighed and sequentially dissolved in DMSO, solutol H-15 and physiological saline, and the final concentrations of DMSO and HS-15 were both 10%.

Compound SN-38: A certain amount of compound was accurately weighed and dissolved in DMSO, solutol H-15 and physiological saline. The final concentrations of DMSO and HS-15 were 5% and 10%, respectively; DMSO and HS were administered by intragastric administration. The final concentration of -15 is 10%.

3.2.2 Test method

One day before the test, the animals were fasted and could not help but water. Animals were randomly divided into 3 groups, 3 in each group, divided into Compound 49 was administered intragastrically, SN-38 intravenously and intragastrically. Compound 49 was orally administered at a dose of 25 mg/kg, and SN-38 was administered intravenously and orally at a dose of 2 mg/kg and 16 mg/kg, respectively. The administration volume was 10 ml/kg and the vein was 5 ml/kg.

Each animal was given a blood sample of 0.3 ml from the ocular venous plexus before and at the time of administration, and heparin was anticoagulated, centrifuged at 3500 rpm for 10 minutes, and plasma was collected. The time of blood collection by intragastric administration: 5 min, 10 min, 30 min, 1 h, 2 h, 4 h after administration; the time of blood collection by intravenous administration: 2 min, 5 min, 10 min, 30 min, 1 h, 2 h, 4 h after administration . All plasma samples were stored at -80 °C for testing.

Sample testing: Prototypes in plasma were analyzed by HPLC-MS/MS quantitative analysis, and pharmacokinetic parameters were fitted using Phoenix WinNolin 6.3 software.

Remarks: Po is given compound 49 and SN-38 is detected (n=3, both male)

Conclusion: The oral bioavailability of the compounds of the invention in rats is significantly improved compared to the prototype drug.

3.3 Compound 8-a rat pharmacokinetic test

3.3.1 Test materials

(1) Test animals: SD rats, 6-8 weeks old, 180-220 g, male. The supplier is Weitong Lihua and the license number is SCXK (Beijing) 2012-0001.

(2) Test drug: Compound 8-a was formulated into a desired concentration of the drug solution using 10% DMSO + 10% solutol HS-15 + 80% physiological saline. (R)-2-(1-Cyclopropylmethyl)-6-isopropylphenol was formulated into a desired concentration of the drug solution using 5% DMSO + 10% solutol HS-15 + 80% physiological saline.

3.3.2 Test methods

(1) Sampling: The day before the test, the animals were fasted without water. Three animals were taken. Each animal was given 0.3 ml of blank blood from the ocular venous plexus before administration. Heparin was anticoagulated, centrifuged at 3500 rpm for 10 min, and plasma was taken. Thereafter, the rats were orally administered with Compound 8-a at a dose of 25 mg/kg in a dose of 10 ml/kg. Blood samples were taken in the same manner after administration, and the time of blood collection was set at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h after administration. All blood samples were stored at -80 °C for testing.

One day before the test, the animals were fasted and could not help but water. Three animals were taken. Each animal was given 0.3 ml of blank blood from the ocular venous plexus before administration. Heparin was anticoagulated, centrifuged at 3500 rpm for 10 min, and plasma was taken. Thereafter, the (R)-2-(1-cyclopropylmethyl)-6-isopropylphenol solution was administered to the tail vein of the rat at a dose of 1 mg/kg, and the administration volume was 5 ml/kg. Blood samples were taken in the same manner after administration, and the time of blood collection was set at 5 min, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h after administration. All blood samples were stored at -80 °C for testing.

(2) Sample detection: The prototype drug in plasma was analyzed by HPLC-MS/MS quantitative analysis, and the pharmacokinetic parameters were fitted by Phoenix WinNolin 6.3 software.

Remarks: Po was given compound 8-a, and (R)-2-(1-cyclopropylmethyl)-6-isopropylphenol (n=3, both male) was detected.

Conclusion: The compounds of the present invention have high oral bioavailability in rats and have good oral absorption characteristics compared to the prototype drugs.

3.4 MiGlu pharmacokinetics

3.4.1 MiGlu pharmacokinetic method (Zhao Yan):

The compound of the invention and the corresponding prototype drug were administered by single-dose intragastric administration, and the corresponding prototype drug was intravenously administered to study the pharmacokinetic properties of the compound in the dog.

Experimental animals: MiGlu, 6-10 months old, 7-9 kg, male, provided by Zhaoyan (Suzhou) New Drug Research Center Co., Ltd., animal production license number is SYXK (Su) 2014-0050.

Drug preparation: accurately weigh a certain amount of test compound, dissolved in 5% DMSO, add 5% Solutol HS-15 to solubilize and mix, then add 90% physiological saline, vortex and mix. All test compounds were freshly prepared on the day of administration.

MiGlu fasted overnight (more than 12h) and was fed 4h after the drug. On the day of the experiment, Migru was randomly grouped according to body weight, 3/group. The prototype drug was administered intravenously at a dose of 2 mL/kg. Before the administration and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after the administration, blood was collected from the forelimb/hind limb subcutaneous vein by about 1 mL. In heparinized tubes, 1500g, centrifuged for 10min, Plasma was collected and stored at -80 °C. One week after the Migru rush, the same Migru was given a prototype drug or a test compound by gavage, and the administration volume was 5 mL/kg. Before the administration and 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 8 h, 12 h and 24 h after administration, about 1 mL of blood was collected from the forelimb/hind limb subcutaneous vein, placed in heparinized tubes, 1500 g, centrifuged for 10 min, and plasma was collected. , -80 ° C to save. Prototypes in plasma were analyzed by HPLC-MS/MS quantitative analysis, and the pharmacokinetic parameters were fitted using Phoenix WinNolin 6.3 software.

Remarks: PO is administered to the compound of the present invention to detect its prototype drug

Conclusion: The above-mentioned compound of the present invention, Migru, can be absorbed after the intragastric administration, and can be smoothly converted into the corresponding prototype drug, indicating that the compound of the present invention has oral absorption characteristics.

Remarks: PO is administered to the compound of the present invention to detect its prototype drug

Conclusion: After the above-mentioned compound of the present invention, Migru is administered by gavage, the bioavailability is significantly improved. The body can be smoothly converted into the corresponding prototype drug, indicating that the compound of the present invention is well absorbed orally.

3.4.2 MiGlu pharmacokinetic method (Da Shuo):

The compound of the invention and the corresponding prototype drug were administered by single-dose intragastric administration, and the corresponding prototype drug was intravenously administered to study the pharmacokinetic properties of the compound in the dog.

Experimental animals: MiGlu, 6-10 months old, about 8 kg, male, provided by Chengdu Dashuo Experimental Animal Co., Ltd., animal production license number is SCXK (Chuan) 2013-24.

Drug preparation: Accurately weigh a certain amount of test compound, dissolve in 5% DMSO, add 5% Solutol HS-15 to solubilize and mix, then add 90% normal saline, shake and mix. All test compounds were freshly prepared on the day of administration.

MiGlu fasted overnight (more than 12h) and was fed 4h after the drug. On the day of the experiment, Migru was randomly grouped according to body weight, 3/group. The prototype drug was administered intravenously at a dose of 0.5 mL/kg. Blood was collected from the forelimb/hind limb subcutaneous vein before administration and 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after administration. 0.5 mL, placed in a heparinized tube, centrifuged at 3500 rpm for 10 min, collected plasma, and stored at -80 °C. One week after the Migru rush, the same Migru was given a prototype drug or a test compound by gavage, and the administration volume was 5 mL/kg. Before the administration and 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after the administration, about 0.5 mL of blood was collected from the forelimb/hind limb subcutaneous vein, placed in heparinized tubes, centrifuged at 3500 rpm for 10 min. Plasma was collected and stored at -80 °C. Prototypes in plasma were analyzed by HPLC-MS/MS quantitative analysis, and the pharmacokinetic parameters were fitted using Phoenix WinNolin 6.3 software.

Remarks: PO is administered to the compound of the present invention to detect its prototype drug

Conclusion: The bioavailability of compounds 7-b, 8-a, 49-a and 49-b in Migru is high, especially the bioavailability of compound 7-b is 97.6%.

Remarks: PO is administered to the compound of the present invention to detect its prototype drug; BLOQ: lower than the detection line, undetectable; Conclusion: Compared with the prototype drug, the compound of the present invention can significantly improve bioavailability, such as bioavailability of compounds 82 and 83. The degrees were 17.8% and 22.5%, respectively, and the prototype drug was not detected orally, and the compound bioavailability of compounds 47, 50, 78, 101, 132, and 140 was increased by 1.2-5 times.

Remarks: PO is administered to the compound of the present invention to detect its prototype drug; Conclusion: Compared with the prototype drug, the compound of the present invention can significantly prolong the half-life, such as compound 56, 60, 107, 110, 111, the half-life is extended by 1.2- compared with the prototype drug. 36 times, can reduce the number of doses, improve patient compliance.

Table 13 MiGlu pharmacokinetic parameters

Remarks: PO is administered to the compound of the present invention to detect its prototype drug; Conclusion: The above-mentioned compound of the present invention, Migru, can be absorbed after gavage administration, and can be smoothly converted into a corresponding prototype drug, indicating that the compound of the present invention has oral absorption characteristics. .

Claims (47)

A compound of the formula (Z) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Y is selected from O or S; R ¹ and R ² are each independently selected from H, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _{1- a 10} alkyl or amino acid side chain which, when said amino acid side chain contains a hydroxyl group, a thiol group or a carboxyl group, is selectively esterified, said CH ₂ , alkyl group, carbocyclic ring or heterocyclic ring Optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxy, thiol, carboxyl, amino, thiol or ester groups, the heterocycle containing from 1 to 6 selected from N, a hetero atom of O or S; optionally, R ¹ and R ² together with the atom to which they are attached may form a 3 to 6 membered ring, optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I Substituted by a substituent of a hydroxyl group, a carboxyl group or an amino group, the ring containing 0 to 6 hetero atoms selected from N, O or S; R ^{3 being} selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, -(CH ₂ ) _m -C _3-10 carbocyclic ring, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m- C _3-10 carbocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m -3 to 10 membered heterocyclic ring or -(CH ₂ ) _m -OC _1-4 alkyl group, said CH ₂ , alkenyl group Alkynyl, alkyl, carbocyclic or hetero Optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxy, amino, 1-cyclopropylethyl, C _1-4 alkyl, C _1-4 alkoxy, OC Substituted by a substituent of (=O)OR ^3a or OC(=O)R ^3a containing from 1 to 6 heteroatoms selected from N, O or S; R ^{3a is} selected from C _1-4 alkyl a C _3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring, optionally further 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C Substituted by a substituent of _1-4 alkyl, C _1-4 alkoxy, C _3-10 carbocyclic or 3 to 10 membered heterocyclic ring containing from 1 to 6 selected from N, O or S a hetero atom; M _{2 is} selected from H, OH, L-OH, a leaving group or an L-releasing group; L is selected from a bond or a linking group; R _{5 is} selected from H or C _1-10 alkyl; And R ¹ and R ₅ together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S, optionally further to 0 to 4 Substituted by a substituent selected from H, F, Cl, Br, I, OH, amino, carboxyl, C _1-4 alkyl or C _1-4 alkoxy; R ⁶ and R ⁷ are each independently selected from H or C _1-10 alkyl; selective, R ⁶ and R ⁷ thereto The attached atoms together form a 3 to 6 membered ring containing 0 to 3 heteroatoms selected from N, O or S, optionally further 0 to 4 selected from H, F, Cl, Br Substituted by a substituent of I, OH, C _1-4 alkyl or C _1-4 alkoxy; X is selected from the absence, -O-, -S- or -NR ^8a -R ^{8 is} selected from H, C _1-6 alkyl, -(CH2) _m C _3-6 carbocyclic, -(CH ₂ ) _m 3 to 6 membered heterocyclic ring, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p O ( CH ₂ ) _p R ^8c , —(CH ₂ ) _p O(C=O)R ^8d or —(CH ₂ ) _p O(C=O)OR ^8d , the alkyl group, carbocyclic ring or heterocyclic ring optionally further Substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl or C _1-4 alkoxy; the heterocyclic ring contains 1 to 3 a hetero atom selected from N, O or S; R ^8a and R ^8b are each independently selected from H or C _1-6 alkyl, and the alkyl group is optionally further further selected from 0 to 6 selected from H, F, Cl, Substituted by a substituent of Br, I, OH, carboxyl, C _1-4 alkyl, C _1-4 alkoxy or C _3-6 cycloalkyl; optionally, R ^8a and R ^{8b are} attached to the atom Forming a 3 to 6 membered ring together, the ring containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted One step is substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; R ^8c , R ^{8d are} selected from H, C _{a 1-6} alkyl group, a C _3-6 carbocyclic ring or a 3 to 6 membered heterocyclic ring, optionally further 0 to 6 selected from the group consisting of H, F, Cl, Br, I, Substituted by a substituent of OH, a carboxyl group, a C _1-4 alkyl group or a C _1-4 alkoxy group containing 1 to 3 hetero atoms selected from N, O or S; m and p are each independently It is selected from 0, 1, 2 or 3; n is selected from 1, 2, 3, 4 or 5. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: M ^{2 is} selected from the group consisting of R ^M , H, L-halogen or L-OH; and R ^{M is} selected from the group consisting of F and Cl. , Br, I or OH; L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N(C _1-6 Alkyl)-, -C(=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(= O) ₂ -, -S(=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl ) -; W is selected from optionally substituted 0-10 W ^a phenyl group, the C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group, the ^a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, an O, S, N group of 0 to 10 carbon atoms in an alkylene group, an alkenylene group or an alkynylene group, optionally substituted by 0 to 10 W ^a Or (C=O) substitution, the divalent group formed above is optionally further substituted by 0 to 10 W ^a , the heterocyclic ring containing 0 to 4 hetero atoms selected from O, S or N; ^{a is} selected from C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, -OC ( =O)C _1-6 alkyl, -(=O)OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _{1 -6} Alkylthio, azido, cyano, nitro, halogen, amino, hydroxy, (=O), carboxy, C _3-10 carbocyclic, 3 to 10 membered heterocyclic ring, -OC _3-10 carbocyclic ring or - O-3 to 10 membered heterocycle substituted with a substituent, the heterocycle containing from 0 to 4 heteroatoms selected from O, S or N heteroatoms; 3 is formed together with the two atoms of W ^a can be selectively connected thereto To a 6-membered ring, the ring includes a carbocyclic or heterocyclic ring, and optionally further from 0 to 4 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 Substituted by a substituent of an alkoxy group containing from 0 to 4 heteroatoms selected from O, S or N. The compound of claim 2, wherein the compound is selected from the group consisting of a compound of the formula (Z-1) or (Z'-1), wherein the compound is selected from the group consisting of the compound of the formula (Z-1) or (Z'-1), wherein : M ^{2 is} selected from R ^M , H, L-halogen or L-OH; R ^{M is} selected from F, Cl, Br, I or OH; L is selected from a bond or L ₁ -W; L _{1 is} selected from -O- or - S-;W is selected from phenyl or C _1-10 alkylene groups, wherein 0 to 10 carbon atoms in the alkylene group are optionally substituted or unsubstituted phenyl, O, S, N or (C=O) is substituted, and the divalent group formed above or the phenyl group is further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, azide, cyano, nitro, Substituted by a substituent of an amino group, a hydroxyl group, (=O), a carboxyl group, a methyl group, an ethyl group, an isopropyl group, a methoxy group, an ethoxy group, an isopropoxy group or a cyclopropyl group. The compound of claim 3, wherein the compound is selected from the group consisting of the formula (Z-1-1) or (Z`-1-1), and a pharmaceutically acceptable salt or stereoisomer thereof. compound of: The compound of claim 4, wherein R <sup>1</sup> and R <sup>2</sup> are each independently selected from H, methyl, ethyl, isopropyl or amino acid, and a pharmaceutically acceptable salt or stereoisomer thereof. a side chain, when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, the thiol group, the hydroxyl group or the carboxyl group is selectively esterified; the amino acid is selected from the group consisting of glycine, alanine, leucine, isoleucine, Serine or valine, and the amino acid is D-form or L-form; optionally, R <sup>1</sup> and R <sup>2</sup> may form a cyclopropyl or cyclobutyl group together with the atom to which they are attached; optionally, R <sup>1</sup> and R <sup>5</sup> may form an azacyclopropyl, azetidinyl or azacyclopentyl group together with the atom to which they are attached. The compound according to any one of claims 1 to 5, wherein R <sup>3 is</sup> selected from substituted or unsubstituted methyl, ethyl or isopropyl, and a pharmaceutically acceptable salt or stereoisomer thereof. Base, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl, -(CH <sub>2</sub> ) <sub>m</sub> -O-methyl or -(CH <sub>2</sub> ) <sub>m</sub> -O-ethyl, when When substituted, optionally further 1 to 4 are selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl Substituted by a substituent of methoxy, ethoxy, isopropoxy, propoxy, OC(=O)OR <sup>3a</sup> or OC(=O)R <sup>3a</sup> ; R <sup>3a is</sup> selected from substituted or unsubstituted methyl , ethyl, isopropyl or propyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or Substituted by a substituent of an ethoxy group; R <sup>M is</sup> selected from F, Cl, Br, I or OH; R <sup>5 is</sup> selected from H, methyl, ethyl, isopropyl or propyl; R <sup>6</sup> and R <sup>7</sup> are each independently selected from H, methyl, ethyl, propyl or isopropyl; selective, R <sup>6</sup> and R <sup>7</sup> atom to which they are attached form a cyclopropyl group, cyclobutyloxy Or cyclopentyl, the cyclopropyl, cyclobutyl or cyclopentyl group is further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, methyl, ethyl, isopropyl, Substituted by a substituent of propyl, methoxy, ethoxy, isopropoxy or propoxy; X is selected from the group consisting of absent, -O-, -S- or -NR <sup>8a</sup> -; R <sup>8 is</sup> selected from substituted or Unsubstituted H, methyl, ethyl, isopropyl, propyl, phenyl, acridine, pyridazinyl, morpholinyl, azacyclopentyl, oxetanyl, oxacyclohexyl , -(CH <sub>2</sub> ) <sub>m</sub> NR <sup>8a</sup> R <sup>8b</sup> , -(CH <sub>2</sub> ) <sub>p</sub> OR <sup>8c</sup> , -(CH <sub>2</sub> ) <sub>p</sub> O(C=O)R <sup>8d</sup> or -(CH <sub>2</sub> ) <sub>p</sub> O(C=O)OR <sup>8d</sup> When substituted, optionally further from 1 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, iso Substituted by a substituent of a propoxy group or a propoxy group; R <sup>8a</sup> and R <sup>8b</sup> are each independently selected from a substituted or unsubstituted H, methyl, ethyl, isopropyl or propyl group, when substituted, optionally Further 1 to 6 selected from H, F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy or C Substituted by a <sub>3-6</sub> cycloalkyl substituent; optionally, R <sup>8a</sup> and R <sup>8b</sup> together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 selected from N, O or S. a hetero atom, the ring optionally being further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C <sub>1-4</sub> alkyl or C <sub>1-4</sub> alkoxy; R <sup>8c</sup> , R <sup>8d is</sup> selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl, phenyl, acridine, pyridazinyl, morpholinyl, azacyclopentyl or oxe a base, when substituted, optionally further from 1 to 6 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy Substituted by a substituent of a benzyl group, an isopropoxy group or a propoxy group. A compound represented by the formula (Z) or a pharmaceutically acceptable salt or stereoisomer thereof according to the first aspect of the invention, wherein the compound is selected from the compound represented by the formula (Z-2) or a pharmaceutically acceptable thereof. An acceptable salt or stereoisomer, wherein: Y is selected from O or S; R <sup>8 is</sup> selected from H or C <sub>1-4</sub> alkyl. The compound of claim 7 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of the formula (Z-2-1) or (Z`-2-1) Compounds of which: L is selected from a bond or L ₁ -W; L _{1 is} selected from -O- or -S-; W is selected from phenyl or C _1-10 alkylene groups, and 0 to 10 carbons in said alkylene group The atom is optionally substituted with a substituted or unsubstituted phenyl, O, S, N or (C=O), and the divalent group formed above or the phenyl group is optionally further selected from 0 to 5 From F, Cl, Br, I, azido, cyano, nitro, amino, hydroxy, (=O), carboxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyl Substituted by an oxy or cyclopropyl substituent. The compound of claim 8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: M ^{2 is} selected from H, L-halogen or L-OH; L is selected from the group consisting of a bond, O-phenyl -CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl- CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) Or OCH ₂ ; the phenyl group optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, NO ₂ , trifluoromethyl, methyl, methoxy, B Substituted by a substituent of a ethoxy group, an isopropyl group, an isopropoxy group, a propyl group or a propoxy group. The compound of claim 9 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ¹ and R ² are each independently selected from H, methyl, ethyl, isopropyl or amino acid. a side chain, when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, the thiol group, the hydroxyl group or the carboxyl group is selectively esterified; the amino acid is selected from the group consisting of glycine, alanine, leucine, isoleucine, Serine or valine, and the amino acid is D-form or L-form; optionally, R ¹ and R ² may form a cyclopropyl or cyclobutyl group together with the atom to which they are attached; optionally, R ¹ and R ⁵ may form an azacyclopropyl, azetidinyl or azacyclopentyl group together with the atom to which they are attached. The compound according to any one of claims 7 to 10, wherein R ^{3 is} selected from substituted or unsubstituted methyl, ethyl or isopropyl, and a pharmaceutically acceptable salt or stereoisomer thereof. Base, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl, -(CH ₂ ) _m -O-methyl or -(CH ₂ ) _m -O-ethyl, when When substituted, optionally further 1 to 4 are selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, methyl, ethyl, isopropyl, propyl Substituted by a substituent of methoxy, ethoxy, isopropoxy, propoxy, OC(=O)OR ^3a or OC(=O)R ^3a ; R3 ^{a is} selected from substituted or unsubstituted methyl , ethyl, isopropyl or propyl, when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or Substituted by a substituent of an ethoxy group; R ^{5 is} selected from H, methyl, ethyl, isopropyl or propyl; and R ⁶ and R ⁷ are each independently selected from H, methyl, ethyl, isopropyl or C. group; selective, R ⁶ together form cyclopropyl, and R ⁷ atom to which they are attached, cyclobutyl or cyclopentyl group, a cyclopropylmethyl Cyclobutyl or cyclopentyl is optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy. Substituted with a substituent of isopropoxy or propoxy; R ^{8 is} selected from substituted or unsubstituted H, methyl, ethyl, isopropyl, propyl, phenyl, acridinyl, pyridazinyl, Morpholinyl, azacyclopentyl, oxolyl, oxacyclohexyl, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p OR ^8c , -(CH ₂ ) _p O( C=O)R ^8d or -(CH ₂ ) _p O(C=O)OR ^8d , when substituted, optionally further from 1 to 4 selected from H, F, Cl, Br, I, OH, A Substituted by a substituent of a group, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy; R ^8a , R ^8b are each independently selected from substituted or unsubstituted H , methyl, ethyl, isopropyl or propyl, when substituted, optionally further from 1 to 6 selected from the group consisting of H, F, Cl, Br, I, OH, methyl, ethyl, isopropyl Substituted by a substituent of propyl, methoxy, ethoxy, isopropoxy, propoxy or C _3-6 cycloalkyl; optionally, R ^8a and R ^8b The attached atoms together form a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S, optionally further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br Substituted with a substituent of I, OH, C _1-4 alkyl or C _1-4 alkoxy; R ^8c , R ^{8d are} selected from substituted or unsubstituted H, methyl, ethyl, propyl, isopropyl a group, a phenyl group, an acridinyl group, a pyridazinyl group, a morpholinyl group, a nitrogen heterocyclopentyl group or an oxolyl group, when substituted, optionally further 1 to 6 selected from the group consisting of H, F, Cl, Substituted by a substituent of Br, I, OH, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy. The compound of any one of claims 1-11, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Selected from one of the following structures: M _{2 is} selected from R ^M , H, L-halogen or L-OH; R ^{M is} selected from Cl, Br, I or OH; L is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O- Phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH (CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further 0 to 4 are selected from the group consisting of H, F, Cl, Br, I, OH, NH2, CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropyl A substituent of an oxy group, a propyl group or a propoxy group is substituted. A compound of the formula (Z-5): and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: G is selected from any group; M _{1 is} selected from OH or a leaving group; R ^{8 is} selected from H, C _1-6 alkyl, -(CH ₂ ) _m -C _3-6 carbocycle, -(CH ₂ ) _m -3 to 6 membered heterocyclic ring, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p O(CH ₂ ) _p R ^8c , -(CH ₂ ) _p O(C=O)R ^8d or -(CH2) _p O(C=O)OR ^8d , the alkyl group, carbocyclic ring or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, C _1-4 Substituted with a substituent of an alkyl group or a C _1-4 alkoxy group; the heterocyclic ring contains 1 to 3 hetero atoms selected from N, O or S; and R ^8a and ^R 8 ^b are each independently selected from H or C. _{a 1-6} alkyl group, optionally further selected from 0 to 6 selected from H, F, Cl, Br, I, OH, C _1-4 alkyl, C _1-4 alkoxy or C _3- Substituted by a ₆ cycloalkyl substituent; optionally, R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S The ring is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; R ^8c , R ^{8d is} selected from the group consisting of H, C _1-6 alkyl, C _3-6 carbocyclic or 3 to 6 membered heterocyclic ring, and the alkyl, carbocyclic or heterocyclic ring is optionally further Substituted to 6 substituents selected from H, F, Cl, Br, I, OH, carboxyl, C _1-4 alkyl or C _1-4 alkoxy, the heterocyclic ring containing 1 to 3 The hetero atom of N, O or S; the definition of R ⁶ , R ⁷ , L, X, m, p, s, n is identical to the definition described in the scope of claim 1. The compound of claim 13 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ⁶ and R ⁷ are each independently selected from H, methyl, ethyl, isopropyl or propyl. Optionally, R ⁶ and R ⁷ together with the atom to which they are attached form a cyclopropyl, cyclobutyl or cyclopentyl group, optionally further 0 to 3 Substituted with a substituent selected from F, Cl, Br, I, hydroxy, amino, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy; X Selected from the absence, -O-, -S- or -NR ^8a -; M _{1 is} selected from OH, F, Cl, Br or I; R ^{8 is} selected from substituted or unsubstituted H, methyl, ethyl, iso Propyl, propyl, phenyl, acridinyl, pyridazinyl, morpholinyl, azacyclopentyl, oxolyl, -(CH ₂ ) _m NR ^8a R ^8b , -(CH ₂ ) _p OR ^8c , —(CH ₂ ) _p O(C=O)R ^8d or —(CH ₂ ) _p O(C=O)OR ^8d , when substituted, optionally further from 1 to 4 selected from H, Substituted by a substituent of F, Cl, Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy R ^8a, R ^8b are independently selected from a substituted or unsubstituted H, methyl, ethyl, propyl or isopropyl group, when substituted, optionally further substituted by 1-6 selected H, F, Cl Substituted with a substituent of Br, I, OH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy or C _3-6 cycloalkyl; Optionally, R ^8a and R ^8b together with the atom to which they are attached form a 3 to 6 membered ring containing from 1 to 3 heteroatoms selected from N, O or S, said ring optionally further being 0 to Substituted by four substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy; R ^8c , R ^{8d are} selected from substituted or unsubstituted H, Methyl, ethyl, propyl, isopropyl, phenyl, acridine, pyridazinyl, morpholinyl, azacyclopentyl or oxolyl, when substituted, optionally further Up to 6 substituents selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy or propoxy Substituted by the base. The compound of claim 14 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein G contains at least one group selected from the group consisting of a functional group selected from the group consisting of a carboxyl group, a hydroxyl group, a nitrogenoxy group, an oxynitride group, a thiol group, an amino group, an amine group, and an anthracene group. a group, a mercapto group, a mercapto group, a mercapto group, a urea group, an amine carbonate or a mercapto group; wherein: the carboxyl group-containing compound is selected from the group consisting of a carboxylic acid compound and a derivative thereof; and the hydroxyl group-containing compound is selected from the group consisting of a phenol compound and naphthalene a phenolic compound, a heterocyclic phenolic compound, a primary alcohol compound, a secondary alcohol compound, an enol compound, an amino alcohol compound, and a derivative thereof; the nitrogenoxy group-containing compound is selected from the group consisting of nitrogen oxides or Oxygen-nitrogen-based compounds and derivatives thereof; the ruthenium-functional group-containing compound is selected from the group consisting of anthraquinone compounds and derivatives thereof; the amino group-containing compound is selected from the group consisting of ammonia compounds and derivatives thereof; and amine group-containing compounds are selected From aliphatic amine compounds, cyclic amine compounds, aromatic amine compounds, hydroxylamine compounds and their derivatives; compounds containing thiol functional groups Terpenoids, sulfoniums and derivatives thereof; thiol-containing compounds are selected from the group consisting of terpenoids and derivatives thereof; biological activities of guanamine-containing functional groups and selected from chain amides, a guanamine compound, a sulfonamide compound, and a derivative thereof; the thiol group-containing compound is selected from the group consisting of an anthraquinone compound and a derivative thereof; and the ureido group-containing compound is selected from the group consisting of urea compounds and derivatives thereof; The amine carbonate-containing compound is selected from the group consisting of amine carbonate compounds and derivatives thereof; the thiol group-containing compound is selected from the group consisting of thiol compounds, thiophenol compounds, and derivatives thereof. The compound of claim 15 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the corresponding compound of the formula (GH) containing the functional group is selected from the structures of Table 1 shown in the specification. one. a compound of the formula (I): wherein, and a pharmaceutically acceptable salt or stereoisomer thereof, L is selected from a bond or a linking group; Q is selected from R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X, n are as defined in the definition of claim 1; s is selected from ¹ , ² , ³ , ⁴ , 5 or 6; The definition of G is consistent with the definitions set forth in Sections 13, 15 or 16 of the patent application. The compound of claim 17 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of formula (II), (II'), (III) or (III). ) the compound shown: L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N(C _1-6 alkyl)-, -C (=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S (=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl)-; is selected from 0-10 W ^a substituted phenyl group, the C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group, the alkylene group, alkenylene group Or ^a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, an O, S, N or (C=O) substituted with 0 to 10 carbon atoms in the alkynylene group, optionally substituted with 0 to 10 W ^a The divalent group formed above is optionally further substituted by 0 to 10 W ^a , the heterocyclic ring containing 0 to 4 hetero atoms selected from O, S or N; W ^{a is} selected from C _1-6 Alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, -OC(=O)C _1-6 Alkyl, -(=O)OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _1-6 alkylthio, stack Nitro, cyano, nitro, halogen, amino, hydroxy, (=O), carboxy, C _3-10 carbocyclic, 3 to 10 membered heterocyclic ring, -OC _3-10 carbocyclic ring or -O-3 to 10 Substituent of heterocyclic ring Generation membered heterocyclic ring containing 0-4 selected from O, S or N heteroatoms; form 3-6 ring together selectively, two W ^a can atoms connected thereto, said ring comprising carbon a ring or a heterocyclic ring, and optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy, said The ring contains 0 to 4 heteroatoms selected from O, S or N. The compound of claim 18, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of formula (IV), (IV-1), (IV') or (IV' -1) Compounds shown: The compound of claim 19, wherein the L is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl, and a pharmaceutically acceptable salt or stereoisomer thereof. -CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group is optionally further 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy Substituted by a substituent of a propyl group or a propyloxy group. The compound of claim 20, wherein the R ¹ and R ² are each independently selected from H, methyl, ethyl, isopropyl or amino acid, and pharmaceutically acceptable salts or stereoisomers thereof. a side chain, when the amino acid side chain contains a thiol group, a hydroxyl group or a carboxyl group, the thiol group, the hydroxyl group or the carboxyl group is selectively esterified; the amino acid is selected from the group consisting of glycine, alanine, leucine, isoleucine, Serine or proline, and the amino acid is D-form or L-form; alternatively, R ¹ and R ² may form a cyclopropyl or cyclobutyl group together with the atom to which they are attached. The compound of claim 21, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ^{8 is} selected from the group consisting of H, phenyl or C _1-4 alkyl. A compound of the formula (IV-1-1) or (IV'-1-1) and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is selected from a bond or L ₁ -W; L _{1 is} selected from -N(C _1-6 alkyl)C(=O)-, -C(=O)N(C _1-6 alkyl)-, -C (=O)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S (=O) ₂ N(C _1-6 alkyl)-, -N(C _1-6 alkyl)S(=O) ₂ - or -N(C _1-6 alkyl)-; is selected from 0-10 W ^a substituted phenyl group, the C _1-25 alkylene, C _2-25 alkenylene group or a C _2-25 alkynylene group, the alkylene group, alkenylene group Or ^a C _3-6 carbocyclic ring, a 3 to 10 membered heterocyclic ring, an O, S, N or (C=O) substituted with 0 to 10 carbon atoms in the alkynylene group, optionally substituted with 0 to 10 W ^a The divalent group formed above is optionally further substituted by 0 to 10 W ^a , the heterocyclic ring containing 0 to 4 hetero atoms selected from O, S or N; W ^{a is} selected from C _1-6 Alkyl, halogen-substituted C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-6 cycloalkyl, -OC(=O)C _1-6 Alkyl, -(=O)OC _1-6 alkyl, -NHC(=O)C _1-6 alkyl, -C(=O)NHC _1-6 alkyl, C _1-6 alkylthio, stack Nitro, cyano, nitro, halogen, amino, hydroxy, (=O), carboxy, C _3-10 carbocyclic, 3 to 10 membered heterocyclic ring, -OC _3-10 carbocyclic ring or -O-3 to 10 Substituent of heterocyclic ring Generation membered heterocyclic ring containing 0-4 selected from O, S or N heteroatoms; form 3-6 ring together selectively, two W ^a can atoms connected thereto, said ring comprising carbon a ring or a heterocyclic ring, and optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-4 alkyl or C _1-4 alkoxy, said The ring contains 0 to 4 hetero atoms selected from O, S or N; the definitions of R1, R2, R3, R4, R5, s and G are the same as defined in the first item of the patent application. The compound of claim 23, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: L is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl -CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ -OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC(=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group is optionally further 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , trifluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy Substituted by a substituent of a propyl group or a propyloxy group. The compound of claim 24, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ¹ and R ² are each independently selected from H, -(CH ₂ ) _m -C _3-10 Carbocyclic, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, C _1-10 alkyl or amino acid side chain, when the amino acid side chain contains a hydroxyl group, a thiol group or a carboxyl group, the hydroxyl group, a thiol group or a carboxyl group is selected Optionally esterified, the CH ₂ , alkyl, carbocyclic or heterocyclic ring optionally further from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxy, thiol, carboxyl, amino, thiol or ester Substituted by a substituent having from 1 to 6 heteroatoms selected from N, O or S; optionally, R ¹ and R ⁵ together with the atom to which they are attached form a 3 to 6 membered ring, The ring contains 1 to 3 heteroatoms selected from N, O or S, and the ring is optionally further further selected from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, amino, carboxyl, C _1- Substituted by a substituent of a _4- alkyl or C _1-4 alkoxy group; the amino acid is selected from the group consisting of lysine, methionine, isoleucine, valine, threonine, tryptophan, serine, and cysteine Amino acid, tyrosine, aspartic acid, histamine Acid, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, aspartame or arginine, and the amino acid is D-form or L-form; R ¹ and R ² may form a C _3-6 cycloalkyl group together with the atom to which they are attached, and the cycloalkyl group may be further further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, hydroxyl, and carboxyl groups. Or substituted with an amino substituent. The compound of claim 25, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ¹ and R ² are each independently selected from H, methyl, ethyl, isopropyl or amino acid. a side chain, when the amino acid side chain contains a mercapto group, a hydroxyl group or a carboxyl group, the mercapto group, the hydroxyl group or the carboxyl group is selectively esterified; optionally, R ¹ and R ⁵ may form an aziridine group together with the atom to which they are attached Or azetidinyl, azetidinyl or azacyclopentyl, optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I Substituted with a substituent of a hydroxyl group, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a carboxyl group or an amino group; the amino acid is selected from the group consisting of lysine, methionine, isoleucine, valine, and threonine , tryptophan, serine, cysteine, tyrosine, aspartic acid, histidine, glutamic acid, glutamine, glycine, alanine, leucine, phenylalanine, day Amides winter or arginine, and the amino acid is D- or L- type type; selectivity, R ¹ and R ² may form together with the atoms to which they are attached cyclopropylmethyl of , cyclobutyl or cyclopentyl, said cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted by 0 to 3 substituents selected from F, Cl, Br, I, hydroxy, carboxy or amino groups . The compound according to any one of claims 17 to 26, wherein the G is selected from any group, and the pharmaceutically acceptable salt or stereoisomer thereof, wherein the group is at least one selected from the group consisting of And a functional group selected from the group consisting of a carboxyl group, a hydroxyl group, a nitrogenoxy group, an oxynitride group, a thiol group, an amino group, an amine group, a decyl group, a fluorenyl group, an anthranyl group, a fluorenyl group, and a functional group. a ureido group, a thiol group, an amine carbonate or a thiophenol group, wherein: the carboxyl group-containing compound is selected from the group consisting of carboxylic acid compounds and derivatives thereof; and the hydroxyl group-containing compound is selected from the group consisting of phenol compounds, naphthol compounds, and impurities a cyclic phenolic compound, a primary alcohol compound, a secondary alcohol compound, an enol compound, an amino alcohol compound, and a derivative thereof; the nitrogenoxy group-containing compound is selected from the group consisting of nitrogen oxides and oxygen nitrogen compounds; Their derivatives; the guanidine-functional compound is selected from the group consisting of anthraquinones and derivatives thereof; the amino group-containing compound is selected from the group consisting of ammonia compounds and derivatives thereof; and the combination of amine-containing functional groups The compound is selected from the group consisting of a fatty amine compound, a cyclic amine compound, an aromatic amine compound, a hydroxylamine compound, and a derivative thereof; the thiol group-containing compound is selected from the group consisting of an anthraquinone compound, a sulfonium compound, and a derivative thereof; The thiol-functional compound is selected from the group consisting of anthraquinone compounds and derivatives thereof; biological activity of a guanamine-containing functional group and a compound selected from the group consisting of a chain amide compound and an indoleamine compound And sulfonamide compounds and derivatives thereof; the thiol group-containing compound is selected from the group consisting of hydrazine compounds and derivatives thereof; the ureido group-containing compound is selected from the group consisting of urea compounds and derivatives thereof; The functional group-containing compound is selected from the group consisting of an amine carbonate-based compound and a derivative thereof; the thiol-functional group-containing compound is selected from the group consisting of a thiol compound, a thiophenol compound, and a derivative thereof; wherein the compound having the above functional group passes through the functional group and the L Connected. The compound of claim 27, wherein the compound of the formula (GH) containing the functional group is selected from the structures of Table 1 shown in the specification, and a pharmaceutically acceptable salt or stereoisomer thereof. one. A compound of the formula (I): wherein: a compound of the formula (I) or a pharmaceutically acceptable salt thereof Stereoisomers, L is selected from OCH(CH ₃ ), OC(CH ₃ ) ₂ or OCH ₂ ; R ¹ and R ² are each independently selected from H, a side chain of a natural or pharmaceutically acceptable amino acid or a C _1-4 alkyl group, When the amino acid side chain contains a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group is selectively esterified; optionally, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group; The alkyl group, cycloalkyl group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, hydroxyl or amino; R ^{3 is} selected from C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, -(CH ₂ ) _m -C _3-10 carbocyclic, -(CH ₂ ) _m -3 to 10 membered heterocyclic ring, -(CH ₂ ) _m -O-(CH _{2 m-} C _3-10 carbocyclic ring, -(CH ₂ ) _m -O-(CH ₂ ) _m -3 to 10 membered heterocyclic ring or -(CH ₂ ) _m -OC _1-4 alkyl group, said CH ₂ Or alkenyl, alkynyl, alkyl, carbocyclic or heterocyclic ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, C Substituted by a substituent of _1-4 alkyl, C _1-4 alkoxy, OC(=O)OR ^3a or OC(=O)R ^3a containing from 1 to 6 selected from N, O or S, hetero atoms; R ^3a is selected from C _1-4 alkyl, C _3-10 carbocyclic or heterocyclic 3-10 Said alkyl, carbocyclic or heterocyclic ring optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxy, C _1-4 alkyl, C _1-4 alkoxy, C Substituted by a substituent of a _3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring containing from 1 to 6 heteroatoms selected from N, O or S; R ^{4 is} selected from , , or ; A is selected from F, Cl, Br, I, -OR ^4b or ; B is selected from ; T is selected from H, F, OH or carboxyl; R is selected from H, -C(=O)OC _1-4 alkyl, -C(=O)O-(3-8 membered carbocyclyl), -C (=O)O-(5-8 membered heterocyclic group) or ; L` is selected from the group consisting of a bond, O-phenyl-CH ₂ -OC(=O), O-phenyl-CH(CH ₃ )-OC(=O), O-phenyl-C(CH ₃ ) ₂ - OC(=O), O-phenyl-CH ₂ , O-phenyl-CH(CH ₃ ), OC(CH ₃ ) ₂ OC(=O), OCH(CH ₃ )OC(=O), OCH ₂ OC (=O), OCH(CH ₃ ) or OCH ₂ ; the phenyl group optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, NO ₂ , III Substituted by a substituent of fluoromethyl, methyl, methoxy, ethyl, ethoxy, isopropyl, isopropoxy, propyl or propoxy; R ^4a1 , R ^4a2 , R ^4a3 , R ^4a4 Each is independently selected from H, F, Cl, B _r , I, C _1-4 alkoxy or C _1-4 alkyl, C _3-5 carbocyclyl or -C _1-4 alkyl-C _3-5 Carbocyclyl, said alkyl, alkoxy, carbocyclic group may be further further selected from 0 to 5 selected from OH, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkane Substituted by a substituent of an oxy group, -C(=O)OC _1-4 alkyl or a C _3-5 carbocyclyl; R ^{4a5 is} selected from H, F, Cl, Br, I or C _1-4 alkyl, The alkyl group is optionally further substituted with from 1 to 5 substituents selected from OH, F, Cl, Br, I or -C(=O)OC _1-4 alkyl; R4 ^b1 and R ^4b2 are each independently Selected from H, F, Cl, Br, I, , Cyano, C _1-4 alkyl, C _1-4 alkoxy, C 3-5 cycloalkyl group or 3-5 heterocyclyl, said alkyl, alkoxy, carbocyclyl, or The heterocyclic group is optionally further substituted with 0 to 5 substituents selected from a hydroxyl group, a C _1-4 alkyl group, a C _1-4 alkoxy group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group. The heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S; optionally, R ^4b1 and R ^4b2 may form a 3 to 5 membered ring, and the 3 to 5 membered ring may be Containing 0 to 2 heteroatoms selected from N, O or S, and the formed 3 to 5 membered ring may be further optionally 0 to 4 selected from the group consisting of F, Cl, Br, hydroxy, C _1-4 alkyl, Substituted by a substituent of a C _1-4 alkoxy group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S R ^{4b5 is} selected from H or a hydroxyl group; R ^4b3 , R ^4b4 , R ^4b6 and R ^4b7 are each independently selected from H, F, Cl, Br, I, hydroxy, C _1-4 alkyl or C _1-4 alkoxy R ^4b8 , R ^4b9 and R ^4b10 are each independently selected from H, F, Cl, Br, I, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, 3 to 5 membered carbocyclyl or 3 To 5 members Cycloalkyl group, said alkyl, alkoxy, carbocyclyl or heterocyclyl group is optionally further selected from 0-5 F, Cl, Br, I, hydroxy, C _1-4 alkyl, C _1- Substituted by a substituent of a ₄ -alkoxy group, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S; Any one of R ^4b8 and R ^4b9 , R ^4b9 and R ^4b10 or R ^4b8 and R ^4b10 form a 3 to 5 membered ring, and the 3 to 5 membered ring contains 0 to 2 selected from N, O or S. a hetero atom, and the formed 3 to 5 membered ring is optionally further 0 to 4 selected from the group consisting of F, Cl, Br, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, 3 to 5 membered carbon Substituted by a ring group or a substituent of a 3 to 5 membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S; R ^4c1 and R ^4c2 are each independently selected from H, hydroxy , C _1-4 alkyl, cyano, azido, C _1-4 alkoxy or a 3 to 5 membered carbocyclic group, said alkyl, alkoxy or carbocyclic group may optionally be further to 3 substituents selected from C _1-4 alkyl or C _1-4 alkoxy ^substituted; R ^4c3, R 4c4 and ^R 4c5 is independently selected from H or C _1-4 Group, wherein ^{R 4c3,} R 4c4 and ^R 4c5 at least one group is ^{H; R 4d1, R 4d2,} R 4d3, R 4d4, R 4d5, R 4d6, R 4d7, R 4d8 are each independently selected from H, F, Cl, Br, I, C _1-4 alkoxy or C _1-4 alkyl, C _3-5 carbocyclyl or -C _1-4 alkyl-C _3-5 carbocyclyl, said alkyl The alkoxy group, carbocyclic group may be further optionally 0 to 5 selected from the group consisting of OH, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, -C(=O) Substituted by a substituent of OC _1-4 alkyl or C _3-5 carbocyclyl; R ^{5 is} selected from H or C _1-4 alkyl; R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl ; R ^{8 is} selected from C _1-4 alkyl, -(CH ₂ ) _m -OC _1-4 alkyl, -(CH2) _m -C _3-8 carbocyclic, -(CH2) _m -C _3-8 Ring, -(CH ₂ ) _m -C(=O)-C _3-8 carbocyclic ring, -(CH ₂ ) _m -C(=O)-C _3-8 heterocyclic ring or -(CH ₂ ) _m -NR ^8a R ^8b , wherein the CH ₂ , alkyl, carbocyclic or heterocyclic ring is further optionally 0 to 5 selected from the group consisting of F, Cl, hydroxy, amino, C _1-4 alkyl or —OC _1-4 alkyl Substituted by a substituent having 1 to 3 heteroatoms selected from N, O or S, R ^8a and R ^8b are each independently selected from H or C _1-4 alkyl; X is selected from the absence of -O-, -S- or -NR ⁹ -; R ^{9 is} selected from H or C _1-4 alkyl; alternatively, R ⁸ and R ⁹ form a 3 to 6 membered heterocyclic ring with the attached nitrogen, and the heterocyclic ring is optionally further further selected from 0 to 5 selected from F Substituted by a substituent of a Cl, a hydroxyl group, an amino group, a C _1-4 alkyl group or a -OC _1-4 alkyl group, the heterocyclic ring containing 1 to 3 hetero atoms selected from N, O or S; q selected From 1, 2 or 3; m is selected from 0, 1, 2 or 3; n is selected from 1, 2, 3, 4 or 5. The compound of claim 29, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ and R ² are each independently selected from the group consisting of H, a side chain of a natural or pharmaceutically acceptable amino acid or C _{a 1-4} alkyl group, wherein the amino acid side chain contains a hydroxyl group, a mercapto group or a carboxyl group, the hydroxyl group, a mercapto group or a carboxyl group is selectively esterified; optionally, R ¹ and R ² together with the carbon atom to which they are attached C _3-6 cycloalkyl; the alkyl group, cycloalkyl group optionally further substituted by 0 to 3 substituents selected from F, Cl, Br, I, hydroxyl or amino; R ^{3 is} selected from substituted or not Substituted methyl, ethyl, isopropyl, propyl, butyl, cyclopropyl, cyclopropylmethylene, phenyl, benzyl, -(CH ₂ ) _m -O-methyl or -(CH ₂ ) _m -O-ethyl, when substituted, optionally further from 1 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, amino, 1-cyclopropylethyl, methyl Substituted by a substituent of ethyl, isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, OC(=O)OR ^3a or OC(=O)R ^3a ; ^{3a is} selected from substituted or unsubstituted methyl, ethyl, isopropyl or propyl groups, when When substituted, optionally further substituted with 1 to 4 substituents selected from H, F, Cl, Br, I, OH, carboxyl, methyl, ethyl, methoxy or ethoxy; R ⁴ selected from , , , , , or R ^{5 is} selected from H or C _1-4 alkyl; R ⁶ and R ⁷ are each independently selected from H or C _1-4 alkyl; R ^{8 is} selected from C _1-4 alkyl, -(CH ₂ ) _m - OC _1-4 alkyl, -(CH ₂ ) _m -C _3-8 carbocyclic ring, -(CH ₂ ) _m -C _3-8 heterocyclic ring, -(CH ₂ ) _m -C(=O)-C _{3 -8} carbocycle, -(CH ₂ ) _m -C(=O)-C _3-8 heterocycle or -(CH ₂ ) _m -NR ^8a R ^8b , said CH ₂ , alkyl, carbocyclic or hetero The ring is optionally further substituted with from 0 to 5 substituents selected from the group consisting of F, Cl, hydroxy, amino, C _1-4 alkyl or -OC _1-4 alkyl, said heterocycle containing from 1 to 3 a hetero atom from N, O or S; R ^8a and R ^8b are each independently selected from H or C _1-4 alkyl; X is selected from the group consisting of absent, -O-, -S- or -NR ⁹ -; R ^{9 is} selected From H or C _1-4 alkyl; optionally, R ⁸ and R ⁹ form a 3 to 6 membered heterocyclic ring with the attached nitrogen, optionally further 0 to 5 selected from F, Cl, Substituted by a substituent of a hydroxyl group, an amino group, a C _1-4 alkyl group or a -OC _1-4 alkyl group, the heterocyclic ring containing 1 to 3 hetero atoms selected from N, O or S; m is selected from 0, 1, 2 or 3; n is selected from 1, 2, 3, 4 or 5. The compound of claim 17 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of compounds of the formula (B), wherein: B ₁ and B ₂ are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _1-6 alkoxy, (C _{1 -6} alkyl) _t1 NHC _1-6 alkyl or (C _1-6 alkyl) _t1 N(C _1-6 alkyl) ₂ , t1 is selected from 0 or 1; nb, mb are each independently selected from 0, 1, 2, 3 or 5. The compound of claim 17 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of compounds of the formula (C), wherein: "-----" represents a single bond or a double bond; C _{1 is} independently selected from H, F, Cl, Br, I, OH, C _1-6 alkyl or C _1-6 alkoxy, The alkyl or alkoxy group is optionally further substituted with from 0 to 4 substituents selected from H, F, Cl, Br, I, OH, C _1-6 alkyl or C _1-6 alkoxy; C ₂ , C ₃ , C ₄ are each independently selected from the group consisting of H, F, Cl, Br, I, =0, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkoxy, OC(=O)(C _1-6 alkyl) or OC(=O)(C _1-6 alkoxy), optionally alkyl, alkenyl, alkynyl or alkoxy Further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, C _1-6 alkyl, C _1-6 alkoxy or a 3 to 6 membered ring, The ring contains 0 to 4 heteroatoms selected from N, O or S; nc, mc, pc, qc are each independently selected from 0, 1, 2, 3 or 5. The compound of claim 17 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of compounds of the formula (D), wherein: D _{1 is} independently selected from the group consisting of H, F, Cl, Br, I, OH, ureido, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy , S(=O) ₂ NR ^1D1 R ^1D2 or (C _1-6 alkyl) _0-1 -3 to 6 membered ring, said alkyl, alkenyl, alkynyl, alkoxy or ring optionally further Substituted by 0 to 4 substituents selected from the group consisting of H, F, Cl, Br, I, OH, =O, C _1-6 alkyl, C _1-6 alkoxy, 3 to 6 membered ring, The ring contains 0 to 4 heteroatoms selected from N, O or S; D _{2 is} independently selected from the group consisting of H, F, Cl, Br, I, OH, carboxyl, C _1-6 alkyl, C _1-6 Alkoxy, (C _1-6 alkyl) _0-1 -3 to 6 membered ring, (C _1-6 alkyl) _0-1 C(=O)R ^2D1 or (C _1-6 alkyl) _{0 -1} C(=O)NR ^2D1 R ^2D2 , the alkyl group, alkoxy group or ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, amino, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C(=O)R ^2d1 R ^2d2 , C(=O)NR ^2d1 R ^2d2 , (C _1-6 alkyl) _0-1 NR ^2d1 R ^2d2 Substituted by a substituent, the ring contains 0 to 4 heteroatoms selected from N, O or S; optionally, two D ₂ may form a 3 to 8 membered ring together with the atoms to which they are attached, said ring Optional one 0-4 is selected from H, F, Cl, Br, I, OH, amino, carboxy, C _1-6 alkyl, (C _{1-6 ^{alkyl) 0-1 NR 2D1 R 2D2, C}} 1-6 Substituted by alkoxy or a substituent of C(=O)R ^2d1 , which is optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, amino, Substituted by a carboxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group or a substituent of a 3 to 6 membered ring containing 0 to 4 hetero atoms selected from N, O or S; R ^1D1 , R ^1D2 , R ^2D1 , R ^2D2 , R ^2d1 , and R ^2d2 are each independently selected from the group consisting of H, OH, C _1-6 alkyl, C _1-6 alkoxy, (C _1-6 alkyl) _0-1 N(C _1-6 alkyl) ₂ or 3 to 6 membered ring, said alkyl, alkoxy or ring optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, Substituted by a substituent of =O, NR ^2D1 R ^2D2 , C _1-6 alkyl, C _1-6 alkoxy or a 3 to 6 membered ring, the ring containing 0 to 4 selected from N, O or S Heteroatoms; nd or md are each independently selected from 0, 1, 2, 3 or 5. The compound of claim 17 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of compounds of the formula (E) or (E'), wherein: or Each of E _{1 is} independently selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, N ₃ , C _1-6 alkyl or C _1-6 alkoxy, said OH, NH ₂ , The alkyl or alkoxy group is further optionally from 0 to 4 selected from H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy or C (= O) substituted by a R ^1E1 substituent; E ₁ is preferably H, F or OH; alternatively, two E ₁ may form a 3 to 6 membered ring together with the atom to which they are attached, optionally further 0 to 4 Substituted by a substituent selected from H, F, Cl, Br, I, OH, NH ₂ , C _1-6 alkyl or C _1-6 alkoxy, said ring containing 0 to 4 selected from N a hetero atom of O or S; E ₂ and E ₃ are each independently selected from H, OH or C(=O)R ^1E1 ; E ₂ and E _{3 are} preferably H; V is selected from CH ₂ or S; and V _{2 is} selected from C or N; R ^1E1 are each independently selected from H or C _1-20 alkyl, and the alkyl group is optionally further from 0 to 4 selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , C Substituted by a substituent of _1-6 alkyl, C _1-6 alkoxy or C _3-6 carbocycle; E _{4 is} independently selected from H, F, Cl, Br or I, preferably H or F; E ₅ is selected from H or ^{C (= O) R 1E1;} me or ne are each independently selected from 0,1,2,3 5. The compound of claim 17 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the group consisting of the compound of the formula (F), wherein: "-----" represents a single bond or a double bond; F _{1 is} selected from C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl; the alkyl, alkenyl, alkynyl or The alkoxy group is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, =O, C _1-6 alkyl, C _1-6 alkoxy or a 3 to 6 membered ring. Substituted, the ring contains 0 to 4 heteroatoms selected from N, O or S; F _{2 is} selected from H, OH, C _1-6 alkyl or C _1-6 alkoxy, said alkane Or alkoxy optionally further selected from 0 to 4 selected from H, F, Cl, Br, I, OH, =O, C _1-6 alkyl, C _1-6 alkoxy or 3 to 6 membered rings Substituted by a substituent comprising 0 to 4 heteroatoms selected from N, O or S; F ₃ are each independently selected from H, hydroxy or (C=O)NH ₂ ; F _{4 is} selected from H Or C _1-6 alkyl; F ₅ , F ₆ are each independently selected from H, OH, NH(CH ₂ ) _1-3 COOH, O(CH ₂ CH ₂ O) _0-10 CH ₃ , Alternatively, F5 and F6 can form = or =O. The compound of any one of claims 17 to 35, and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from one of the structures of Table 2 shown in the specification. A method for preparing a compound of the formula (I), and a pharmaceutically acceptable salt or stereoisomer thereof, wherein the method comprises the following method: Wherein M _{1 is} selected from F, Cl, Br or I; M _{2 is} selected from R ^M , H, L-halogen or L-OH; R ^{M is} selected from F, Cl, Br, I or OH; R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , L, X, G, n, s, Q are as defined in the definition of the compound of the formula (I); the first step: the formula (Z- 3) The compound is reacted with a compound of the formula (Z-2) in the presence of a base to obtain a compound of the formula (Z-1); the second step: a compound of the formula (Z-1) in the presence of a base and a formula (Z) -4) The compound is reacted to give a compound of the formula (I); optionally, the compound of the formula (Z-3) is reacted with a compound of the formula (Z-2) in the presence of a base, and the formula (Z- is directly added. 4) Compound reaction to obtain a compound of the formula (I); Method 2: Wherein M _{1 is} selected from OH, F, Cl, Br or I; M _{2 is} selected from R ^M , H, L-halogen or L-OH; R ^{M is} selected from F, Cl, B _r , I or OH; R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , L, X, G, n, s, Q are as defined in the definition of the compound of the formula (I); (Z-3) a compound is reacted with a compound of the formula (Z-4) in the presence of a base to obtain a compound of the formula (Z-5); and a second step: a compound of the formula (Z-5) is present in the presence of a base. The compound of the formula (Z-2) is reacted to obtain a compound of the formula (I); optionally, the compound of the formula (Z-3) is directly reacted with the compound of the formula (Z-4) in the presence of a base, and then the formula is directly added. The (Z-2) compound is reacted to give a compound of the formula (I). A pharmaceutical composition, which comprises an effective amount of a compound according to any one of claims 17 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof, or further comprising a Or a plurality of other therapeutic agents together with a pharmaceutically acceptable carrier or excipient. A method for increasing the oral bioavailability of a drug, prolonging the pharmacodynamic half-life of the parent drug, reducing the dose and frequency of administration, increasing patient compliance or prolonging the half-life, by administering to the subject a patentable scope containing an effective dose The compound according to any one of the items 17 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof. The pharmaceutical composition according to any one of claims 17 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 39, which is prepared for improvement The use of the drug for oral bioavailability, prolonging the pharmacodynamic half-life of the parent drug, reducing the dose and frequency of administration, or prolonging the half-life of the drug. The use of a compound as shown in any one of claims 1 to 16 or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a prodrug. The compound of any one of claims 17 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof, for the preparation of a therapeutic respiratory disease, a digestive system disease, a circulatory disease, a urinary system disease , blood system diseases, endocrine and metabolic diseases, cardiovascular diseases, lymphatic diseases, neuropsychiatric diseases, obstetrics and gynecology diseases, pediatric diseases, otolaryngology diseases, eye diseases, oral diseases, bone diseases, tumors The application of disease drugs. A compound according to claim 42 or a pharmaceutically acceptable salt or stereoisomer thereof, which is useful for the preparation and induction of anesthesia, brain protection, promotion of sedative hypnosis, treatment and treatment of animals or humans in animals or humans. / or use in the prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy drugs, preferably in the preparation of anesthetic drugs for inducing and maintaining animals or humans. A method for improving drug absorption, which comprises: forming a prodrug by directly or via a linking group L with one or more groups of the formula (Q), wherein: L and Q are defined and claimed The definitions described in item 17 are the same. A method for improving oral bioavailability of a medicament, comprising: forming the prodrug by directly or via a linking group L with one or more groups of the formula (Q), wherein: L and Q are defined The definitions described in item 17 of the scope of application for patents are the same. A method for extending the half-life of a parent drug, the method comprising: forming the prodrug by directly or via a linking group L with one or more groups of the formula (Q), wherein: L and Q are defined and applied The definitions described in item 17 of the patent scope are the same. The method of any one of claims 44 to 46, which comprises: hydrolyzing a prodrug in the body to release the original drug.