WO2017063563A1 - Octahydrocyclopenta[c]pyrrole derivative, preparation method therefor, and pharmaceutical use - Google Patents

Abstract

A compound as shown in formula (I), or a stereoisomer, hydrate, metabolic product, solvate, pharmaceutically acceptable salt, co-crystal or produg thereof, a preparation method, and an application in the preparation of a drug used for treating obstructive airway diseases. The definition of each substituent in the compound of formula (I) is consistent with the description.

Description

Arhydrocyclopenta[c]pyrrole derivative, preparation method thereof and use in medicine Technical field

The invention relates to an octahydrocyclopenta[c]pyrrole derivative, a preparation method thereof and a medicine application thereof, in particular to a muscarinic receptor (M receptor) antagonist and β ₂ -adrenalin Novel octahydrocyclopenta[c]pyrrole derivatives capable of receptor agonism, or stereoisomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof, Its pharmaceutical composition and its use in medicine.

Background technique

Bronchodilators play an important role in the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Bronchodilators in clinical use include widely muscarinic receptor antagonist and β ₂ - adrenergic agonist. A muscarinic receptor antagonist exerts potency in bronchodilation by reducing the level of vagal cholinergic energy in airway smooth muscle. Inhaled muscarinic receptor antagonists currently used include ipratropium bromide, oxitropium bromide, glycopyrrolate, tiotropium bromide, adiponium bromide and indole bromide. _{2 2} -adrenergic agonists bronchodilate by stimulating adrenergic receptors in airway smooth muscle, reversing the response of bronchoconstrictors to various mediators such as acetylcholine. The β ₂ -adrenergic agonists currently used include albuterol, salmeterol, arformoterol, formoterol, vilantrol and indacaterol. In addition to improving lung function, these drugs can improve the quality of life of patients and reduce the deterioration of their condition.

As more clinical studies have found that the combination of muscarinic receptor antagonists and β ₂ -adrenergic agonists is more effective than the use of one of the therapeutic agents alone, the current prion base receptor antagonists And β ₂ -adrenergic agonists are prepared as a combination preparation for the treatment of asthma and moderate to severe COPD. These compound preparations mainly include Anoro Ellipta (Ambroxol/Vylantro) and Ultibro Breezhaler (Glon Brom). Ammonium / indacaterol) and ipratropium bromide / salbutamol. Although the combination preparation has a better therapeutic effect than the single preparation, there is a higher requirement in the preparation of the preparation.

Therefore, it is desirable to develop while having muscarinic receptor antagonist and β ₂ - adrenergic agonists dual-acting drugs, drugs with this dual function the advantages of both pharmaceutical ingredient combination, along with a single molecule pharmacokinetics. These compounds are administered as a single therapeutic agent and can provide bronchodilation by two different and possibly synergistic modes of action. In addition, compounds with muscarinic receptor antagonism and β ₂ -adrenergic agonistic dual action (MABA) can also be combined with corticosteroid (ICS) anti-inflammatory drugs to form two therapeutic agents (MABA/ICS) to provide triple Therapeutic effect of action (Expert Opin. Investig. Drugs (2014) 23(4): 453-456).

Therefore, it is necessary to develop novel dual active drugs with both muscarinic receptor antagonism and β ₂ -adrenergic agonism to provide more effective single therapeutic doses or combination preparations, providing patients with more clinical drug options.

Summary of the invention

The present invention provides a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

among them:

R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3- 6} cycloalkyl, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(=O)R ^1d , -S(=O) ₂ R ^1e or -NR ^1f R ^1g ;

R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl;

W is selected from -O-, -NH- or -NC _1-4 alkyl-;

R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

R ³ and R ⁴ are each independently selected from H or C _1-4 alkyl;

R ^{5 is} selected from H or OH;

a is 0, 1, 2, 3 or 4;

b is 0, 1, 2, 3, 4 or 5;

c or d is independently selected from 0, 1, 2, 3 or 4;

B is selected from

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ are each independently selected from the group consisting of H, F, Cl, Br, I, CF ₃ , OH, -CH ₂ OH , cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, -C(=O)C _1-4 alkyl, -C(=O)OC _1-4 alkyl, -NHC ( =O)H, -NHS(=O) ₂ -C _1-4 alkyl, -NHS(=O) ₂ -NH ₂ or -NHS(=O) ₂ -NHC _1-4 alkyl, Q is selected from - CR ^q1 =CR ^q2 -, ^{-CR q1} R ^q2 CR ^q3 R ^q4 -, -O-, -S-, -OCR ^q1 R ^q2 -, ^{-CR q1} R ^q2 O-, -SCR ^q1 R ^q2 -, -CR ^Q1 R ^q2 S-, wherein R ^q1 , R ^q2 , R ^q3 or R ^q4 are each independently selected from the group consisting of H, F, Cl, Br, I or C _1-4 alkyl;

B is more preferred

Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH ₃ ) ₂ -;

B further preferred

L is selected from

The condition is that the number of connected atoms of the L shortest chain is in the range of 6 to 26;

R ^3a , R ^3c , and R ^3d are each independently selected from a C _1-6 alkylene group, and the alkylene group is optionally further substituted with 0, ₁ , 2, 3, 4 or 5 R ^3e ;

R ^{3b is} selected from C _1-6 alkylene, phenylene or 5 to 6 membered heteroarylene, said alkylene, phenylene or heteroarylene optionally further 0, 1, 2, 3 Or substituted with four substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

R ^{3e is} selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

Alternatively, two R ^3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

A ₁ and A ₂ are each independently selected from a C _3-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC _3-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, and a C _3-11 carbocyclic ring-O-. Or a 5- to 11-membered heterocyclic ring-O-, said carbocyclic or heterocyclic ring optionally further substituted by 0, 1, 2, 3, 4 or 5 R ⁶ and said heterocyclic ring containing 1 to 3 a hetero atom selected from N, O or S;

X ₁ and X ₂ are each independently selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -S-, -S(=O). )-, -S(=O) ₂ -, -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O) O-, -NR ^x C(=O)NR ^x -, -NR ^x S(=O) ₂ -, -S(=O) ₂ NR ^x -, -NR ^x S(=O) ₂ NR ^x - or -NR ^x -;

R ^{x is} each independently selected from H, C _1-6 alkyl or C _3-8 cycloalkyl, and the alkyl or cycloalkyl group is optionally further selected from 0, 1, 2, 3, 4 or 5 Substituted with a substituent of F, Cl, Br, I, C _1-4 alkyl, C _3-6 cycloalkyl or C _1-4 alkoxy;

R ^{6 is} each independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , =0, carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(=O)-C _1-4 alkyl, -S (=O) ₂ -C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OC _1-4 alkyl, -OC(=O)-C _{1- 4-} alkyl, -C(=O)NH ₂ or 5- to 6-membered heteroaryl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, NH ₂ , -C(=O)NH ₂ or a heteroaryl group optionally further selected from 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C ( Substituted by a substituent of -O)-C _1-4 alkyl;

Alternatively, R ⁶ is directly bonded to R ^x to form a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further further selected from 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, I, Substituted by a substituent of OH, NH ₂ , =0, C _1-4 alkyl or C _1-4 alkoxy;

m, n, p or q are each independently selected from 0 or 1.

A preferred embodiment of the invention, a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , NH ₂ , OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio , -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

W is selected from -O-, -NH- or -NC _1-4 alkyl-;

R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

R ³ and R ⁴ are each independently selected from H or C _1-4 alkyl;

R ^{5 is} selected from H or OH;

B is selected from

Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH ₃ ) ₂ -;

B preferred

L is selected from

The condition is that the number of connected atoms of the L shortest chain is in the range of 6 to 26;

R ^3a , R ^3c , and R ^3d are each independently selected from a C _1-6 alkylene group, and the alkylene group is optionally further substituted with 0, ₁ , 2, 3, 4 or 5 R ^3e ;

R ^{3b is} selected from C _1-6 alkylene, phenylene or 5 to 6 membered heteroarylene, said alkylene, phenylene or heteroarylene optionally further 0, 1, 2, 3 Or substituted with four substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

R ^{3e is} selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

Alternatively, two R ^3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

A ₁ and A ₂ are each independently selected from a C _3-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC _3-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, and a C _3-11 carbocyclic ring-O-. Or a 5- to 11-membered heterocyclic ring-O-, preferably a C _5-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC _5-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, a C _5-11 carbocyclic ring. -O- or a 5- to 11-membered heterocyclic ring-O-, said carbocyclic or heterocyclic ring optionally further substituted by 0, 1, 2, 3, 4 or 5 R ⁶ and said heterocyclic ring containing 1 Up to 3 heteroatoms selected from N, O or S;

X ₁ and X ₂ are each independently selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -S-, -S(=O). )-, -S(=O) ₂ -, -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O) O-, -NR ^x C(=O)NR ^x -, -NR ^x S(=O) ₂ -, -S(=O) ₂ NR ^x -, -NR ^x S(=O) ₂ NR ^x - or -NR ^x -, preferred bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O)O- or -NR ^x -;

R ^{x is} each independently selected from H, C _1-6 alkyl or C _3-8 cycloalkyl, and the alkyl or cycloalkyl group is optionally further selected from 0, 1, 2, 3, 4 or 5 Substituted with a substituent of F, Cl, Br, I, C _1-4 alkyl, C _3-6 cycloalkyl or C _1-4 alkoxy;

R ^{6 is} each independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , =0, carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _3-6 naphthenic , C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(=O)-C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OC _1-4 alkyl, -OC(=O)-C _1-4 alkyl or 5 to 6 a heteroaryl group, the alkyl, alkynyl, alkoxy, cycloalkyl, NH ₂ or heteroaryl group optionally further selected from 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, I Substituted with a substituent of CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(=O)-C _1-4 alkyl;

Alternatively, R ⁶ is directly bonded to R ^x to form a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further further selected from 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, I, Substituted by a substituent of OH, NH ₂ , =0, C _1-4 alkyl or C _1-4 alkoxy;

m, n, p or q are each independently selected from 0 or 1;

a is 0, 1, 2, 3 or 4;

b is 0, 1, 2, 3, 4 or 5;

c or d is independently selected from 0, 1, 2, 3 or 4.

A preferred embodiment of the invention, a compound of the formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,

among them:

R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , NH ₂ , OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio , -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

W is selected from -O-, -NH- or -NC _1-4 alkyl-, preferably -O-, -NH- or -NCH ₃ -;

R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy, preferably F, Cl, Br, I, OH, cyanide Base, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;

R ³ and R ⁴ are each independently selected from H or C _1-4 alkyl, preferably H, methyl or ethyl;

R ^{5 is} selected from H or OH;

B is selected from

R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ are each independently selected from the group consisting of H, F, Cl, Br, I, CF ₃ , OH, -CH ₂ OH , cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, -C(=O)C _1-4 alkyl, -C(=O)OC _1-4 alkyl, -NHC ( =O)H, -NHS(=O) ₂ -C _1-4 alkyl, -NHS(=O) ₂ -NH ₂ or -NHS(=O) ₂ -NHC _1-4 alkyl, Q is selected from - CR ^q1 =CR ^q2 -, ^{-CR q1} R ^q2 CR ^q3 R ^q4 -, -O-, -S-, -OCR ^q1 R ^q2 -, ^{-CR q1} R ^q2 O-, -SCR ^q1 R ^q2 -, -CR ^Q1 R ^q2 S-, wherein R ^q1 , R ^q2 , R ^q3 or R ^q4 are each independently selected from the group consisting of H, F, Cl, Br, I or C _1-4 alkyl;

B is selected from

Wherein Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC(CH) ₃ ) ₂ -;

B further preferred

R ^3a , R ^3c , and R ^3d are each independently selected from a C _1-6 alkylene group, preferably a C _1-5 alkylene group, more preferably a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group. Said alkylene, methylene, ethylene, propylene, butylene or pentylene group is optionally further substituted by 0, 1, 2, 3, 4 or 5 R ^3e ;

R ^{3b is} selected from C _1-6 alkylene, phenylene or 5- to 6-membered heteroarylene, preferably C _1-5 alkylene, phenylene or 5- to 6-membered heteroarylene, more preferably sub- Methyl, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene, said alkylene, Methylene, ethylene, propylene, butylene, pentylene, phenylene, heteroarylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridyl Further substituted with 0, 1, 2, 3 or 4 substituents selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

R ^{3e is} selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

Alternatively, two R ^3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, said carbon ring optionally further being 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br Substituted with a substituent of I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

A _{2 is} selected from a C _5-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC _5-11 carbon ring, a -O-5 to 11 membered heterocyclic ring, a C _5-11 carbon ring-O- or a 5 to 11 member Heterocyclic-O-, further preferably benzene ring-O-, -O-benzene ring, benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring, said carbocyclic ring, heterocyclic ring, benzene ring The thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring is optionally further substituted by 0, 1, 2, 3, 4 or 5 R ⁶ and the heterocyclic ring contains 1 to 3 selected from N a hetero atom of O or S;

X ₁ and X ₂ are each independently selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -S-, -S(=O). )-, -S(=O) ₂ -, -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O) O-, -NR ^x C(=O)NR ^x -, -NR ^x S(=O) ₂ -, -S(=O) ₂ NR ^x -, -NR ^x S(=O) ₂ NR ^x - or -NR ^x -, preferred bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O)O- or -NR ^x -;

R ^{x is} each independently selected from H, C _1-6 alkyl or C _3-8 cycloalkyl, and the alkyl or cycloalkyl group is optionally further selected from 0, 1, 2, 3, 4 or 5 Substituted with a substituent of F, Cl, Br, I, C _1-4 alkyl, C _3-6 cycloalkyl or C _1-4 alkoxy;

R ^x each independently is preferably H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, said methyl, ethyl , propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl are optionally further selected from 0, 1, 2, 3, 4 or 5 selected from F, Cl, Substituted with Br, I, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy or ethoxy;

R ^{6 is} each independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , =0, carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _3-6 naphthenic , C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(=O)-C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OC _1-4 alkyl, -OC(=O)-C _1-4 alkyl or 5 to 6 a heteroaryl group, preferably F, Cl, Br, I, OH, NH ₂ , =0, cyano, C _1-4 alkyl, C _2-4 alkynyl or _1-4 alkoxy, said alkyl Or alkynyl, alkoxy, cycloalkyl, NH ₂ or heteroaryl optionally further 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkane Substituted with a substituent of a C _1-4 alkoxy group or a -C(=O)-C _1-4 alkyl group;

R ^{6 is} each independently preferably F, Cl, Br, OH, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, CHF ₂ , CF ₃ , methoxy, ethoxy, -OCHF ₂ , -OCF ₃ , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl;

Alternatively, R ⁶ and R ^{x are} directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, preferably a 4 to 6 membered nitrogen-containing heterocyclic ring, which is optionally further substituted by 0, 1, 2, 3 or 4 Substituted by a substituent selected from F, Cl, Br, I, OH, NH ₂ , =0, C _1-4 alkyl or C _1-4 alkoxy, preferably further by 0, 1, 2, 3 or Substituted by four substituents selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , =0, methyl, ethyl, methoxy or ethoxy;

Provided that the number of linking atoms of the shortest chain of R ^3a to R ^3d is in the range of 6 to 26;

a is 0, 1, 2, 3 or 4, preferably 0 or 1;

b is 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2;

c or d is independently selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3.

A preferred embodiment of the invention is a compound represented by the formula (III): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , NH ₂ , OH, cyano, methyl, ethyl, methoxy, ethoxy, -NHCH ₃ or -N (CH) ₃ ) ₂ ;

W is selected from -O-, -NH- or -NC _1-4 alkyl-, preferably -O-, -NH- or -NCH ₃ -;

R' and R" are each selected from the group consisting of F, Cl, Br, I, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;

R ³ and R ⁴ are each independently selected from H, methyl or ethyl;

R ^{5 is} selected from H or OH;

B is selected from

R ^{3a is} selected from methylene, ethylene, propylene, butylene, pentylene or

The methylene, ethylene, propylene, butylene, pentylene or

Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

R ^{3b is} selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene, Methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene optionally further 0, 1 Substituting 2, 3 or 4 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

R ^3c and R ^3d are each independently selected from a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group, and the methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group. Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

A _{2 is} selected from the group consisting of a benzene ring-O-, a -O-benzene ring, a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, said benzene ring-O-, -O-benzene ring, a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring is optionally further substituted with 0, 1, 2, 3 or 4 R ⁶ ;

X ₁ and X ₂ are each independently selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR ^x - , -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O)O- or -NR ^x -;

R ^{x is} selected from H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, said methyl, ethyl, propyl The base, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl are optionally further 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, Substituting I, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy or ethoxy;

R ^{6 is} selected from the group consisting of F, Cl, Br, OH, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, CHF ₂ , CF ₃ , methoxy, ethoxy, - OCHF ₂ , -OCF ₃ , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl;

Alternatively, R ⁶ is directly bonded to R ^x to form a 4 to 6 membered nitrogen-containing heterocyclic ring, which is optionally further 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, I, Substituted by a substituent of OH, NH ₂ , =O, methyl, ethyl, methoxy or ethoxy;

Provided that the number of linking atoms of the shortest chain of R ^3a to R ^3d is in the range of 6 to 26;

a is 0 or 1;

b is 0, 1 or 2;

c or d are each independently selected from 0, 1, 2 or 3.

A preferred embodiment of the invention, a compound of the formula (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , NH ₂ , OH, cyano, methyl, ethyl, methoxy, ethoxy, -NHCH ₃ or -N (CH) ₃ ) ₂ ;

W is selected from -O-, -NH- or -NC _1-4 alkyl-, preferably -O-, -NH- or -NCH ₃ -;

R' and R" are each selected from the group consisting of F, Cl, Br, I, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;

R ³ and R ⁴ are each independently selected from H, methyl or ethyl;

R ^{5 is} selected from H or OH;

B is selected from

R ^{3a is} selected from the group consisting of methylene, ethylene, propylene, -CH ₂ CH(CH ₃ )-, -CH(CH ₃ )CH ₂ -, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, n-n-butyl, -CH(CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -,

Or pentylene;

R ^{3b is} selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene, Methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene optionally further 0, 1 Substituting 2, 3 or 4 substituents selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

R ^3c and R ^3d are each independently selected from the group consisting of methylene, ethylene, propylene, -CH ₂ CH(CH ₃ )-, -CH(CH ₃ )CH ₂ -, n-butylene, -CH ( CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ - or pentylene;

A _{2 is} selected from the group consisting of a benzene ring-O-, a -O-benzene ring, a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, said benzene ring-O-, -O-benzene ring, a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring is optionally further substituted with 0, 1, 2, 3 or 4 R ⁶ ;

R ^{6 is} selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, CHF ₂ , CF ₃ , methoxy, ethoxy, -OCHF ₂ or -OCF ₃ Substituted by a substituent;

X ₁ and X ₂ are each independently selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR ^x - , -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O)O- or -NR ^x -;

R ^{x is} selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, said methyl, ethyl, propyl Base, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl are optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, methyl, ethyl, Substituted by cyclopropyl, cyclobutyl, cyclopentyl, methoxy or ethoxy;

R ^x is preferably H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, -CH ₂ -cyclopropyl, -CH ₂ - cyclobutyl, -CH ₂ -cyclopentyl or -CH ₂ -cyclohexyl;

Alternatively, R ⁶ is directly bonded to R ^x to form a 4 to 6 membered nitrogen-containing heterocyclic ring, which is optionally further 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, I, Substituted by a substituent of OH, NH ₂ , =O, methyl, ethyl, methoxy or ethoxy;

Provided that the number of linking atoms of the shortest chain of R ^3a to R ^3d is in the range of 6 to 26;

a, b, c, and d are all 0.

In a preferred embodiment of the invention, the compounds of the invention include, but are not limited to, one of the following compounds:

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the formula (I) or (III) or a stereoisomer, hydrate or metabolite thereof Solvent, pharmaceutically acceptable Accepted salts, eutectic or prodrugs, and pharmaceutically acceptable carriers, diluents, adjuvants, vehicles or excipients; said compositions may further comprise one or more additional therapeutic agents; preferably The other therapeutic agent is selected from one or more of a PDE4 inhibitor, a M receptor antagonist, a corticosteroid, and a β-adrenergic receptor agonist.

The present invention also relates to providing a compound of the formula (I) or (III) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, for preparation Use in the treatment of a medicament for an airway obstructive disease, preferably, in the preparation of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.

The present invention also provides a method for treating an airway obstructive disease, which comprises administering a compound of the above formula (I) or (III) or a stereoisomer, hydrate, metabolite, solvent thereof. a pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition as described above.

The present invention also provides a method for treating asthma, chronic obstructive pulmonary disease or bronchitis, which comprises administering a compound of the above formula (I) or (III) or a stereoisomer or hydrate thereof. a metabolite, a solvate, a pharmaceutically acceptable salt, a co-crystal or a prodrug, or a pharmaceutical composition as described above.

The present invention provides an intermediate for preparing a compound of the formula (III) or a stereoisomer thereof, which is selected from a compound represented by the formula (IV) or a stereoisomer thereof:

M is selected from the group consisting of a carboxyl group, -C(=O)OC(CH ₃ ) ₃ , -X ₁ -R ^3f -CHO, -X ₁ -R ^3f -C(OC _1-4 alkyl) ₂ ;

R ^{3f is} selected from a methylene group, an ethylene group or a propylene group;

R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , NH ₂ , OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio , -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

W is selected from -O-, -NH- or -NC _1-4 alkyl-;

R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

R ^3c , R ^3d are each independently selected from a C _1-6 alkylene group, and the alkylene group is optionally further substituted with 0 to 5 R ^3e ;

R ^{3b is} selected from C _1-6 alkylene, phenylene or 5- to 6-membered heteroarylene, and the alkylene, phenylene or heteroarylene is optionally further 0 to 4 selected from F Substituted with a substituent of Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

R ^{3e is} selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

Alternatively, the two R ^3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C _1-4 alkyl group or a C _1-4 alkoxy group;

A _{2 is} selected from a C _5-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC _5-11 carbon ring, a -O-5 to 11 membered heterocyclic ring, a C _5-11 carbon ring-O- or a 5 to 11 member a heterocyclic ring-O- wherein said carbocyclic or heterocyclic ring is optionally further substituted with 0 to 5 R ⁶ and said heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;

X ₁ and X ₂ are each independently selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -S-, -S(=O). )-, -S(=O) ₂ -, -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O) O-, -NR ^x C(=O)NR ^x -, -NR ^x S(=O) ₂ -, -S(=O) ₂ NR ^x -, -NR ^x S(=O) ₂ NR ^x - or -NR ^x -;

R ^{x is} each independently selected from H, C _1-6 alkyl or C _3-8 cycloalkyl, and the alkyl or cycloalkyl group is further further selected from 0 to 5 selected from F, Cl, Br, I, Substituted with a substituent of a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a C _1-4 alkoxy group;

R ^{6 is} each independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , =0, carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _3-6 naphthenic , C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(=O)-C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OC _1-4 alkyl or 5- to 6-membered heteroaryl, said alkyl, alkynyl, alkane The oxy, cycloalkyl, NH ₂ or heteroaryl group is further optionally from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or - Substituted by a C(=O)-C _1-4 alkyl group;

Alternatively, R ⁶ and R ^{x are} directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , = Substituted with a substituent of O, C _1-4 alkyl or C _1-4 alkoxy;

a is 0, 1, 2, 3 or 4, preferably 0 or 1;

b is 0, 1, 2, 3, 4 or 5, preferably 0, 1 or 2;

c or d is independently selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3.

In a preferred embodiment of the invention, the compound of the formula (IV) is selected from one of the following structures:

The ditrifluoroacetate salt of the specific example compound of the present invention can be dissolved in a polar organic solvent (such as a mixed solvent of methanol and dichloromethane (v/v = 1/90) by adding alkaline Reagents (such as saturated sodium bicarbonate solution or saturated sodium carbonate solution) adjust the pH to alkaline, stir and extract with organic solvent (such as dichloromethane, ethyl acetate, etc.) The free phase of the corresponding compound can be obtained after concentration of the organic phase under reduced pressure.

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention. The nitrogen or halogen 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 isotopes including ¹⁴ N and ¹⁵ N, the fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" means a straight-chain and branched monovalent saturated hydrocarbon group, and the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-glycol a base, an n-octyl group, a n-decyl group, a n-decyl group, etc.; the alkyl group may optionally be further from 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocycle , C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _k -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -( CH ₂ ) _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a the substituent group, wherein R ¹⁹ and R ^19a are each independently selected from H, Group, amino, carboxy, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, 3-10 yuan carbocyclyl 4 to 10-membered heterocyclic group a 3 to 10 membered carbocyclic oxy group or a 4 to 10 membered heterocyclic oxy group, k is selected from 0, 1, 2, 3, 4 or 5, and j is selected from 0, 1 or 2. The alkyl, k, l or R ¹⁸ and R ^18a appearing herein are as defined above.

"Alkylene" means a straight-chain or branched divalent saturated hydrocarbon group, including -(CH ₂ ) _v - (v is an integer from 1 to 10), and alkylene examples include, but are not limited to, methylene, sub Ethyl, propylene, butylene, etc.; the alkylene group may optionally be further from 0 to 5 selected from the group consisting of F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _k -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ a substituent of _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a Alternatively, when the number of substituents in the alkylene group is 2 or more, the substituents may be fused together to form a cyclic structure. The alkylene groups appearing herein are as defined above.

"Alkoxy" means a monovalent group of an O-alkyl group, wherein alkyl is as defined herein, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2 -propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy , 3-methyl-1-butoxy and 2-methyl-1-butoxy and the like.

"Alkenyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, and alkenyl examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octene , 3-octenyl, 1-decenyl, 3-decenyl, 1-decenyl, 4-nonenyl, 1,3-butadiene, 1,3-pentadiene, 1, 4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group may optionally be further from 0 to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH ₂ F, -CHF _{2 , -CF 3, -OCH 2 F,} -OCHF 2, -OCF 3, hydroxyl, -SR ^19, a nitro group, a cyano group, an isocyano group, an alkyl group Hydroxyalkyl, alkoxy, carbocyclic group, heterocyclic group, C _2-8 alkenyl, C _{2-8 alkynyl, - (CH 2) k -C} (= O) -R 19, - (CH 2 _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC( Substituted by a substituent of =O)-OR ¹⁹ or -NR ¹⁹ R ^19a . The alkenyl groups appearing herein are as defined above.

"Alkynyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, the main chain comprising 2 to 10 carbon atoms, further preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl and 4-decynyl, etc.; the alkynyl group may be optionally Further from 0 to 5 selected from the group consisting of F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , hydroxyl, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _k -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or a substituent of -NR ¹⁹ R ^19a is substituted. The alkynyl groups appearing herein are as defined above.

"Cycloalkyl" means a monovalent saturated carbocyclic hydrocarbon group, usually having from 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The cycloalkyl group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 Alkynyl, -(CH ₂ ) _k -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ Substituents of R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a are substituted. The cycloalkyl groups appearing herein are as defined above.

"Carbocycle" or "carbocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member. A tricyclic system, a carbocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl -2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl , cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cyclodecyl, cyclododecyl, phenyl, naphthyl, benzocyclopropenyl, 2,3-dihydrobenzo ring Propylene

The carbocyclic group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 Alkynyl, -(CH ₂ ) _k -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ Substituents of R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a are substituted. The carbocyclic group appearing herein is defined as described above.

"Heterocycle" or "heterocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member. a tricyclic system comprising 1 to 4 heteroatoms selected from N, O or S, preferably a 3 to 10 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized to various oxidations state. The heterocyclic group may be bonded 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 an epoxyethyl group, a glycidyl group, an azacyclopropyl group, and an oxocyclic ring. Butyl, azetidinyl, thioheterobutyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, azacycloheptyl , oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyr Cyclo, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl , thiazolidine, 1,3-dithia, dihydrofuranyl, dihydropyranyl, dithylpentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrroline, 3-pyrroline, indanyl, 2H-pyranyl , 4H-pyranyl, dioxolane, 1,3-dioxolanyl, pyrazolinyl, dithiaalkyl, dithialimyl, dihydrothienyl, pyrazolidinyl, imidazoline Base, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolyl, benzotriazolyl, 3-azabicyclo[3.1. 0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothio Morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]decyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and Oxanspiro[3.3]heptyl. The heterocyclic group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, =O, -CH ₂ F, -CHF ₂ , -CF ₃ , -OCH ₂ F, -OCHF ₂ , -OCF ₃ , hydroxy, -SR ¹⁹ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 Alkynyl, -(CH ₂ ) _k -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k -C(=O)-NR ¹⁹ Substituents of R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a are substituted. The heterocyclic group appearing herein is as defined above.

"β-adrenergic receptor binding group" refers to a group capable of binding to a β-adrenergic receptor; for example, see review article "β-adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, BEMain, p187 (Pergamon Press) ". The above-mentioned groups are also described, for example, in WO/2005092841, US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373, WO/2006087315 and WO/2006032627. Non-limiting examples include

R ³ and R ⁴ are each independently selected from H or C _1-4 alkyl, R ^{5 is} selected from H or OH, and B is selected from

Wherein Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC(CH) ₃ ) ₂ -.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "alkyl group optionally substituted by F" means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.

"Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, with other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.

"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.

"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.

"Prodrug" means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention, which modifications can be The procedure is either removed or removed in the body to give the parent compound.

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

"Effective dose" refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.

"Solvate" means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

"IC ₅₀ " refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

Detailed ways

The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD). ), the internal standard is tetramethylsilane (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 chromatograph (Zorbax SB-C18 100 x 4.6 mm).

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a 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 reaction was carried out under a nitrogen atmosphere.

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 an optimum reaction temperature of 20 ° C to 30 ° C.

TBS is tert-butyldimethylsilyl.

Boc is a tert-butyloxycarbonyl group.

Bn is a benzyl group.

HATU is 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (CAS: 148893-10-1)

Intermediate 1: [(3aR,5r,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate

[(3aR,5r,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

(3aR,5r,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (1a (prepared by reference to CN102146084) (2.27g, 10mmol) and 2-phenylphenylisocyanate (1.95g, 10mmol) were placed in a 100mL round bottom flask, tetrahydrofuran (40mL) and triethylamine (2.77mL, 20mmol) Heat to reflux for 6 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj Methyl chloride (20 mL), triethylamine was added to EtOAc (3 mL), EtOAc (EtOAc) The filtrate was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Intermediate 1), brown solid (1.91 g, yield The rate is 59%).

Intermediate 2: [(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate

[(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl] N-(2-phenylphenyl)carbamate

(3aR,5s,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (2a) (Prepared by reference to CN102146084) (4.56g, 20mmol) and 2-phenylphenylisocyanate (3.90g, 20mmol) were placed in a 250mL round bottom flask, tetrahydrofuran (80mL) and triethylamine (5.54mL, 40mmol). The system was heated to reflux and allowed to react for 6 hours. After completion of the reaction, the system was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjj Methane (40 mL), triethylamine was adjusted to basic. EtOAc (EtOAc) (EtOAc) The organic layer was concentrated under reduced EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Intermediate 2), brown solid (5.0 g, Yield 77%).

LCMS m/z = 323.3 [M + 1].

Intermediate 3: tert-butyl 3-[2-[3-(2-bromoethyl)phenyl]ethoxy]propanoate

Tert-butyl 3-[2-[3-(2-bromoethyl)phenyl]ethoxy]propanoate

3-(2-Bromoethyl)-phenylethanol (3a) (2.24 g, 9.78 mmol) (prepared by reference to CN 102625808) and tert-butyl acrylate (3b) (7.1 mL, 48.9 mmol) were placed in a 100 mL round bottom. Add acetonitrile (1.5 mL) to the flask, and add 40% benzyltrimethylammonium hydroxide in methanol (1.23 mL) to the reaction solution. After the addition is complete, react at room temperature for 10 minutes, then directly react the reaction solution. The residue was concentrated to drynesshhhhhhhhhhhhhhhhhh ]Ethoxy]tert-butyl propionate (Intermediate 3), pale yellow liquid (0.8 g, yield 23%).

LCMS m/z = 379.1 [M+23].

Intermediate 4: tert-butyl 3-[2-[4-(2-bromoethyl)phenyl]ethoxy]propanoate

Tert-butyl 3-[2-[4-(2-bromoethyl)phenyl]ethoxy]propanoate

4-(2-Bromoethyl)-phenylethanol (4a) (2.24 g, 9.78 mmol) (prepared by reference to WO2009153536A1) And tert-butyl acrylate (3b) (7.1 mL, 48.9 mmol) was placed in a 100 mL round bottom flask, acetonitrile (1.5 mL) was added, and 40% benzyltrimethylammonium hydroxide in methanol (1.23 mL) was added dropwise. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 10 minutes, then the residue was evaporated to dryness. tert-Butyl 2-[3-(2-bromoethyl)phenyl]ethoxy]propanoate (Intermediate 4), pale yellow liquid (0.9 g, yield 26%).

Intermediate 5: tert-butyl 3-[2-[3-(3-(bromomethyl)phenyl]ethoxy]propanoate

Tert-butyl 3-[2-[3-(bromomethyl)phenyl]ethoxy]propanoate

First step: tert-butyl 3-[2-(m-methylphenyl)ethoxy]propanoate (5b)

Tert-butyl 3-[2-(m-tolyl)ethoxy]propanoate

Methylphenethyl alcohol (5a) (4.3 g, 31.6 mmol) and tert-butyl acrylate (3b) (23 mL, 158 mmol) were placed in a 100 mL round bottom flask, and acetonitrile (4 mL) was added to 40% benzyltrimethyl A methanol solution of ammonium hydroxide (2.64 mL) was added dropwise to the system. After the dropwise addition was completed, the mixture was reacted at room temperature for 10 minutes, and then the mixture was concentrated under reduced pressure. v) = 40:1) gave the title compound, tert-butyl 3-[2-(m-methylphenyl)ethoxy]propanoate (5b) as a pale yellow liquid (2.8 g, yield: 34%).

LCMS m/z = 287.3 [M+23].

Second step: t-butyl 3-[2-[3-(3-(bromomethyl)phenyl]ethoxy]propanoate (intermediate 5)

Tert-butyl 3-[2-[3-(bromomethyl)phenyl]ethoxy]propanoate

3-[2-(Methylphenyl)ethoxy]propanoic acid tert-butyl ester (5b) (2.8 g, 10.6 mmol) was placed in a 100 mL round bottom flask, and chlorobenzene (30 mL) was added, N-bromine Desuccinimide (1.89 g, 10.6 mmol) and benzoyl peroxide (50 mg) were heated to reflux under reflux for 4 hours. Cool to room temperature, wash twice with water (30 mL × 2), and combine the organic phases. Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) tert-Butyl (bromomethyl)phenyl]ethoxy]propanoate (Intermediate 5), pale yellow liquid (1.2 g, yield 33%).

LCMS m/z = 365.1 [M+23].

Intermediate 6: 3-[2-[4-(Bromomethyl)phenyl]ethoxy]propanoate (Intermediate 6)

Tert-butyl 3-[2-[4-(bromomethyl)phenyl]ethoxy]propanoate

First step: tert-butyl 3-[2-(p-methylphenyl)ethoxy]propanoate (6b)

Tert-butyl 3-[2-(p-tolyl)ethoxy]propanoate

P-Methylphenylethanol (6a) (2.72 g, 20 mmol) and tert-butyl acrylate (3b) (16.7 mL, 100 mmol) were placed in a 100 mL round bottom flask, and acetonitrile (3 mL) was added to give benzyltrimethylhydrogen. Ammonium oxide (40% in methanol, 1.67 mL) was added dropwise to the system. After the addition was completed, the mixture was reacted at room temperature for 10 minutes, and then the mixture was concentrated under reduced pressure. /v)=40:1) The title compound 3-(2-(p-methylphenyl)ethoxy]propanoic acid tert-butyl ester (6b) was obtained as a pale yellow liquid (2.9 g, yield 55%).

LCMS m/z = 287.3 [M+23].

Second step: tert-butyl 3-[2-[4-(bromomethyl)phenyl]ethoxy]propanoate (intermediate 6)

Tert-butyl 3-[2-[4-(bromomethyl)phenyl]ethoxy]propanoate

3-[2-(p-Methylphenyl)ethoxy]propanoic acid tert-butyl ester (6b) (2.9 g, 11 mmol) was placed in a 100 mL round bottom flask, chlorobenzene (30 mL), N-bromo Succinimide (1.95 g, 11 mmol) and benzoyl peroxide (0.5 mg) were reacted under reflux for 4 hours. Cool to room temperature, wash with water (30 mL×2), combine organic phases, anhydrous Dry over sodium sulfate, EtOAc (EtOAc m.) Tert-butyl methyl)phenyl]ethoxy]propanoate (Intermediate 6), pale yellow liquid (1.4 g, yield 37%).

LCMS m/z = 365.1 [M+23].

Intermediate 7: N-(2,2-dimethoxyethyl)-4-formyl-N-methyl-benzamide

N-(2,2-dimethoxyethyl)-4-formyl-N-methyl-benzamide

4-formylbenzoic acid (7a) (1.0 g, 6.7 mmol) was dissolved in dichloromethane (20 mL). Methylaminoacetaldehyde dimethylacetal (7b) (0.95 g, 8.0 mmol), triethylamine (4.6 mL, 33.3 mmol), HATU (3.8 g, 10.0 mmol), and stirred at room temperature 1 at room temperature. hour. The reaction was quenched with EtOAc EtOAc (EtOAc m. Chromatography (dichloromethane/methanol (v/v) = 15:1) afforded N-(2,2-dimethoxyethyl)-4-formyl-N-methyl- Formamide (Intermediate 7) (1.5 g, yield 90%).

Intermediate 8: tert-butyl (Z/E)-3-(4-formylphenoxy)prop-2-enoate

Tert-butyl(Z/E)-3-(4-formylphenoxy)prop-2-enoate

4-Hydroxybenzaldehyde (8a) (1.22 g, 0.10 mmol) was dissolved in acetonitrile (20 mL). To the reaction flask was added tert-butyl propiolate (8b) (1.26 g, 0.10 mmol) and 4-methyl Morpholine (0.10 g, 1 mmol). The reaction was stirred at room temperature for 2 hours. The system was concentrated under reduced pressure to give (Z/E)-3-(4-formylphenoxy)prop-2-enoic acid tert-butyl ester ( Intermediate 8) (2.2 g, yield 89%) ).

Intermediate 9: tert-butyl (Z/E)-3-(3-formylphenoxy)prop-2-enoate

Tert-butyl(Z/E)-3-(3-formylphenoxy)prop-2-enoate

3-Hydroxybenzaldehyde (9a) (1.22 g, 0.10 mmol) was dissolved in acetonitrile (20 mL). To the reaction flask was added tert-butyl propiolate (8b) (1.26 g, 0.10 mmol) and 4-methyl Morpholine (0.10 g, 1 mmol). The reaction was quenched after stirring at room temperature for 2 hours. The system was concentrated under reduced pressure to give (Z/E)-3-(3-formylphenoxy)prop-2-enoic acid tert-butyl ester ( Intermediate 9) (2.1 g, yield 85%) ).

Example 1: [(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 1)

[(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

First step: tert-butyl 3-[4-(bromomethyl)phenyl]propanoate (1B)

Tert-butyl 3-[4-(bromomethyl)phenyl]propanoate

3-(p-tolyl)propionic acid tert-butyl ester (1A) (1.74 g, 7.9 mmol) was placed in a 50 mL round bottom flask, chlorobenzene (20 mL) was added, and after stirring, N-bromine was added sequentially to the system. Succinimide (1.78 g, 10 mmol) and benzoyl peroxide (0.2 g, 0.8 mmol) were refluxed for 4 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (ethyl acetate/petroleum ether (v/v) = 1:20) to give the title compound 3-[4-(bromomethyl)phenyl]propanoic acid tert-butyl ester (1B), brown-yellow liquid (1.2 g, yield Rate: 51%).

LCMS m/z = 323.1 [M+23].

Second step: 3-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]propanoic acid tert-butyl ester (1C)

Tert-butyl 3-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -2-yl]methyl]phenyl]propanoate

3-(4-(Bromomethyl)phenyl]propanoic acid tert-butyl ester (1B) (0.9 g, 3 mmol) and [(3aR, 5s, 6aS)-1, 2, 3, 3a, 4, 5, 6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Intermediate 2) (0.97 g, 3 mmol) placed in a 50 mL round bottom In the flask, tetrahydrofuran (20 mL) and triethylamine (0.61 g, 6 mmol) were added, and the system was heated to 40 ° C for 3 hours. After the reaction was completed, saturated brine (30 mL) was added and extracted with dichloromethane (30 mL×2) The organic phase was combined, washed with EtOAc EtOAc m. Compound 3-[4-[[(3aR,5s,6aS)-5-[(2-Phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro-1H - tert-Butylcyclopenta[c]pyrrol-2-yl]methyl]phenyl]propanoate (1C), colorless liquid (0.35 g, yield: 20%).

LCMS m/z = 541.4 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[[4-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propyl]phenyl ]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (1D)

[(3aR,5s,6aS)-2-[[4-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6 ,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking tert-butyl 3-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]propionate (1C) (0.35 g, 0.65 mmol) was placed in a 50 mL round bottom flask at 0 °C Dichloromethane (10 mL) was added, and trifluoroacetic acid (5 mL) was added dropwise to the mixture, and the mixture was evaporated. The mixture was concentrated at room temperature for 1 hour, then concentrated under reduced pressure. Toluene (20 mL) Dichloromethane (15 mL) and triethylamine (0.26 g, 2.6 mmol) were added to the residue sequentially at 0 ° C under nitrogen, and then stirred and then added with methylaminoacetal dimethylacetal (0.12 g, 1 mmol) and HATU. (0.38 g, 1 mmol), and allowed to react to room temperature for 10 minutes. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) The title compound [(3aR,5s,6aS)-2-[[4-[3-[2,2-dimethoxyethyl) was obtained by chromatography (dichloromethane/methanol (v/v) = 1 : 80). (Methyl)amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)carbamate (1D), colorless liquid (0.35 g, yield 93%).

LCMS m/z = 586.4 [M + 1].

Fourth step: [(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (1F)

[(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5s,6aS)-2-[[4-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propyl]phenyl]methyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (1D) (0.35 g, 0.6 mmol) was placed in a 50 mL round bottom flask, tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.57 g, 3 mmol) were added and reacted at 40 ° C for 30 minutes, cooled to room temperature, and hydrogen carbonate was added. Sodium (0.42g, 5mmol) The aqueous solution (10 mL) was stirred for 10 min. EtOAc EtOAc (EtOAc) 5-[2-Amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) was added (preparation see WO2007102771A1) (0.2 g, 0.6 mmol), methanol (8 mL) and dichloromethane (8 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.42 g, 2 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[[4-[3-[2-[[[(2))] tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3 -oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (1F), yellow solid (0.23 g, yield: 45%).

Step 5: [(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 1)

[(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-) Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (1F) (0.23 g, 0.27 mmol) The mixture was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added thereto. After stirring, triethylamine trihydrofluoride (0.22 g, 1.35 mmol) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1 : 10) gave the title compound [(3aR,5s,6aS)-2-[[4-[3-[2-[[[(2)] -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 1) , yellow solid (0.12 g, yield: 66%).

LCMS m/z = 744.3 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.27 (s, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.37 (m, 8H), 7.23-7.01 (m, 4H), 6.92 (d, J = 10.1 Hz, 1H), 6.47 (d, J = 10.1 Hz, 1H), 5.75 (s, 1H), 5.31 (s, 1H), 5.00 (s, 2H), 3.45 (s, 2H) , 2.91 (s, 2H), 2.73m, 7H), 2.35 (m, 1H), 2.24 (s, 2H), 1.69 (s, 2H), 1.56 (s, 2H), 1.24 (s, 1H), 0.98 (s, 6H).

Example 2: [(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 2)

[(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

First step: tert-butyl 3-[3-(bromomethyl)phenyl]propanoate (2B)

Tert-butyl 3-[3-(bromomethyl)phenyl]propanoate

3-(m-tolyl)propionic acid tert-butyl ester (2A) (2.5 g, 11 mmol) was placed in a 100 mL round bottom flask, chlorobenzene (30 mL) was added, and after stirring, N-brominated amber was sequentially added to the system. The imide (2.4 g, 13 mmol) and benzoyl peroxide (0.24 g, 1 mmol) were refluxed for 4 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (ethyl acetate/petroleum ether (v/v) = 1:20) to give the title compound 3-[3-(bromomethyl)phenyl]propanoic acid tert-butyl ester (2B) as a brown liquid (1.8 g, yield Rate: 53%).

LCMS m/z = 323.1 [M+23].

Second step: 3-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]propanoic acid tert-butyl ester (2C)

Tert-butyl 3-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -2-yl]methyl]phenyl]propanoate

3-(3-(Bromomethyl)phenyl]propanoic acid tert-butyl ester (2B) (1.1 g, 3.6 mmol) and [(3aR,5s,6aS)-1,2,3,3a,4,5 6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Intermediate 2) (0.97 g, 3 mmol) in 50 mL round In the bottom flask, tetrahydrofuran (20 mL) and triethylamine (0.61 g, 6 mmol) were added, and the system was heated to 40 ° C for 3 hours. After the reaction was completed, saturated brine (30 mL) was added and dichloromethane (30 mL×2) was extracted. The organic phase was combined, washed with EtOAc EtOAc m. Compound 3-[3-[[(3aR,5s,6aS)-5-[(2-Phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro-1H - tert-Butyl cyclopenta[c]pyrrol-2-yl]methyl]phenyl]propanoate (2C), colorless liquid (0.45 g, yield: 28%).

LCMS m/z = 541.3 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[[3-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propyl]phenyl ]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (2D)

[(3aR,5s,6aS)-2-[[3-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6 ,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking tert-butyl 3-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]propionate (2C) (0.45 g, 0.85 mmol) was placed in a 50 mL round bottom flask at 0 ° C Dichloromethane (10 mL) was added, and trifluoroacetic acid (5 mL) was added dropwise to the mixture, and the mixture was evaporated. The mixture was concentrated at room temperature for 1 hour, then concentrated under reduced pressure. Toluene (20 mL) Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were added to the residue sequentially at 0 ° C under nitrogen, and then stirred and then added with methylaminoacetal dimethylacetal (0.12 g, 1 mmol) and HATU ( 0.38 g, 1 mmol), and allowed to react to room temperature for 10 minutes. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) The title compound [(3aR,5s,6aS)-2-[[3-[3-[2,2-dimethoxyethyl) was obtained by chromatography (dichloromethane/methanol (v/v) = 1 : 80). (Methyl)amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)carbamate (2D), colorless liquid (0.42 g, yield 86%).

LCMS m/z = 586.4 [M + 1].

Fourth step: [(3aR, 5s, 6aS)-2-[[3-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (2E)

[(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5s,6aS)-2-[[3-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propyl]phenyl]methyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (2D) (0.42 g, 0.72 mmol) was placed in a 50 mL round bottom flask, tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.57 g, 3 mmol) were added, and reacted at 40 ° C for 30 minutes, cooled to room temperature, and hydrogen carbonate was added. Aqueous solution of sodium (0.42 g, 5 mmol) (10 mL), EtOAc (EtOAc) The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl -8-Hydroxy-1H-quinolin-2-one (1E) (0.23 g, 0.7 mmol), methanol (8 mL) and dichloromethane (8 mL). Sodium (0.42 g, 2 mmol) was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[[3-[3-[3-[2-[[(2R)-2-[ tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3 -oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (2E), yellow solid (0.32 g, yield: 52%).

LCMS m/z = 858.5 [M + 1].

Step 5: [(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 2)

[(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-) Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (2E) (0.32 g, 0.37 mmol) The mixture was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.26 g, 1.6 mmol) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1 : 10) gave the title compound [(3aR,5s,6aS)-2-[[3-[3-[2-[2-[[(2R)-2-hydroxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl]phenyl]methyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 2) , yellow solid (0.16 g, yield: 58%).

LCMS m/z = 744.3 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.25 (s, 1H), 8.49 (s, 1H), 8.18 (dd, J = 14.1,9.9Hz, 1H), 7.54-6.99 (m, 12H), 6.92 (m, 1H), 6.49 (dd, J = 12.9, 9.9 Hz, 1H), 5.33 (s, 1H), 5.01 (s, 2H), 3.46 (d, J = 8.0 Hz, 3H), 2.90 (s, 2H), 2.85–2.56 (m, 10H), 2.41–2.31 (m, 3H), 2.26 (s, 2H), 2.05–1.94 (m, 1H), 1.74 (s, 2H), 1.56 (s, 2H) , 1.24 (s, 3H).

Example 3: [(3aR,5s,6aS)-2-[2-[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]ethyl]-3,3a,4,5,6,6a- Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 3)

[(3aR,5s,6aS)-2-[2-[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5- Yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl] N-(2-phenylphenyl)carbamate

First step: 3-[4-(2-hydroxyethyl)phenolyl]propionic acid tert-butyl ester (3B)

Tert-butyl 3-[4-(2-hydroxyethyl)phenoxy]propanoate

P-hydroxyphenylethanol (3A) (1.38 g, 10 mmol) and tert-butyl propiolate (1.26 g, 10 mmol) were placed in a 50 mL round bottom flask, and acetonitrile (20 mL) and N-methylmorpholine (0.1 g) were added. , 1 mmol), reacted at room temperature for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure. methanol (30mL) and 10% (w/w) palladium carbon (0.25 g) was added to the residue, and the mixture was reacted at room temperature for 6 hours in a hydrogen atmosphere. After completion of the reaction, the celite was filtered and the filtrate was evaporated. The residue was purified by EtOAc EtOAcjjjjjjjjj (3B), colorless liquid (2.4 g, yield: 90%).

Step 2: 3-[4-(2-Bromoethyl)phenolyl]propionic acid tert-butyl ester (3C)

Tert-butyl 3-[4-(2-bromoethyl)phenoxy]propanoate

3-[4-(2-Hydroxyethyl)phenolyl]propanoic acid tert-butyl ester (3B) (2.4 g, 9 mmol) was dissolved in dichloromethane (20 mL). To the reaction flask were successively added carbon tetrabromide (5.97 g, 18 mmol), imidazole (0.92 g, 13.5 mmol), triphenylphosphine (3.54 g, 13.5 mmol), and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (30 mL). EtOAc (EtOAc m. After pressure concentration and column chromatography (petroleum ether / ethyl acetate (v / v) = 15:1) to give the title compound 3-[4-(2-bromoethyl)phenolyl]propanoic acid tert-butyl ester (3C) , colorless oil (2.6 g, yield 87%).

LCMS m/z = 351.1 [M+23].

The third step: 3-[4-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenoxy]propanoic acid tert-butyl ester (3D)

Tert-butyl 3-[4-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrol-2-yl]ethyl]phenoxy]propanoate

3-(4-(2-Bromoethyl)phenolyl]propionic acid tert-butyl ester (3C) (0.99 g, 3 mmol) and [(3aR,5s,6aS)-1,2,3,3a,4, 5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Intermediate 2) (0.65 g, 2 mmol) in 50 mL In a round bottom flask, acetonitrile (15 mL) was added and water (0.25 mL) and carbon were added. Potassium acid (0.55 g, 4 mmol), the system was heated to 70 ° C for 8 h. After the reaction was completed, saturated brine (30 mL) was added, dichloromethane (30 mL×2) was extracted, and the organic phase was combined and washed with water (40 mL) The residue was dried over EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole Tert-butyl 2-yl]ethyl]phenoxy]propanoate (3D), brown liquid (0.6 g, yield: 50%).

LCMS m/z = 571.4 [M + 1].

Fourth step: [(3aR, 5s, 6aS)-2-[2-[4-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (3E)

[(3aR,5s,6aS)-2-[2-[4-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]phenyl]ethyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[4-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenoxy]propanoic acid tert-butyl ester (3D) (0.6 g, 1.05 mmol) was placed in a 50 mL round bottom flask at 0 ° C Dichloromethane (10 mL) was added thereto, and trifluoroacetic acid (5 mL) was added dropwise to the mixture, and the mixture was evaporated to dryness. Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were added to the residue sequentially at 0 ° C under nitrogen, and then stirred and then added with methylaminoacetal dimethylacetal (0.18 g, 1.5 mmol) and HATU. (0.57 g, 1.5 mmol), and allowed to react to room temperature for 20 minutes. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[3-[2,2-dimethoxy] Ethyl (methyl)amino]-3-oxo-propoxy]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (3E), colorless liquid (0.48 g, yield 74%).

LCMS m/z = 616.3 [M + 1].

Step 5: [(3aR, 5s, 6aS)-2-[2-[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]ethyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3F)

[(3aR,5s,6aS)-2-[2-[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2 -oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[4-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]phenyl) ]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3E) (0.48 g, 0.78 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (30 mL) and p-toluenesulfonic acid monohydrate (0.74 g, 3.9 mmol) were added, and reacted at 40 ° C for 30 minutes, and cooled to room temperature. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) -amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.27 g, 0.79 mmol), methanol (10 mL After stirring with dichloromethane (10 mL) at room temperature for 1 hour, sodium triacetoxyborohydride (0.63 g, 3 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[3-[2-[[(2)) -[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino] 3-oxo-propoxy]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N- (2-Phenylphenyl)carbamate (3F), yellow solid (0.42 g, yield: 61%).

LCMS m/z = 445.0 [M/2+1].

Step 6: [(3aR, 5s, 6aS)-2-[2-[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H) -quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]ethyl]-3,3a,4,5,6,6a- Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 3)

[(3aR,5s,6aS)-2-[2-[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5- Yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl] N-(2-phenylphenyl)carbamate

Taking [(3aR,5s,6aS)-2-[2-[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) 8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]ethyl]-3, 3a, 4, 5, 6, 6a-hexahydrogen -1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (3F) (0.42 g, 0.47 mmol) was placed in a 50 mL round bottom flask and added Tetrahydrofuran (20 mL) was stirred well, and triethylamine trihydrofluoride (0.4 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[3-[2-[[(2)) -hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( Compound 3), yellow solid (0.19 g, yield: 51%).

LCMS m/z = 387.8 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.24 (s, 1H), 8.50 (s, 1H), 8.18 (d, J = 9.9Hz, 1H), 7.48-7.23 (m, 10H), 7.15-7.04 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.81 (dd, J = 8.6, 2.7 Hz, 2H), 6.48 (dd, J = 9.9, 1.3 Hz, 1H), 5.31 (s, 1H), 4.98 (m, 2H), 4.14 (t, J = 6.2 Hz, 2H), 3.36 (m, 5H), 2.98 (s, 2H), 2.86 - 2.58 (m, 11H), 2.26 (s, 2H) ), 1.72 (s, 2H), 1.54 (m, 2H), 1.24 (s, 1H).

Example 4: [(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 4)

[(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

First step: (Z/E)-3-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5 ,6,6a-hexahydrogen -1H-cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]prop-2-enoic acid tert-butyl ester (4A)

Tert-butyl (Z/E)-3-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H -cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]prop-2-enoate

[(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Intermediate 2) (2.73 g, 8.5 mmol) and (Z/E)-3-(3-formylphenoxy)prop-2-enoic acid tert-butyl ester (Intermediate 9) (2.1 g, 8.5 mmol) was placed in a 50 mL round bottom flask, methanol (30 mL) was added, dichloromethane (30 mL) was added, and the mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (5.4 g, 25.5 mmol) was added. Continue to react for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave (Z/E)-3-[3-[[(3aR,5s,6aS)-5-[(2-benzene) as a yellow liquid. Phenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]propane tert-Butyl-2-enoate (4A) (2.2 g, yield: 47%).

Second step: 3-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]propanoic acid tert-butyl ester (4B)

Tert-butyl 3-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -2-yl]methyl]phenoxy]propanoate

(Z/E)-3-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6, 6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]prop-2-enoic acid tert-butyl ester (4A) (2.2 g, 4.0 mmol) dissolved in methanol Palladium carbon (0.22 g) was added to (20 mL), and the reaction was stirred at room temperature for 3 hours under a hydrogen atmosphere. The filtrate which was filtered through celite was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) = 1:12) to give 3-[3-[[( 3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] tert-Butyl pyrrol-2-yl]methyl]phenoxy]propanoate (4B) (1.3 g, yield 59%).

The third step: [(3aR, 5s, 6aS)-2-[[3-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]benzene Methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (4C)

[(3aR,5s,6aS)-2-[[3-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6 ,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

3-[3-[[(3aR,5s,6aS)-5-[(2-Phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro-1H - Cyclopentadienyl[c]pyrrol-2-yl]methyl]phenoxy]propanoic acid tert-butyl ester (4B) (1.3 g, 2.3 mmol) in a 50 mL round bottom flask at 0 ° C Dichloromethane (10 mL) was added, and trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was evaporated. The mixture was concentrated at room temperature for 1 hour, then concentrated under reduced pressure. Toluene (20 mL) was then evaporated. Dichloromethane (15 mL) and triethylamine (1.6 mL, 11.5 mmol) were added successively to the residue at 0 ° C under nitrogen, and then stirred, and then N-(2,2-dimethoxyethyl) 1-Ammonia (0.33 g, 2.8 mmol) and HATU (1.31 g, 3.5 mmol) were allowed to react to room temperature for 1 hour. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1:20) gave [(3aR,5s,6aS)-2-[[3-[3-[2,2-dimethoxy] as a yellow liquid. Ethyl (methyl)amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (4C) (0.90 g, yield: 65%).

Fourth step: [(3aR, 5s, 6aS)-2-[[3-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (4D)

[(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[[3-[3-[2,2-Dimethoxyethyl(methyl)amino]-3-oxo-propoxy]phenyl]- -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (4C (0.90 g, 1.5 mmol) was dissolved in tetrahydrofuran (15 mL), and p-toluenesulfonic acid monohydrate (1.42 g, 7.5 mmol) was added thereto. After stirring at 40 ° C for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate was added dropwise. 50 mL) quenching reaction with dichloromethane (100 mL × 2) was extracted, and the combined organic layer was dried over anhydrous sodium sulfate. To this was added 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.50 g, After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (0.95 g, 4.5 mmol) was added and stirred at room temperature for 3 hr. The reaction mixture was quenched with EtOAc (EtOAc m. :Methanol (v/v) = 1:0 to 8:1) gave [(3aR,5s,6aS)-2-[[3-[3-[2-[[(2))) [tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]- 3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-( 2-Phenylphenyl)carbamate (4D) (0.39 g, yield 30%).

Step 5: [(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 4)

[(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[[3-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-) Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (4D) (0.39 g, 0.45 mmol Dissolved in tetrahydrofuran (10 mL), triethylamine trihydrofluoric acid (1.98 g, 12.3 mmol) was added to the reaction mixture and stirred at room temperature for 12 hours. A saturated aqueous solution of sodium hydrogencarbonate (50 mL), EtOAc (5 mL) Chromatography (dichloromethane:methanol (v/v) = 1:0 to 8:1) to give [(3aR,5s,6aS)-2-[[3-[3-[2-[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl Oxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (Compound 4) (0.14 g, yield 41%).

^{1 H NMR (400MHz, DMSO-} d6) δ10.22 (s, 1H), 8.49 (s, 1H), 8.18 (d, J = 9.9Hz, 1H), 7.43-7.26 (m, 9H), 7.19 (td , J=7.9, 2.3 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 6.83-6.84 (m, 2H), 6.76-6.78 (m, 1H), 6.47 (dd, J = 9.9 Hz, 1.2 Hz, 1H), 4.98-5.01 (m, 2H), 4.16 (t, J = 6.3 Hz, 2H), 3.46 (d, J = 3.5 Hz, 2H) , 3.42–3.17(m,4H), 2.97(s,1H), 2.87–2.60(m,8H), 2.35-2.37(m,2H),2.24-2.26(m,2H),1.67-1.77(m, 2H), 1.50-1.59 (m, 2H)

LCMS m/z = 761.5 [M+2].

Example 5: [(3aR,5r,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy) -2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 5)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: 3-[2-[3-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5, 6,6a-hexahydrogen -1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (5A)

Tert-butyl 3-[2-[3-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoate

3-[2-[3-(2-Bromoethyl)phenyl]ethoxy]propanoic acid tert-butyl ester (Intermediate 3) (0.8 g, 2.26 mmol) and [(3aR, 5r, 6aS)- 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (intermediate 1 (0.73g, 2.26mmol) was placed in a 50mL round bottom flask, acetonitrile (15mL) was added, water (0.25mL) and potassium carbonate (0.62g, 4.52mmol) were added, the system was heated to 70 ° C for 5 hours, the reaction After completion, a saturated aqueous solution of sodium chloride (30 mL) was added, and dichloromethane (30 mL × 2) was evaporated. Chromatography (dichloromethane/methanol (v/v) = 1: 20) afforded the title compound 3-[2-[3-[2-[(3aR,5r,6aS)-5-[(2-benzene Phenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy Tert-butyl tert-propionate (5A), colorless liquid (0.72 g, yield 53%).

LCMS m/z = 599.4 [M + 1].

The second step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-(butyl(2,2-dimethoxyethyl))amino)-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (5C)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-(butyl(2,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[3-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (5A) (0.72 g, 1.2 mmol) placed in a 50 mL round bottom In the flask, dichloromethane (10 mL) was added at 0 ° C, and trifluoroacetic acid (5 mL) was added dropwise to the system. After 1 hour of warm reaction, the system was concentrated under reduced pressure, and dichloromethane (15 mL) and triethylamine (0.66 mL, 4.8 mmol) were sequentially added to the residue under 0 ° C under nitrogen. 2,2-Dimethoxyethyl)butan-1-amine (5B) (0.19 g, 1.2 mmol) (prepared by reference to WO2011012896A2) and HATU (0.55 g, 1.44 mmol) were allowed to react to room temperature for 1 hour. Water (30 mL) and dichloromethane (30 mL × 2) were added to the mixture, and the organic layer was combined, washed with brine (40 mL×1), dried over anhydrous sodium sulfate Purification by silica gel column chromatography (dichloromethane /methanol (v/v) = : : : : : : : : : : : Butyl (2,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (5C), colorless liquid (0.73 g, yield 89%).

LCMS m/z = 686.4 [M + 1].

The third step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2))) )silyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (5D)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a -hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5r,6aS)-2-[2-[3-[2-[3-(butyl(2,2-dimethoxyethyl))amino)-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (5C) (0.24 g, 0.35 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.33 g, 1.75 mmol) were added and reacted at 40 °C. After a few minutes, it was cooled to room temperature, and aq. EtOAc (EtOAc (EtOAc) The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8- Hydroxy-1H-quinolin-2-one (1E) (0.12 g, 0.35 mmol), methanol (8 mL) and dichloromethane (8 mL), stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.22 g) , 1.05 mmol), the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave the title compound [(3aR,5r,6aS)-2-[2-[3-[2-[3-[ -[2-[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene And [c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (5D), yellow solid (0.17 g, yield 51%).

LCMS m/z = 479.9 [M+2]/2.

The fourth step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy) -2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)aminocarbonate (Compound 5)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5r,6aS)-2-[2-[3-[2-[3-[butyl][2-[[(2R)-2-(tert-butyl(dimethyl))) )oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl ]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (5D) (0.17 g, 0.18 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (10 mL) was added. After stirring, triethylamine trihydrofluoride (0.12 mL, 0.72 mmol) was added to the system, and the reaction was carried out at room temperature. hour. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5r,6aS)-2-[2-[3-[2-[3-[butyl-[2- [[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Compound 5), pale yellow solid (0.1 g, yield 67%).

LCMS m/z = 845.5 [M + 1].

Example 6: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy) -2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 6)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1 H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: 3-[2-[3-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propionic acid tert-butyl ester (6A)

Tert-butyl 3-[2-[3-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoate

3-(2-[3-(2-Bromoethyl)phenyl]ethoxy]propanoic acid tert-butyl ester (Intermediate 3) (0.9 g, 2.52 mmol) and [(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (Intermediate 2) (0.81 g, 2.52 mmol) was placed in a 50 mL round bottom flask, acetonitrile (15 mL), water (0.25 mL) and potassium carbonate (0.7 g, 5.04 The mixture was reacted for 5 hours. After the reaction was completed, saturated brine (30 mL) was added, and dichloromethane (30 mL × 2) was evaporated. The residue was purified by EtOAcjjjjjjjjjjjjjj 5-[(2-Phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]B Tert-butyl]phenyl]ethoxy]propanoate (6A), colorless liquid (0.82 g, yield 54%).

LCMS m/z = 599.4 [M + 1].

The second step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-(butyl(2,2-dimethoxyethyl))amino)-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (6B)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-(butyl(2,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[3-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (6A) (0.82 g, 1.37 mmol) in 50 mL round bottom In the flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise thereto. After reacting for 1 hour at room temperature, the system was concentrated under reduced pressure, and the mixture was evaporated at 0 ° C under nitrogen. Dichloromethane (15 mL) and triethylamine (0.76 mL, 5.4 mmol) were added successively to the residue, and then, after stirring, N-(2,2-dimethoxyethyl)butan-1-amine (5B) was added ( 0.22 g, 1.36 mmol) and HATU (0.62 g, 1.63 mmol) were allowed to react to room temperature for 1 hour. After the reaction, water (30 mL) was added, and the mixture was evaporated. Purification by silica gel column chromatography (dichlorohexane/methanol (v/v) = : : : : : : : : : : : Butyl (2,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (6B), colorless liquid (0.81 g, yield 87%).

LCMS m/z = 686.5 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2))) )silyl)oxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (6C)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a -hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-(butyl(2,2-dimethoxyethyl))amino)-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (6B) (0.81 g, 1.18 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (1.12 g, 5.9 mmol) were added and reacted at 40 ° C. After a few minutes, the mixture was cooled to room temperature. EtOAc (EtOAc) (EtOAc) The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8- Hydroxy-1H-quinolin-2-one (1E) (0.40 g, 1.18 mmol), methanol (10 mL) and dichloromethane (10 mL), and stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.75 g) , 3.54 mmol), the reaction was continued for 3 hours. The reaction mixture was quenched with EtOAc EtOAc EtOAc. Purification (dichloromethane/methanol (v/v) = 1 : 12) gave the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[butyl-[2 -[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrol-5-yl]N-(2-phenylphenyl)aminocarbonate (6C), yellow solid (0.62 g, yield 55%).

LCMS m/z = 479.9 [M+2]/2.

Fourth step: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy) -2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 6)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1 H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[butyl][2-[[(2R)-2-(tert-butyl(dimethyl))) )oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl ]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (6C) (0.6 g, 0.63 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.41 mL, 2.52 mmol) was added to the system, and the reaction was carried out at room temperature. hour. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[butyl-[2- [[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Compound 6), pale yellow solid (0.28 g, yield 53%).

LCMS m/z = 845.5 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.27 (s, 1H), 8.50 (s, 1H), 8.18 (d, J = 9.6Hz, 1H), 7.48-7.23 (m, 8H), 7.14 (s , 1H), 7.05 (m, 3H), 6.93 (d, J = 5.6 Hz, 1H), 6.50 (s, 1H), 5.05 (m, 1H), 4.96 (m, 1H), 4.43 (s, 2H) , 3.68–3.50 (m, 4H), 3.40 (s, 6H), 3.21 (s, 4H), 2.81–2.61 (m, 7H), 2.45 (s, 2H), 2.27 (s, 2H), 1.72 (s) , 2H), 1.54m, 2H), 1.45 (m, 1H), 1.37 (m, 1H), 1.22 (m, 5H), 0.92 - 0.81 (m, 3H).

Example 7: [(3aR,5s,6aS)-2-[2-[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy) -2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 7)

[(3aR,5s,6aS)-2-[2-[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: 3-[2-[4-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (7A)

Tert-butyl 3-[2-[4-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoate

3-[2-[4-(2-Bromoethyl)phenyl]ethoxy]propanoic acid tert-butyl ester (Intermediate 4) (0.9 g, 2.52 mmol) and [(3aR, 5s, 6aS)- 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (intermediate 2 (0.81g, 2.52mmol) was placed in a 50mL round bottom flask, acetonitrile (15mL), water (0.25mL) and potassium carbonate (0.7g, 5.04mmol) were added, the system was heated to 70 ° C for 5 hours, the reaction was finished After adding saturated brine (30 mL), dichloromethane (30 mL×2), and the organic phase was combined, washed with water (40 mL×1), dried over anhydrous sodium sulfate, and filtered. Chromatography (dichloromethane/methanol (v/v) = 1 : 20) to give the title compound tert-butyl 3-[2-[4-[2-[(3aR,5s,6aS)-5-[( 2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl Ethoxy]propionate (7A), colorless liquid (0.9 g, yield 60%).

LCMS m/z = 599.4 [M + 1].

Second step: [(3aR, 5s, 6aS)-2-[2-[4-[2-[3-(butyl(2,2-dimethoxyethyl))amino)-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (7B)

[(3aR,5s,6aS)-2-[2-[4-[2-[3-(butyl(2,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (7A) (0.9 g, 1.51 mmol) placed in a 50 mL round bottom In the flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise thereto. After reacting for 1 hour at room temperature, the system was concentrated under reduced pressure, and the mixture was evaporated at 0 ° C under nitrogen. Dichloromethane (15 mL) and triethylamine (0.84 mL, 6.04 mmol) were added to the residue, and then stirred, and then N-(2,2-dimethoxyethyl)butan-1-amine (5B) was added. 0.24 g, 1.51 mmol) and HATU (0.69 g, 1.81 mmol) were allowed to react to room temperature for 1 hour. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 20) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[2-[3-(butyl(2) 2-Dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (7B), colorless liquid (0.73 g, yield 70%).

LCMS m/z = 686.3 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[2-[4-[2-[3-[butyl-[2-[[(2)))) )silyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (7C)

[(3aR,5s,6aS)-2-[2-[4-[2-[3-[butyl-[2-[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2- (8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a -hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[4-[2-[3-(butyl(2,2-dimethoxyethyl))amino)-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (7B) (0.36 g, 0.52 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.49 g, 2.6 mmol) were added and reacted at 40 ° C. The mixture was cooled to room temperature, and aq. The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8- Hydroxy-1H-quinolin-2-one (1E) (0.18 g, 0.52 mmol), methanol (8 mL) and dichloromethane (8 mL), stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.33 g) , 1.56 mmol), the reaction was continued for 3 hours. The reaction mixture was quenched with EtOAc EtOAc EtOAc. Purification (dichloromethane/methanol (v/v) = 1 : 12) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[2-[3-[butyl-[2 -[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrol-5-yl]N-(2-phenylphenyl)aminocarbonate (7C), yellow solid (0.31 g, yield 62%).

LCMS m/z = 479.9 [M+2]/2.

Fourth step: [(3aR, 5s, 6aS)-2-[2-[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy) -2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 7)

[(3aR,5s,6aS)-2-[2-[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[4-[2-[3-[butyl][2-[[(2R)-2-(tert-butyl(dimethyl))) )oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl ]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)aminocarbonate ( 7C) (0.31g, 0.33mmol) was placed in a 50mL round bottom flask, tetrahydrofuran (20mL) was added, and after stirring, triethylamine trihydrofluorate (0.22mL, 1.32mmol) was added to the system, and reacted at room temperature for 16 hours. . The reaction mixture was quenched with sodium bicarbonate (20 mL). Purification (dichloromethane/methanol (v/v) = 1 : 10) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[2-[3-[butyl-[2 -[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy Ethyl]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl) carbamate (compound 7), pale yellow solid (0.19 g, yield 67%).

LCMS m/z = 422.9 [M+2]/2, 866.5 [M+23].

Example 8: [(3aR,5s,6aS)-2-[[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 8)

[(3aR,5s,6aS)-2-[[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol- 5-yl]N-(2-phenylphenyl)carbamate

First step: 3-[2-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6, 6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (8A)

Tert-butyl 3-[2-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[ c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoate

3-(2-[3-(Bromomethyl)phenyl]ethoxy]propanoic acid tert-butyl ester (Intermediate 5) (1.2 g, 3.5 mmol) and [(3aR, 5s, 6aS)-1, 2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Intermediate 2) ( 0.65 g, 2 mmol) was placed in a 50 mL round bottom flask, acetonitrile (15 mL) was added, water (0.25 mL) and potassium carbonate (0.55 g, 4 mmol) were added, and the system was heated to 70 ° C for 5 hours. The organic layer was combined with water (40 mL×1), dried over anhydrous sodium sulfate and filtered, The title compound 3-[2-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyl) was obtained from methylene chloride/methanol (v/v): Oxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene [c] tert-Butyl pyrrol-2-yl]methyl]phenyl]ethoxy]propanoate (8A), colorless liquid (0.52 g, yield 44%).

LCMS m/z = 585.4 [M + 1].

Second step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-(butyl(2,2-dimethoxyethyl))amino)-3-oxo-propoxy Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (8B)

[(3aR,5s,6aS)-2-[[3-[2-[3-(butyl(2,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

3-[2-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (8A) (0.52 g, 0.89 mmol) was placed in a 50 mL round bottom flask Dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and the residue was evaporated at 0 ° C under nitrogen. Dichloromethane (15 mL) and triethylamine (0.49 mL, 3.56 mmol) were added successively, and then stirred, and then N-(2,2-dimethoxyethyl)butan-1-amine (5B) (0.14 g) was added. , 0.89 mmol) and HATU (0.41 g, 1.07 mmol) were allowed to react to room temperature for 1 hour. After the reaction, water (30 mL) was added, and the mixture was evaporated. Purification by column chromatography (dichloromethane/methanol (v/v) = 1: 20) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-(butyl(2) ,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopentyl Dienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (8B), colorless liquid (0.38 g, yield 67%).

LCMS m/z = 672.3 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[butyl][2-[[(2R)-2-(tert-butyl(dimethyl))) Ethyloxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]benzene Methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (8C)

[(3aR,5s,6aS)-2-[[3-[2-[3-[butyl-[2-[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2-(8 -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[3-[2-[3-(butyl(2,2-dimethoxyethyl)amino)-3-oxo-propoxy]B Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (8B) (0.38 g, 0.57 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.54 g, 2.85 mmol) were added and reacted at 40 ° C for 30 minutes. After cooling to room temperature, an aqueous solution (10 mL) of sodium hydrogencarbonate (0.34 g, 3.99 mmol) was added, and the mixture was stirred for 10 minutes, and then a saturated sodium hydrogen carbonate solution (20 mL), ethyl acetate (30 mL×2) Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. To the residue was added 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy- 1H-quinolin-2-one (1E) (0.19 g, 0.57 mmol), methanol (8 mL) and dichloromethane (8 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.39 g, 1.85) was added. Methyl), continue to react for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[butyl-[2-[[ (2R)-2-(tert-butyl(dimethyl)silyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl] Amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)carbamate (8C), yellow solid (0.38 g, yield 71%).

LCMS m/z = 473.0 [M+2]/2.

The fourth step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 8)

[(3aR,5s,6aS)-2-[[3-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol- 5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[3-[2-[3-[butyl][2-[[(2R)-2-(tert-butyl(dimethyl)silyl))oxy) 2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]- -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (8C (0.38 g, 0.4 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.27 mL, 1.6 mmol) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[butyl-[2-[[ (2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]B Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (Compound 8), pale yellow solid (0.23 g, yield 69%).

LCMS m/z = 415.9 [M+2]/2.

^{1 H NMR (400MHz, DMSO-} d6) δ10.32 (s, 1H), 8.50 (s, 1H), 8.18 (dd, J = 9.9,3.9Hz, 1H), 7.37 (m, 8H), 7.25-7.02 (m, 4H), 6.94 (m 1H), 6.71 - 6.35 (m, 1H), 5.76 (s, 2H), 5.01 (m, 2H), 3.83 - 3.49 (m, 5H), 2.78 (m, 5H) , 2.44–2.32 (m, 2H), 2.26 (m, 2H), 1.99 (m, 1H), 1.71 (m, 1H), 1.55 (m, 2H), 1.46 (m, 1H), 1.36 (m, 1H) ), 1.24 (m, 4H), 0.99 - 0.72 (m, 3H).

Example 9: [(3aR,5s,6aS)-2-[[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 9)

[(3aR,5s,6aS)-2-[[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol- 5-yl]N-(2-phenylphenyl)carbamate

First step: 3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6, 6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (9A)

Tert-butyl 3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[ c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoate

3-[2-[4-(Bromomethyl)phenyl]ethoxy]propanoic acid tert-butyl ester (Intermediate 6) (0.69 g, 2 mmol) and [(3aR, 5s, 6aS)-1,2 ,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Intermediate 2) (0.65 g, 2 mmol) was placed in a 50 mL round bottom flask, acetonitrile (15 mL) was added, water (0.25 mL) and potassium carbonate (0.55 g, 4 mmol) were added, and the system was heated to 70 ° C for 5 hours. After the reaction, saturated salt was added. Water (30 mL), dichloromethane (30 mL×2), EtOAc (EtOAc m. Methyl chloride / methanol (v / v) = 1: 20) to give the title compound 3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy) a group of -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester ( 9A), colorless liquid (0.41 g, yield 35%).

LCMS m/z = 585.4 [M + 1].

Second step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-(butyl(2,2-dimethoxyethyl))amino)-3-oxo-propoxy Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (9B)

[(3aR,5s,6aS)-2-[[4-[2-[3-(butyl(2,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (9A) (0.41 g, 0.7 mmol) was placed in a 50 mL round bottom flask Dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and the residue was evaporated at 0 ° C under nitrogen. Dichloromethane (15 mL) and triethylamine (0.38 mL, 2.8 mmol) were added successively, and then stirred, and then N-(2,2-dimethoxyethyl)butan-1-amine (5B) (0.11 g) was added. , 0.7 mmol) and HATU (0.32 g, 0.84 mmol) were allowed to react to room temperature for 1 hour. After the reaction, water (30 mL) was added, and the mixture was evaporated. Purification by column chromatography (dichloromethane/methanol (v/v) = 1: 20) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-(butyl(2) ,2-dimethoxyethyl)amino)-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopentyl Dienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (9B), colorless liquid (0.41 g, yield 87%).

LCMS m/z = 672.3 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[butyl-[2-[[(2R)-2-(tert-butyl(dimethyl))) Ethyloxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]benzene Methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (9C)

[(3aR,5s,6aS)-2-[[4-[2-[3-[butyl-[2-[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2-(8 -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[2-[3-(butyl(2,2-dimethoxyethyl)amino)-3-oxo-propoxy]B Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (9B) (0.41 g, 0.61 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.58 g, 3.05 mmol) were added, and reacted at 40 ° C for 30 minutes, cooled to room temperature, and sodium hydrogencarbonate was added. (0.36 g, 4.27 mmol), EtOAc (3 mL),EtOAc. The filtrate was concentrated under reduced pressure, and 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one was added to the residue. (1E) (0.2 g, 0.61 mmol), methanol (8 mL) and dichloromethane (8 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.39 g, 1.83 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[butyl-[2-[[ (2R)-2-(tert-butyl(dimethyl)silyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl] Amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)aminocarbonate (9C), yellow solid (0.32 g, yield 56%).

LCMS m/z = 473.0 [M+2]/2.

Step 4: [(3aR,5s,6aS)-2-[[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2) -oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 9)

[(3aR,5s,6aS)-2-[[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol- 5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[2-[3-[butyl][2-[[(2R)-2-(tert-butyl(dimethyl)silyl))oxy) 2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]- -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (9C (0.32 g, 0.34 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.23 mL, 1.36 mmol) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (dichloromethane/methanol (v/v) = 1:10) to give the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[butyl-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl]amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 9), pale yellow solid (0.18 g, yield 64%) ).

LCMS m/z = 415.8 [M+2]/2.

^{1 H NMR (400MHz, DMSO-} d6) δ10.28 (s, 1H), 8.50 (s, 1H), 8.18 (d, J = 10.1Hz, 1H), 7.35 (m, 8H), 7.15 (s, 3H ), 7.07 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 9.9 Hz, 1H), 5.76 (s, 1H), 5.33 (m, 2H) ), 5.00 (m, 2H), 3.66 - 3.53 (m, 3H), 3.44 (s, 1H), 3.19 (s, 2H), 2.73 (m, 4H), 2.35 (m, 2H), 2.21 (m, 2H), 2.05–1.92 (m, 2H), 1.70 (m, 2H), 1.56 (m, 2H), 1.46 (m, 1H), 1.37 (m, 1H), 1.24 (s, 11H), 0.92–0.77 (m, 4H).

Example 10: [(3aR,5s,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 10)

[(3aR,5s,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo- Propyl]ethyl] Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (10A)

[(3aR,5s,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (7A) (0.55 g, 0.92 mmol) placed in a 50 mL round bottom In a flask, dichloromethane (20 mL) was added at 0 ° C, trifluoroacetic acid (10 mL) was added dropwise to the system, and the mixture was added dropwise thereto. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was then evaporated. concentrate. Dichloromethane (20 mL) and triethylamine (0.36 g, 3.6 mmol) were added successively to the residue at 0 ° C under nitrogen, and then stirred and then added with methylaminoacetal dimethylacetal (0.12 g, 1 mmol) and HATU. (0.38 g, 1 mmol), and allowed to react to room temperature for 30 minutes. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[2-[3-[2,2- Methoxyethyl (methyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentyl Dienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (10A), colorless liquid (0.32 g, yield: 54%).

LCMS m/z = 644.4 [M + 1].

Second step: [(3aR, 5s, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl] Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (10B)

[(3aR,5s,6aS)-2-[2-[4-[2-[3-[2-[[(2S)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (10A) (0.32 g, 0.5 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.48 g, 2.5 mmol) were added and reacted at 40 ° C. After 30 minutes, it was cooled to room temperature, and aq. sodium hydrogen sulfate (0.34 g, 4 mmol) (10 mL) The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8- Hydroxy-1H-quinolin-2-one (1E) (0.17 g, 0.5 mmol), methanol (10 mL) and dichloromethane (10 mL), and stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.32 g) , 1.5 mmol), the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[2-[3-[2-[[(2) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl -amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole- 5-Methoxy]N-(2-phenylphenyl)carbamate (10B), yellow solid (0.12 g, yield: 26%).

LCMS m/z = 458.9 [M/2+1].

The third step: [(3aR, 5s, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 10)

[(3aR,5s,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( 10B) (0.12g, 0.13mmol) was placed in a 50mL round bottom flask, tetrahydrofuran (20mL) was added, and after stirring, triethylamine trihydrofluoride was added to the system. (0.2 mL), reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[2-[4-[2-[3-[2-[[(2) )-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy] Ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (Compound 10), pale yellow solid (0.48 g, yield: 48%).

LCMS m/z = 401.7 [M/2+1].

Example 11: [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxy) -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 11)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

First step: 3-[2-[4-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propionic acid tert-butyl ester (11A)

Tert-butyl 3-[2-[4-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoate

tert-Butyl 3-[2-[4-(bromoethyl)phenyl]ethoxy]propionate (Intermediate 4) (1.07 g, 3 mmol) and [(3aR,5r,6aS)-1, 2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (intermediate 1) ( 0.97 g, 3 mmol) was placed in a 50 mL round bottom flask, acetonitrile (30 mL) was added, water (0.5 mL) and potassium carbonate (0.83 g, 6 mmol) were added, and the system was heated to 70 ° C for 5 h. After the reaction, saturated salt was added. Water (30 mL), methylene chloride (30 mL×2), EtOAc. /methanol (v/v) = 1:20) to give the title compound tert-butyl 3-[2-[4-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)amino) Formyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propionate (11A), colorless liquid (0.92 g, yield: 51%).

Second step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (11B)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking tert-butyl 3-[2-[4-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propionate (11A) (0.92 g, 1.54 mmol) in 50 mL round In a bottom flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was added to continue. Concentrate under reduced pressure. Dichloromethane (15 mL) and triethylamine (0.85 mL, 6.2 mmol) were added successively to the residue at 0 ° C under nitrogen, and then stirred and then added with methylaminoacetal dimethylacetal (0.21 g, 1.8 mmol) and HATU (0.7 g, 1.85 mmol) was allowed to react to room temperature for 10 minutes. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2- Methoxyethyl (methyl)ammonium]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentyl Dienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (11B), colorless liquid (0.84 g, yield 85%).

Third step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]ammonium]ethyl-methyl-amino]-3-oxo-propoxy]ethyl] Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (11C)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (11B) (0.42 g, 0.65 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.62 g, 3.25 mmol) were added and reacted at 40 ° C. After 30 minutes, it was cooled to room temperature, and aq. EtOAc (EtOAc, EtOAc (EtOAc) The phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8- Hydroxy-1H-quinolin-2-one (1E) (0.22 g, 0.65 mmol), methanol (8 mL) and dichloromethane (8 mL), stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.42 g) , 2 mmol), the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl -Ammonia-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole- 5-Methyl]N-(2-phenylphenyl)carbamate (11C), yellow solid (0.33 g, yield: 55%).

The fourth step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) Generation-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 11)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( 11C) (0.33g, 0.36mmol) was placed in a 50mL round bottom flask, tetrahydrofuran (20mL) was added, and after stirring, triethylamine trihydrofluorate (0.3mL, 1.8mmol) was added to the system, and reacted at room temperature for 16 hours. . After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2) )-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-ammonium]-3-oxo-propoxy] Ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (Compound 11), pale yellow solid (0.13 g, yield: 46%).

LCMS m/z = 401.9 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.80 (s, 1H), 8.45 (s, 1H), 7.77-7.63 (m, 1H), 7.45-7.22 (m, 8H), 7.11 (d, J = 2.3 Hz, 3H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.50 (s, 1H), 5.00 (s, 2H), 4.82 (s, 1H), 4.77 - 4.64 (m, 1H), 4.47(s,2H), 4.23(s,1H), 4.02(d,J=6.5Hz,1H), 3.58(m,4H),2.93(s,1H),2.77(m,3H),2.71–2.57 (m, 5H), 2.34 (m, 4H), 1.97 (m, 3H), 1.73 - 1.60 (m, 1H), 1.53 (m, 1H), 1.39 (m, 1H), 1.27 (m, 4H).

Example 12: [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 12)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexah ydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propan Oxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (12B)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5- Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxo-propoxy Ethyl]benzene Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid The ester (12B) (0.42 g, 0.65 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.62 g, 3.25 mmol) were added and reacted at 40 ° C for 30 minutes and cooled to At room temperature, an aqueous solution (10 mL) of sodium hydrogencarbonate (0.67 g, 8 mmol) was added, and the mixture was stirred for 10 minutes, and then a saturated sodium hydrogen carbonate solution (20 mL), ethyl acetate (30 mL × 2) The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. <[""""""""""" -4H-1,4-benzoxazin-3-one (12A) (0.22 g, 0.65 mmol), methanol (8 mL) and dichloromethane (8 mL). Sodium hydride (0.42 g, 2 mmol) was continued and the reaction was continued for 3 h. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino Ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene And [c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (12B), white solid (0.29 g, yield: 48%).

The second step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 12)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(5-Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy] Ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (12B) (0.29 g, 0.31 mmol) was placed in a 50 mL round bottom flask, tetrahydrofuran (20 mL) was added, and after stirring, triethylamine trihydrofluoride (0.5 mL, 3.2 mmol) was added to the system. ), reacted at room temperature for 16 hours. After the reaction, the reaction was quenched with EtOAc EtOAc (EtOAc) The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjj [2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino) Ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene And [c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 12), white solid (0.11 g, yield: 44%).

LCMS m/z = 403.8 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.24 (s, 2H), 8.45 (s, 1H), 8.18 (d, J = 9.9Hz, 1H), 7.79-7.64 (m, 1H), 7.44-7.22 (m, 7H), 7.16 - 7.03 (m, 3H), 6.92 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 9.8 Hz, 1H), 5.32 (m, 2H), 5.00 (m, 1H), 4.77–4.61 (m, 1H), 4.23 (t, J=6.6 Hz, 1H), 4.02 (d, J=6.5 Hz, 1H), 3.65–3.51 (m, 3H), 2.92 (s, 1H) ), 2.73 (d, J = 37.6 Hz, 7H), 2.41 (m, 5H), 2.07 - 1.93 (m, 3H), 1.91 (s, 2H), 1.71 - 1.61 (m, 1H), 1.51 (m, 2H), 1.44 - 1.34 (m, 1H), 1.24 (s, 5H).

Example 13: [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-) 4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 13)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4 -benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (13A)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (8A) (3.6 g, 6.2 mmol) was placed in a 50 mL round bottom flask. Methylene chloride (30 mL) was added at 0 ° C, and trifluoroacetic acid (15 mL) was added dropwise to the system. After the mixture was stirred at room temperature for 1 hour, the system was concentrated under reduced pressure. Toluene (20 mL) was then evaporated. Dichloromethane (30 mL) and triethylamine (2.63 mL, 19 mmol) were added successively to the residue at 0 ° C under nitrogen, and then stirred and then added with methylaminoacetal dimethylacetal (0.91 g, 7.6 mmol) and HATU. (2.9 g, 7.6 mmol), and allowed to react to room temperature for 30 minutes. After the reaction, water (50 mL) was added, and the mixture was evaporated. Chromatography (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[2 Oxyethyl (methyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (13A), colorless liquid (3.5 g, yield: 89%).

LCMS m/z = 630.4 [M + 1].

Second step: [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(5-Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy ]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (13B)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-) 3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6, 6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxo-propoxy]B Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) The carbamate (13A) (1.26 g, 2.0 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (1.9 g, 10 mmol) were added and reacted at 40 ° C for 30 minutes. After cooling to room temperature, an aqueous solution of sodium hydrogencarbonate (1.34 g, 16 mmol) (20 mL) was added, and the mixture was stirred for 10 min, and then a solution of sodium hydrogencarbonate (40 mL), ethyl acetate (60 mL×2) The aqueous sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure. <["""""""""""" -Hydroxy-4H-1,4-benzoxazin-3-one (12A) (0.68 g, 2 mmol), methanol (15 mL) and dichloromethane (15 mL). Sodium borohydride (1.27 g, 6 mmol) was added and the reaction was continued for 3 h. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[3-[2-[[(2)) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]B -methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[ c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (13B), white solid (0.81 g, yield: 45%).

LCMS m/z = 454.0 [M/2+1].

The third step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-) 4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 13)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4 -benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (5-Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino The formate (13B) (0.81 g, 0.89 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (10 mL) was added. After stirring, triethylamine trihydrofluoride (0.6 mL, 3.6 mmol) was added to the system. The reaction was carried out for 16 hours at room temperature. Saturated sodium bicarbonate after the reaction The reaction was quenched with EtOAc EtOAc (EtOAc) v/v)=1:10), the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[2-[[(2R)-2-hydroxy-2-) 5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl] Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (Compound 13), white solid (0.54 g, yield: 76%).

LCMS m/z = 792.5 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.80 (s, 1H), 9.69 (s, 1H), 8.49 (s, 1H), 7.47-7.25 (m, 7H), 7.19 (dd, J = 7.4, 3.8 Hz, 1H), 7.09 (s, 3H), 6.86 (d, J = 8.5 Hz, 1H), 6.49 (d, J = 8.4 Hz, 2H), 5.75 (s, 1H), 5.32 (s, 1H) , 5.01 (s, 2H), 4.81 (s, 1H), 4.47 (m, 2H), 3.58 (m, 3H), 3.46 (s, 2H), 2.92 (s, 1H), 2.77 (m, 2H), 2.67 (s, 3H), 2.34 (s, 2H), 2.25 (s, 2H), 2.00 (d, J = 8.1 Hz, 1H), 1.71 (s, 2H), 1.57 (s, 2H), 1.50 - 1.41 (m, 1H), 1.24 (s, 5H), 0.85 (s, 1H).

Example 14: [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 14)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

First step: [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl ]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (14A)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-) 2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-Dimethoxyethyl(methyl)amino]-3-oxo-propoxy]ethyl Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (13A) (1.26 g, 2.0 mmol) was placed in a 50 mL round bottom flask, tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (1.9 g, 10 mmol) were added and reacted at 40 ° C for 30 minutes, cooled To the room temperature, an aqueous solution of sodium hydrogencarbonate (1.34 g, 16 mmol) (20 mL) was added, and the mixture was stirred for 10 min, then aq. sodium hydrogen carbonate (40 mL), ethyl acetate (60 mL×2) Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. <RTIgt; 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H- Quinoline-2-one (1E) (0.68 g, 2 mmol), MeOH (15 mL), dichloromethane (15 mL) Reaction for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[3-[2-[[(2)) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino ]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5- N-(2-phenylphenyl)carbamate (14A), white solid (0.83 g, yield: 46%).

LCMS m/z = 451.9 [M/2+1].

The second step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 14)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (13A) (0.83 g, 0.92 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (10 mL) was added. After stirring, triethylamine trihydrofluoride (0.6 mL, 3.6 mmol) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[3-[2-[[(2)) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (Compound 13), white solid (0.52 g, yield: 72%).

LCMS m/z = 788.5 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.25 (s, 2H), 8.48 (s, 1H), 8.16 (d, J = 10.1Hz, 1H), 7.34 (m, 7H), 7.17 (m, 1H ), 7.14 - 7.00 (m, 3H), 6.90 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 11.7 Hz, 1H), 5.74 (s, 1H), 5.31 (s, 2H), 5.00 (s, 2H), 3.59 (m, 4H), 3.44 (s, 2H), 2.90 (s, 1H), 2.76 (s, 6H), 2.34 (d, J = 9.6 Hz, 2H), 2.25 (m, 2H), 2.06 - 1.90 (m, 1H), 1.69 (m, 2H), 1.55 (m, 2H), 1.50 - 1.40 (m, 1H), 1.23 (m, 4H), 0.84 (m, 1H).

Example 15: [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 15)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (15A)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[3-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (5A) (0.82 g, 1.4 mmol) placed in a 50 mL round bottom In the flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure. Toluene (20 mL) was added and then reduced. Concentrated by pressure. Methylene chloride (15 mL) and triethylamine (0.76 mL, 5.5 mmol) were added successively to the residue at 0 ° C under nitrogen, and then stirred and then added with methylaminoacetal dimethylacetal (0.32 g, 2.7 mmol) and HATU (0.63 g, 1.64 mmol) was allowed to react to room temperature for 10 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 60) gave the title compound [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2,2- Methoxyethyl (methyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentyl Dienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (15A), colorless liquid (0.78 g, yield: 88%).

LCMS m/z = 644.5 [M + 1].

Second step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl] Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (15B)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (15A) (0.78 g, 1.2 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (1.15 g, 6 mmol) were added and reacted at 40 ° C. After cooling to room temperature, aq. Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and adding 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxyl -1H-quinolin-2-one (1E) (0.4 g, 1.2 mmol), methanol (10 mL) and dichloromethane (10 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.77 g, 3.6 mmol), the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl -amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole- 5-N-(2-phenylphenyl)carbamate (15B), yellow solid (0.43 g, yield: 39%).

LCMS m/z = 458.9 [M/2+1].

The third step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 15)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( 15B) (0.43g, 0.47mmol) was placed in a 25mL round bottom flask, tetrahydrofuran (10mL) was added, and after stirring, triethylamine trihydrofluorate (0.48mL, 2.9mmol) was added to the system, and reacted at room temperature for 16 hours. . After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2) )-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy] Ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (Compound 15), white solid (0.28 g, yield: 74%).

LCMS m/z = 802.5 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.47-9.90 (m, 2H), 8.43 (s, 1H), 8.17 (d, J = 9.9Hz, 1H), 7.51-7.21 (m, 9H), 7.15 (m, 1H), 7.04 (m, 4H), 6.91 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 9.9 Hz, 1H), 5.32 (s, 2H), 4.99 (d, J = 4.7 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H), 3.57 (m, 4H), 3.17 (s, 1H), 2.90 (s, 1H), 2.83 - 2.71 (m, 4H), 2.64 ( m, 5H), 2.39 (s, 5H), 1.98 (d, J = 6.7 Hz, 3H), 1.37 - 1.15 (m, 5H).

Example 16: [(3aR,5r,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 16)

[(3aR,5r,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

First step: 3-[2-[4-[[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6, 6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (16A)

Tert-butyl 3-[2-[4-[[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[ c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoate

3-[2-[4-(Bromomethyl)phenyl]ethoxy]propanoic acid tert-butyl ester (Intermediate 5) (1.03 g, 3 mmol) and [(3aR,5r,6aS)-1,2 ,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Intermediate 1) (0.97 g, 3 mmol) was placed in a 50 mL round bottom flask, acetonitrile (30 mL) was added, water (0.5 mL) and potassium carbonate (0.83 g, 6 mmol) were added, and the system was heated to 70 ° C for 5 hours. After the reaction, saturated salt was added. Water (30 mL), methylene chloride (30 mL×2), EtOAc. /methanol (v/v) = 1:20) gave the title compound 3-[2-[4-[[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy]] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (16A) , colorless liquid (0.59 g, yield: 34%).

LCMS m/z = 585.4 [M + 1].

Second step: [(3aR,5r,6aS)-2-[[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (16B)

[(3aR,5r,6aS)-2-[[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]ethyl]phen Yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (16A) (0.59 g, 1 mmol) was placed in a 50 mL round bottom flask. Dichloromethane (10 mL) was added thereto at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was evaporated. The mixture was concentrated at room temperature for 1 hour, then concentrated under reduced pressure. Toluene (20 mL) Dichloromethane (15 mL) and triethylamine (0.2 g, 2 mmol) were added to the residue sequentially at 0 ° C under nitrogen, and then stirred and then added with methylaminoacetal dimethylacetal (0.12 g, 1 mmol) and HATU ( 0.46 g, 1.2 mmol), and allowed to react to room temperature for 1 hour. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 20) gave the title compound [(3aR,5r,6aS)-2-[[4-[2-[3-[2,2-dimethoxy] Ethylethyl (methyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene And [c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16B), colorless liquid (0.58 g, yield: 92%).

LCMS m/z = 630.4 [M + 1].

Third step: [(3aR, 5r, 6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl ]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16C)

[(3aR,5r,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-) 2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5r,6aS)-2-[[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxo-propoxy]B Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (16B) (0.58 g, 0.92 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.87 g, 4.6 mmol) were added and reacted at 40 ° C for 30 minutes. , cooled to room temperature, and added sodium bicarbonate (0.67 g, 8 mmol) The aqueous solution (10 mL) was stirred for 10 min. EtOAc EtOAc (EtOAc) 5-[2-Amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.34 g, After stirring at room temperature for 1 hour, methanol (8 mL) and dichloromethane (8 mL) were evaporated. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave the title compound [(3aR,5r,6aS)-2-[[4-[2-[3-[3-[2-[[(2)) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino ]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5- N-(2-phenylphenyl)carbamate (16C), yellow solid (0.41 g, yield: 49%).

LCMS m/z = 451.9 [M/2+1].

The fourth step: [(3aR, 5r, 6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 16)

[(3aR,5r,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16C) (0.41 g, 0.45 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.38 mL, 2.25 mmol) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2)) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (Compound 16), pale yellow solid (0.28 g, yield: 77%).

LCMS m/z = 788.5 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.29 (s, 2H), 8.51 (s, 1H), 8.18 (d, J = 9.9Hz, 1H), 7.70 (d, J = 13.5Hz, 1H), 7.48–7.26(m,9H), 7.16(d,J=4.0Hz,4H),7.07(d,J=8.1Hz,1H),6.92(d,J=8.1Hz,1H),6.48(d,J = 9.9 Hz, 1H), 5.01 (dd, J = 12.4, 5.4 Hz, 1H), 4.77 - 4.63 (m, 1H), 4.23 (m, 1H), 3.59 (m, 3H), 3.37 - 3.10 (m, 4H), 2.92 (s, 1H), 2.83 - 2.72 (m, 2H), 2.72 - 2.60 (m, 3H), 2.40 (m, 2H), 2.32 (m, 4H), 2.08 - 1.93 (m, 3H) , 1.65 (s, 1H), 1.51 (m, 1H), 1.45 - 1.34 (m, 1H), 1.27 (d, J = 18.9 Hz, 4H).

Example 17: [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 17)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

First step: 3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6, 6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propionic acid (17A)

3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -2-yl]methyl]phenyl]ethoxy]propanoic acid

3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (9A) (0.40 g, 0.68 mmol) was dissolved in dichloromethane (15 mL) )in. Trifluoroacetic acid (5 mL) was added dropwise to the reaction at room temperature and stirred for 4 hr. The reaction solvent was concentrated under reduced pressure. EtOAc (EtOAc m.) Benzene Phenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy Propionate (17A) (0.36 g, yield 100%).

Second step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (17B)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid (17A) (0.36 g, 0.68 mmol) was dissolved in dichloromethane (20 mL). Methylaminoacetaldehyde dimethyl acetal (0.1 g, 0.82 mmol), triethylamine (0.34 g, 3.4 mmol), HATU (0.39 g, 1.0 mmol) was added to the reaction mixture at room temperature, and stirred at room temperature for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc m. After column chromatography (dichloromethane/methanol (v/v) = 15:1), [(3aR,5s,6aS)-2-[[4-[2-[3-[2,2-dimethyl Oxyethyl (methyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Iso[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (17B) (0.37 g, yield 88%).

Third step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl ]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (17C)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-) 2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[[4-[2-[3-[2,2-Dimethoxyethyl(methyl)amino)-3-oxo-propoxy]B Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) The carbamate (17B) (0.37 g, 0.59 mmol) was dissolved in tetrahydrofuran (15 mL), and p-toluenesulfonic acid monohydrate (0.56 g, 2.9 mmol) was added thereto, and the mixture was stirred at 40 ° C for 1 hour, and then added dropwise. The reaction was quenched with EtOAc EtOAc (EtOAc m. ) and a mixed solvent of methanol (3 mL). To this was added 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.20 g, After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (0.38 g, 1.8 mmol) was added and stirred at room temperature for 3 hr. The reaction mixture was quenched with EtOAc (EtOAc m. : methanol (v/v) = 1:0 to 8:1) to give [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2)) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl- Amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)carbamate (17C) (0.19 g, yield 36%).

LCMS m/z = 903.5 [M+2].

The fourth step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 17)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (17C) (0.19 g, 0.21 mmol) was dissolved in tetrahydrofuran (10 mL), and triethylamine trihydrofluoric acid (1.98 g, 12.3 mmol) was added to the reaction mixture and stirred at room temperature for 12 hours. A saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added dropwise, and then methanol (5 mL) (100 mL × 2), the combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and then purified by column chromatography (dichloromethane:methanol (v/v) = 1:0 to 8:1). 3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5) -yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 17) (0.11 g, yield 64%).

^{1 H NMR (400MHz, DMSO-} d6) δ10.26 (br, 1H), 8.49 (s, 1H), 8.18 (dd, J = 10.0,2.2Hz, 1H), 7.43-7.25 (m, 10H), 7.15 (d, J = 3.8 Hz, 4H), 7.07 (d, J = 8.1 Hz, 1H), 6.94 - 6.90 (dd, J = 8.0, 0.8 Hz, 1H), 6.48 (dd, J = 9.9, 2.4 Hz, 1H), 5.04–4.97 (m, 2H), 3.58 (ddd, J = 19.5, 9.5, 6.0 Hz, 6H), 3.44 (s, 3H), 3.28-3.37 (m, 4H), 2.79–2.64 (m, 8H), 2.34 (d, J = 8.6 Hz, 2H), 2.25 - 2.20 (m, 2H), 1.67-1.75 (m, 2H), 1.50-1.56 (m, 2H).

LCMS m/z = 788.4 [M + 1].

Example 18: [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 18)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[2,2-dimethoxyethyl(ethyl)amino]-3-oxo-propoxy Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (18A)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2,2-dimethoxyethyl(ethyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamate]-3,3a,4,5,6,6a-hexahydro) -1H-cyclopentadien[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (9A) (0.48 g, 0.81 mmol) was placed in a 50 mL round bottom flask. Methylene chloride (10 mL) was added thereto at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was evaporated to dryness. Dichloromethane (15 mL) and triethylamine (0.24 g, 2.4 mmol) were added to the residue under nitrogen at 0 ° C, and then stirred and then added with ethylaminoacetal dimethylacetal (refer to CN102526808) (0.13) g, 0.98 mmol) and HATU (0.38 g, 1 mmol) were allowed to react to room temperature for 20 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[2,2-dimethoxy] Ethylethyl (ethyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene And [c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (18A), colorless liquid (0.42 g, yield 80%).

Second step: [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl ]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (18B)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-) 2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[2-[3-[2,2-dimethoxyethyl(ethyl)amino)-3-oxo-propoxy]B Phenyl] Methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( 18A) (0.42 g, 0.67 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.65 g, 3.4 mmol) were added, and reacted at 40 ° C for 30 minutes, and cooled to room temperature. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) -amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.24 g, 0.72 mmol), methanol (10 mL After stirring with dichloromethane (10 mL) at room temperature for 1 hour, sodium triacetoxyborohydride (0.42 g, 2 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2)) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino ]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5- N-(2-phenylphenyl)carbamate (18B), yellow solid (0.35 g, yield: 57%).

LCMS m/z = 458.9 [M/2+1].

The third step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 18)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (18B) (0.35 g, 0.38 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added, and after stirring, triethylamine trihydrofluoric acid salt (0.4 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (dichloromethane/methanol (v/v) = 1:10) to give the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinoline) -5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a- Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 18), yellow solid (0.18 g, yield: 59%) .

LCMS m/z = 401.8 [M/2+1].

¹ H NMR (400 MHz, DMSO-d6) δ 10.21. (s, 1H), 8.50 (s, 1H), 8.18 (d, J = 9.9 Hz, 1H), 7.47 - 7.24 (m, 9H), 7.15 (m) , 4H), 7.07 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 9.9 Hz, 1H), 5.01 (s, 2H), 3.71 - 3.50 (m, 4H), 3.30 (m, 8H), 2.82 - 2.58 (m, 6H), 2.35 (d, J = 8.8 Hz, 2H), 2.21 (s, 2H), 1.78 - 1.66 (m, 2H), 1.54 (m, 2H), 1.36 (s, 1H), 1.25 (s, 3H), 1.05 (s, 1H).

Example 19: [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-isopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 19)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-isopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(isopropyl)amino]-3-oxo-propyl Oxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (19A)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(isopropyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamate]-3,3a,4,5,6,6a-hexahydro) -1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (8A) (0.55 g, 0.94 mmol) was placed in a 50 mL round bottom flask. Methylene chloride (10 mL) was added thereto at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was evaporated to dryness. Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were added to the residue under nitrogen at 0 ° C, and then stirred and then added with isopropylaminoacetaldehyde dimethylacetal (prepared by CN102526808) (0.19) g, 1.3 mmol) and HATU (0.57 g, 1.5 mmol) were allowed to react to room temperature for 20 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 80) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-dimethoxy] Ethylethyl(isopropyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (19A), colorless liquid (0.46 g, yield 70%).

Second step: [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-isopropyl-amino]-3-oxo-propoxy]ethyl]benzene Methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (19B)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-) 2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-isopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(isopropyl)amino]-3-oxo-propoxy]] Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (19A) (0.46 g, 0.7 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate were added. (0.67 g, 3.5 mmol), the reaction was carried out at 40 ° C for 30 minutes, cooled to room temperature, and then the mixture was evaporated to ethyl acetate (30 mL). Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. <RTIgt; 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H- Quinoline-2-one (1E) (0.26 g, 0.78 mmol), MeOH (10 mL), dichloromethane (10 mL) Continue to react for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[3-[2-[[(2R)-) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-isopropyl- Amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)carbamate (19B), yellow solid (0.25 g, yield: 38%).

LCMS m/z = 930.5 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-isopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 19)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-isopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-isopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]- -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (19B (0.25 g, 0.27 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.4 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[3-[2-[[(2)) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-isopropyl-amino]-3-oxo-propoxy]B Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole -5-yl]N-(2-phenylphenyl)carbamate (Compound 19), yellow solid (70 mg, yield: 30%).

LCMS m/z = 408.8 [M/2+1].

¹ H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 7.47 - 7.24 (m, 8H), 7.24 - 7.03 (m, 5H) ), 6.94 (d, J = 8.1 Hz, 1H), 6.50 (s, 1H), 5.30 (s, 1H), 5.08 (d, J = 25.5 Hz, 1H), 5.00 (s, 1H), 3.59 (m) , 3H), 3.45 (s, 2H), 3.26–3.15 (m, 2H), 2.90–2.61 (m, 6H), 2.40–2.30 (m, 2H), 2.24 (s, 2H), 2.07–1.94 (m) , 1H), 1.70 (s, 2H), 1.56 (s, 2H), 1.35 (s, 2H), 1.23 (m, 6H), 1.15 - 0.99 (m, 6H).

Example 20: [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 20)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(cyclopropylmethyl)amino)-3-oxo -propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -phenylphenyl)carbamate (20A)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(cyclopropylmethyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

3-[2-[3-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamic acid tert-butyl ester]-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanate (8A) (0.55 g, 0.94 mmol) was placed in a 50 mL round bottom flask. Dichloromethane (10 mL) was added thereto at 0 ° C, and trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was stirred at room temperature for 2 hours, then the mixture was concentrated under reduced pressure, toluene (20 mL), and then evaporated. Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were successively added to the residue under a nitrogen atmosphere at 0 ° C, and then stirred and then added to the mixture of propyl propylamino acetal dimethyl acetal (refer to CN102526808) 0.16 g, 1 mmol) and HATU (0.57 g, 1.5 mmol) were allowed to react to room temperature for 20 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 80) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-dimethoxy] Ethyl ethyl (cyclopropylmethyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (20A), colorless liquid (0.48 g, yield 80%).

Second step: [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (20B)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-) 2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[3-[2-[3-[2,2-dimethoxyethyl(cyclopropylmethyl)amino)-3-oxo-propoxy Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (20A) (0.48 g, 0.72 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.67 g, 3.5 mmol) were added at 40 ° C The reaction was allowed to proceed for 30 minutes, cooled to room temperature, and saturated sodium bicarbonate solution (20) was added. The reaction was quenched with ethyl acetate (30 mL×2). EtOAcjjjjjjjjjjjjjjjj (Methyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.26 g, 0.78 mmol), MeOH (10 mL) and dichloromethane (10 mL) After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.53 g, 2.5 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[3-[2-[[(2R)-) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl A -amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole -5-yl]N-(2-phenylphenyl)carbamate (20B), yellow solid (0.23 g, yield: 30%).

LCMS m/z = 471.9 [M/2+1].

The third step: [(3aR, 5s, 6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 20)

[(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5s,6aS)-2-[[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl ]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (20B) (0.23 g, 0.24 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.4 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[[3-[2-[3-[3-[2-[[(2)) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy ]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Compound 20), yellow solid (80 mg, yield: 40%).

LCMS m/z = 414.8 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.33 (s, 1H), 8.49 (s, 1H), 8.19 (dd, J = 9.9,6.8Hz, 1H), 7.53-7.03 (m, 11H), 7.01 –6.87(m,1H), 6.50 (dd, J=9.8, 6.5 Hz, 1H), 5.10 (d, J=23.6 Hz, 1H), 5.00 (s, 1H), 3.71–3.52 (m, 4H), 3.46(s,3H), 3.14(m,2H), 2.77(m,13H), 2.34(s,2H), 2.25(s,2H), 2.00(m,1H),1.77(s,2H),1.55 (m, 2H), 1.23 (s, 5H).

Example 21: [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 21)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(ethyl)amino)-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (21A)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(ethyl)amino]-3-oxo-propoxy]ethyl]phen Yl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking tert-butyl 3-[2-[4-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propionate (11A) (0.46 g, 0.77 mmol) in 50 mL round In a bottom flask, dichloromethane (20 mL) was added at 0 ° C, trifluoroacetic acid (10 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was added. Concentrated by pressure. Dichloromethane (20 mL) and triethylamine (0.3 g, 3 mmol) were added to the residue under nitrogen at 0 ° C, and then stirred and then added with ethylaminoacetaldehyde dimethylacetal (prepared by CN102526808) (0.15g) , 1.1 mmol) and HATU (0.38 g, 1 mmol) were allowed to react to room temperature for 30 minutes. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2- Methoxyethyl (ethyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentyl Dienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (21A), colorless liquid (0.4 g, yield: 80%).

LCMS m/z = 658.4 [M + 1].

Second step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl] Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (21B)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(ethyl)amino)-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (21A) (0.4 g, 0.6 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate were added. (0.57 g, 3.0 mmol), the reaction was carried out at 40 ° C for 30 minutes, cooled to room temperature, and then the mixture was evaporated to dryness. The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure, and then 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quine was added to the residue. To the residue was stirred for 1 hour at room temperature and then added sodium triacetoxyborohydride (0.53 g, 2.5 mmol). Continue the reaction for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl -amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole- 5-Methoxy]N-(2-phenylphenyl)carbamate (21B), yellow solid (0.28 g, yield: 50%).

LCMS m/z = 465.9 [M/2+1].

The third step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 21)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( 21B) (0.28 g, 0.3 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.5 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (dichloromethane/methanol (v/v) = 1:10) to give the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6, 6a-Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 21), yellow solid (0.14 g, yield: 57 %).

LCMS m/z = 408.7 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ8.46 (s, 1H), 8.18 (dd, J = 9.9,1.5Hz, 1H), 7.45-7.24 (m, 8H), 7.09 (m, 5H), 6.92 (d, J = 8.1 Hz, 1H), 6.49 (dd, J = 9.9, 2.6 Hz, 1H), 5.32 (s, 1H), 5.07 - 4.97 (m, 1H), 4.77 - 4.66 (m, 1H), 3.61 (m, 2H), 3.55 (m, 2H), 3.43 - 3.17 (m, 2H), 2.73 (m, 4H), 2.70 - 2.62 (m, 4H), 2.56 (s, 3H), 2.42 (s, 4H), 2.34 (s, 2H), 1.99 (m, 2H), 1.91 (s, 1H), 1.36 (s, 1H), 1.26 (m, 7H).

Example 22: [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 22)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[cyclopropyl(2,2-dimethoxyethyl)amino]-3-oxo-propyl Oxy] Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (22A)

[(3aR,5s,6aS)-2-[[4-[2-[3-[cyclopropyl(2,2-dimethoxyethyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamate]-3,3a,4,5,6,6a-hexahydro) -1H-cyclopentadien[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propanoic acid tert-butyl ester (9A) (0.48 g, 0.81 mmol) was placed in a 50 mL round bottom flask. Methylene chloride (10 mL) was added thereto at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was evaporated to dryness. Dichloromethane (15 mL) and triethylamine (0.24 g, 2.4 mmol) were added successively to the residue under nitrogen at 0 ° C, and then stirred and then added with cyclopropylaminoacetaldehyde dimethylacetal (prepared by CN102526808) 0.15 g, 1 mmol) and HATU (0.38 g, 1 mmol) were allowed to react to room temperature for 20 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[cyclo[ -dimethoxyethyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (22A), colorless liquid (0.41 g, yield 77%).

Second step: [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]benzene Methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (22B)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-) 2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[2-[3-[cyclopropyl(2,2-dimethoxyethyl)amino]-3-oxo-propoxy]] Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (22A) (0.41 g, 0.63 mmol) was placed in a 50 mL round bottom flask, tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.61 g, 3.2 mmol) were added, and reacted at 40 ° C for 30 minutes, cooled to room temperature, and saturated. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) 1-(tert-Butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.21 g, 0.63 mmol), methanol (10 mL) Methyl chloride (10 mL) was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.42 g, 2 mmol). After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2)) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl- Amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)carbamate (22B), yellow solid (0.28 g, yield: 48%).

LCMS m/z = 464.9 [M/2+1].

The third step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 22)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]- -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (22B (0.28 g, 0.3 mmol) was placed in a 50 mL round bottom flask, tetrahydrofuran (20 mL) was added, and after stirring, triethylamine trihydrofluoric acid salt (0.4 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2)) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl -cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[ c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 22), yellow solid (0.11 g, yield: 45%).

LCMS m/z = 814.4 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ8.49 (s, 1H), 8.18 (d, J = 10.0Hz, 1H), 7.51-7.22 (m, 7H), 7.15 (s, 3H), 7.07 (d , J = 8.1 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 9.8 Hz, 1H), 5.32 (dd, J = 9.9, 4.5 Hz, 1H), 5.00 (m) , 2H), 4.45 (m, 1H), 3.63 (m, 2H), 3.56 (m, 2H), 3.41 (s, 2H), 2.71 (m, 8H), 2.34 (d, J = 8.6 Hz, 2H) , 2.21 (m, 2H), 2.00 (m, 1H), 1.73 (s, 2H), 1.55 (s, 2H), 1.36 (s, 2H), 1.23 (s, 5H), 1.01 (m, 4H)

Example 23: [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 23)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[cyclopropylmethyl(2,2-dimethoxyethyl)amino]-3-oxo) -propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -phenylphenyl)amino Formate (23A)

[(3aR,5s,6aS)-2-[[4-[2-[3-[cyclopropylmethyl(2,2-dimethoxyethyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking tert-butyl 3-[2-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamate]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenyl]ethoxy]propionate (9A) (0.48 g, 0.81 mmol) in a 50 mL round bottom flask Dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was diluted at room temperature for 2 hours. The system was concentrated under reduced pressure. Toluene (20 mL) was then evaporated. . Dichloromethane (15 mL) and triethylamine (0.24 g, 2.4 mmol) were successively added to the residue under a nitrogen atmosphere at 0 ° C, and then stirred, and then added to the mixture of propyl propylamino acetal dimethyl acetal (refer to CN102526808) (0.16 g, 1 mmol) and HATU (0.38 g, 1 mmol) were allowed to react to room temperature for 20 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[cyclo[ ,2-dimethoxyethyl)amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (23A), colorless liquid (0.39 g, yield 72%).

Second step: [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy) -2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl Phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (23B)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-) 2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[2-[3-[cyclopropylmethyl(2,2-dimethoxyethyl)amino]-3-oxo-propoxy Ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (23A) (0.39 g, 0.58 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate were added. The compound (0.57 g, 3 mmol) was reacted at 40 ° C for 30 min, cooled to rt. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. <RTIgt; 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H- Quinoline-2-one (1E) (0.24 g, 0.72 mmol), MeOH (10 mL) Continue the reaction for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2)) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl A -amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole -5-yl]N-(2-phenylphenyl)carbamate (23B), yellow solid (0.32 g, yield: 58%).

LCMS m/z = 471.9 [M/2+1].

The third step: [(3aR, 5s, 6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-) 1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 23)

[(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5 -yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5 -yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl ]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (23B) (0.32 g, 0.34 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.5 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5s,6aS)-2-[[4-[2-[3-[2-[[(2)) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy ]ethyl]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 23), yellow solid (0.14 g, yield: 50%).

LCMS m/z = 828.4 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.29 (s, 1H), 8.49 (s, 1H), 8.18 (dd, J = 9.9,3.7Hz, 1H), 7.46-7.24 (m, 9H), 7.14 (m, 4H), 7.07 (dd, J = 8.1, 3.5 Hz, 1H), 6.93 (dd, J = 8.0, 4.1 Hz, 1H), 6.49 (dd, J = 9.8, 5.5 Hz, 1H), 5.37 - 5.26 (m, 1H), 5.05 (s, 1H), 5.03 - 4.95 (m, 1H), 4.50 - 4.35 (m, 1H), 3.62 (s, 2H), 3.56 (m, 2H), 3.40 (m, 5H), 3.14 (m, 1H), 2.92 - 2.60 (m, 8H), 2.34 (d, J = 8.5 Hz, 2H), 2.23 (s, 2H), 2.07 - 1.92 (m, 1H), 1.70 (s , 2H), 1.55 (m, 2H), 1.24 (s, 7H).

Example 24: [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 24)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino)-3-oxo -propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -phenylphenyl)carbamic acid Ester (24A)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[3-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (5A) (0.43 g, 0.7 mmol) in 50 mL round bottom In the flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure. Toluene (20 mL) was added and then reduced. Concentrated by pressure. Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were successively added to the residue under a nitrogen atmosphere at 0 ° C, and then, after stirring, cyclopentylaminoacetaldehyde dimethylacetal (prepared by CN102526808) was added (0.17). g, 1 mmol) and HATU (0.38 g, 1 mmol) were allowed to react to room temperature for 10 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 60) gave the title compound [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2,2- Methoxyethyl (cyclopentyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (24A), colorless liquid (0.42 g, yield: 80%).

Second step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (24B)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5- Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino)-3-oxo-propoxy Ethyl]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (24A) (0.42 g, 0.6 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate were added. (0.57 g, 3 mmol), the reaction was carried out at 40 ° C for 30 minutes, cooled to room temperature, and then added to a saturated sodium hydrogen carbonate solution (20 mL), and the mixture was evaporated, ethyl acetate (30 mL × 2) The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. <[""""""""""" -4H-1,4-benzoxazin-3-one (12A) (0.2 g, 0.6 mmol), methanol (10 mL) and dichloromethane (10 mL). Sodium hydride (0.42 g, 2 mmol) was continued and the reaction was continued for 3 h. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino Ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (24B), white solid (0.27 g, yield: 49%).

The third step: [(3aR, 5r, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 24)

[(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(5-Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (24B) (0.27 g, 0.28 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (10 mL) was added, and after stirring, triethylamine trihydrofluorate (0.4 mL) was added to the system. The reaction was carried out for 16 hours at room temperature. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave the title compound [(3aR,5r,6aS)-2-[2-[3-[2-[3-[2-[[(2) )-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3- Oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N- (2-Phenylphenyl)carbamate (Compound 24), white solid (0.11 g, yield: 46%).

LCMS m/z = 430.8 [M/2 + 1].

Example 25: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxopropoxy]ethyl]phenyl]ethyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 25)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxopropan Oxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (25B)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

3-[2-[3-[2-[(3aR,5s,6aS)-5-[(2-Phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (6A) (0.80 g, 1.3 mmol) placed in a 50 mL round bottom In the flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was added and then reduced again. Concentrated by pressure. At 0 ° C and nitrogen Dichloromethane (15 mL) and triethylamine (0.93 mL, 6.8 mmol) were added successively to the residue, and then stirred, and then N-(2,2-dimethoxyethyl)methyl-1-amine (0.19 g) was added. , 1.6 mmol) and HATU (0.77 g, 2.0 mmol) were allowed to react to room temperature for 1 hour. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1:20) gave [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2 -dimethoxyethyl(methyl)amino]-3-oxopropoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-ring Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (25B) (0.87 g, yield: 100%).

Second step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxopropoxy]ethyl]phenyl ]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (25C)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-Dimethoxyethyl(methyl)amino)-3-oxopropoxy] Ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl The carbamate (25B) (0.87 g, 1.3 mmol) was dissolved in tetrahydrofuran (15 mL), p-toluenesulfonic acid monohydrate (1.3 g, 6.7 mmol) was added thereto, and the mixture was stirred at 40 ° C for 1 hour. The reaction was quenched with EtOAc EtOAc (EtOAc) 10 mL) and methanol (3 mL) in a mixed solvent. To this was added 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.50 g, After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (0.86 g, 4.1 mmol) was added, and stirred at room temperature for 3 hr. The reaction mixture was quenched with EtOAc (EtOAc m. : methanol (v/v) = 1:0 to 8:1) to give [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[( 2R)-2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl -amino]-3-oxopropoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)carbamate (25C) (0.73 g, yield 59%).

The third step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxopropoxy]ethyl]phenyl]ethyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 25)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxopropoxy]ethyl]phenyl]ethyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (25C) (0.73 g, 0.80 mmol) was dissolved in tetrahydrofuran (10 mL), and triethylamine trihydrofluoric acid (1.98 g, 12.3 mmol) was added to the reaction mixture and stirred at room temperature for 12 hours. A saturated aqueous solution of sodium hydrogencarbonate (50 mL), EtOAc (5 mL) Chromatography (dichloromethane:methanol (v/v) = 1:0 to 8:1) to give [(3aR,5s,6aS)-2-[2-[3-[2-[3] -[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo 1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3- Oxopropoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-( 2-Phenylphenyl)carbamate (Compound 25) (0.18 g, yield 29%).

^{1 H NMR (400MHz, DMSO-} d6) δ10.22 (br, 1H), 8.49 (s, 1H), 8.17 (d, J = 9.9Hz, 1H), 7.44-7.24 (m, 9H), 7.14 (td , J=7.5, 4.5 Hz, 1H), 7.00-7.07 (m, 4H), 6.91 (d, J=8.1 Hz, 1H), 6.48 (dd, J=9.9, 1.1 Hz, 1H), 4.94-5.02 ( m, 2H), 3.62–3.53 (m, 4H), 3.17-3.36 (m, 11H), 2.80–2.57 (m, 10H), 2.28–2.21 (m, 2H), 1.77–1.66 (m, 2H), 1.57–1.48 (m, 2H).

LCMS m/z = 803.5 [M+2].

Example 26: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 26)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propan Oxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (26A)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5- Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxo-propoxy) ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (25B) (0.38 g, 0.59 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.57 g, 3 mmol) were added and reacted at 40 ° C. The mixture was cooled to room temperature, and aq. The aqueous sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure. <["""""""""""" -Hydroxy-4H-1,4-benzoxazin-3-one (12A) (0.2 g, 0.6 mmol), methanol (10 mL) and dichloromethane (10 mL). Sodium borohydride (0.42 g, 2 mmol) was continued and the reaction was continued for 3 h. After completion of the reaction, the reaction was quenched with saturated sodium hydrogen carbonate solution (30 mL), dichloromethane (30mL×2) The organic phase was combined, dried over anhydrous sodium sulfate EtOAcjjjjjjjjjjjjjjjjjjj ,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5) -hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]benzene Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (26A), white solid (0.21 g, yield: 39%).

The second step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 26)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(5-Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy] Ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (26A) (0.21 g, 0.23 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (10 mL) was added, and after stirring, triethylamine trihydrofluorate (0.4 mL) was added to the system at room temperature. The reaction was continued for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) to give the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2) )-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo -Phenoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-( 2-Phenylphenyl)carbamate (Compound 26), white solid (0.28 g, yield: 74%).

LCMS m/z = 403.8 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.80 (s, 2H), 8.49 (s, 1H), 7.76 (s, 1H), 7.47-7.23 (m, 8H), 7.14 (d, J = 7.3Hz , 1H), 7.10–6.95 (m, 3H), 6.92–6.76 (m, 1H), 6.49 (d, J=8.4 Hz, 1H), 5.01 (s, 1H), 4.95 (s, 1H), 4.82 ( d, J = 8.7 Hz, 1H), 4.46 (s, 2H), 3.71 - 3.49 (m, 4H), 2.94 (s, 1H), 2.82 - 2.71 (m, 3H), 2.65 (m, 4H), 2.31 – 2.22 (m, 2H), 2.04–1.93 (m, 1H), 1.74 (m, 2H), 1.53 (m, 2H), 1.48–1.40 (m, 1H), 1.35 (s, 2H), 1.32–1.15 (m, 8H).

Example 27: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 27)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino)-3-oxo -propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -phenylphenyl)carbamate (27A)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[3-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a -hexahydro-1H-cyclopenta Tert-butyl [c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoate (6A) (0.47 g, 0.8 mmol) was placed in a 50 mL round bottom flask at 0 ° C Dichloromethane (10 mL) was added, and trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Toluene (20 mL) was then evaporated. Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were successively added to the residue under a nitrogen atmosphere at 0 ° C, and then, after stirring, cyclopentylaminoacetaldehyde dimethylacetal (prepared by CN102526808) was added (0.17). g, 1 mmol) and HATU (0.38 g, 1 mmol) were allowed to react to room temperature for 10 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 60) gave the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2- Methoxyethyl (cyclopentyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (27A), colorless liquid (0.45 g, yield: 83%).

LCMS m/z = 698.4 [M + 1].

Second step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (27B)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5- Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino)-3-oxo-propoxy Ethyl]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (27A) (0.45 g, 0.64 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.61 g, 3.2 mmol) were added at 40 ° C. After reacting for 30 minutes, the mixture was cooled to room temperature, and aqueous sodium hydrogen sulfate (0.42 g, 5 mmol) (10 mL) was added, and the mixture was stirred for 10 min, then brine (20 mL), ethyl acetate (30 mL×2) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and adding 8-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl] -5-Hydroxy-4H-1,4-benzoxazin-3-one (12A) (0.19 g, 0.56 mmol), methanol (10 mL) and dichloromethane (10 mL). Sodium acetoxyborohydride (0.42 g, 2 mmol) was continued for 3 hours. After completion of the reaction, the reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 15) gave the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[ (2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl Amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (27B), white solid (0.25 g, yield: 40%).

The third step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 27)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(5-Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (26B) (0.25 g, 0.26 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (10 mL) was added, and after stirring, triethylamine trihydrofluorate (0.4 mL) was added to the system. The reaction was carried out for 16 hours at room temperature. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) to give the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2) )-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3- Oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N- (2-Phenylphenyl)carbamate (Compound 27), white solid (0.12 g, yield: 52%).

LCMS m/z = 860.5 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.81 (s, 2H), 8.49 (s, 1H), 7.54-7.25 (m, 7H), 7.14 (dd, J = 14.4,7.1Hz, 1H), 7.11 – 6.99 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 6.50 (s, 1H), 5.32 (t, J = 4.6 Hz, 1H), 5.01 - 4.91 (m, 1H), 4.81 ( s, 1H), 4.46 (s, 2H), 4.35 (s, 1H), 4.11 (s, 1H), 3.60 (m, 4H), 3.14 (s, 1H), 2.83 - 2.58 (m, 6H), 2.26 (m, 2H), 2.06–1.94 (m, 2H), 1.90 (s, 5H), 1.81–1.70 (m, 2H), 1.65 (s, 3H), 1.47 (m, 5H), 1.23 (s, 8H) ).

Example 28: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[2-(5-hydroxy-3-oxo-4H-1,4-benzene) And oxazin-8-yl)ethylamino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6 ,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 28)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)) Ethylamino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino)-3-oxo-propoxy Ethyl]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (27A) (0.45 g, 0.64 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.61 g, 3.2 mmol) were added at 40 ° C. After reacting for 30 minutes, the mixture was cooled to room temperature, and aqueous sodium hydrogen sulfate (0.42 g, 5 mmol) (10 mL) was added, and the mixture was stirred for 10 min, then brine (20 mL), ethyl acetate (30 mL×2) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and adding acetic acid of 8-(2-aminoethyl)-5-hydroxy-4H-1,4-benzoxazin-3-one to the residue. Salt (prepared by reference to WO2008075025A1) (0.27g, 1mmol), methanol (10mL), N-methylpyrrolidone (10mL) and acetic acid (0.06g, 1mmol), stirred at room temperature for 1 hour, then added sodium triacetoxyborohydride (0.42 g, 2 mmol), the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) and then purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water containing 0.1% ammonium acetate (A ), acetonitrile (B), gradient elution B content 75% to 25%, elution time 15min, flow rate 12.0mL / min, column temperature: 30 ° C), titled [[3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[2-(5-Hydroxy-3-oxo-4H-1,4-benzaldehyde) Pyrazin-8-yl)ethylamino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 28), white solid (50 mg, yield: 9%) .

LCMS m/z = 422.9 [M/2+1].

¹ H NMR (400 MHz, DMSO-d6) δ 9.84 (d, J = 14.8 Hz, 1H), 8.49 (s, 1H), 7.49 - 7.24 (m, 7H), 7.24 - 7.10 (m, 1H), 7.03 (m, 3H), 6.59 (dd, J = 21.6, 8.3 Hz, 1H), 6.43 (dd, J = 8.2, 5.7 Hz, 1H), 5.00 - 4.91 (m, 1H), 4.46 (d, J = 20.0) Hz, 2H), 3.70–3.47 (m, 4H), 3.24–3.06 (m, 4H), 3.06–2.86 (m, 2H), 2.70 (m, 6H), 2.25 (s, 2H), 2.02–1.95 ( m, 1H), 1.90 (s, 5H), 1.79 - 1.62 (m, 4H), 1.55 (m, 3H), 1.40 (m, 4H), 1.23 (s, 7H).

Example 29: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[2-(5-hydroxy-3-oxo-4H-1,4-benzene) And oxazin-8-yl)ethylamino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6, 6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 29)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)) Ethylamino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(methyl)amino)-3-oxo-propoxy) ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (25B) (0.46 g, 0.71 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.67 g, 3.5 mmol) were added and reacted at 40 ° C. After 30 minutes, the mixture was cooled to room temperature. EtOAc (EtOAc m. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. <RTI ID=0.0>> (0.27 g, 1 mmol), methanol (10 mL), N-methylpyrrolidone (10 mL) and acetic acid (0.06 g, 1 mmol), and stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (0.53 g, 2.5 mmol) Continue to react for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Purification by column chromatography (dichloromethane/methanol (v/v) = 1:15) and separation and purification by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparation column, mobile phase containing 0.1% ammonium acetate) Ionic water (A), acetonitrile (B), gradient elution B content 75% to 25%, elution time 15 min, flow rate 12.0 mL / min, column temperature: 30 ° C), the title compound [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[2-(5-Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl) Amino]ethyl-methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 29), white solid (60 mg, yield: 10%).

LCMS m/z = 395.8 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.78 (s, 1H), 8.49 (s, 1H), 7.46-7.22 (m, 8H), 7.15 (m, 1H), 7.10-6.98 (m, 3H) , 6.60 (d, J = 8.3 Hz, 1H), 6.42 (d, J = 8.2, 1H), 5.75 (s, 1H), 4.96 (s, 1H), 4.46 (d, J = 4.5 Hz, 2H), 3.64–3.52 (m, 11H), 2.92 (s, 2H), 2.81–2.53 (m, 12H), 2.27 (m, 2H), 2.07–1.96 (m, 1H), 1.73 (m, 2H), 1.55 ( s, 2H), 1.24 (s, 3H).

Example 30: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 30)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

First step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopropyl)amino]-3-oxo -propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -phenylphenyl)carbamate (30A)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopropyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[3-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (6A) (0.47 g, 0.8 mmol) in 50 mL round bottom In the flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure. Toluene (20 mL) was added and then reduced. Concentrated by pressure. Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were added to the residue under nitrogen at 0 ° C, and then stirred and then added with cyclopropylaminoacetaldehyde dimethylacetal (prepared by CN102526808) (0.15) g, 1 mmol) and HATU (0.38 g, 1 mmol) were allowed to react to room temperature for 10 min. After the completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification (dichloromethane/methanol (v/v) = 1: 60) gave the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2- Methoxyethyl (cyclopropyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (30A), colorless liquid (0.43 g, yield: 83%).

LCMS m/z = 670.4 [M + 1].

Second step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (30B)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5- Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopropyl)amino)-3-oxo-propoxy Ethyl]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (30A) (0.43 g, 0.64 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.61 g, 3.2 mmol) were added at 40 ° C After reacting for 30 minutes, the mixture was cooled to room temperature, and aqueous sodium hydrogen sulfate (0.42 g, 5 mmol) (10 mL) was added, and the mixture was stirred for 10 min, then brine (20 mL), ethyl acetate (30 mL×2) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure, and adding 8-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl] -5-Hydroxy-4H-1,4-benzoxazin-3-one (12A) (Kelly Blue, Shanghai) (0.21 g, 0.64 mmol), methanol (10 mL) and dichloromethane (10 mL) After stirring for 1 hour, sodium triacetoxyborohydride (0.42 g, 2 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino Ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (30B), white solid (0.26 g, yield: 43%).

The third step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl] -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 30)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1 , 4-benzoxazin-8-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(5-Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (30B) (0.28 g, 0.3 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (10 mL) was added, and after stirring, triethylamine trihydrofluorate (0.4 mL) was added to the system. The reaction was carried out for 16 hours at room temperature. After completion of the reaction, the reaction was quenched with EtOAc EtOAc (EtOAc) The residue was purified by EtOAc EtOAcjjjjjjjjjjj [3-[2-[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]ethyl -cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[ c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 30), white solid (0.12 g, yield: 49%).

LCMS m/z = 832.4 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.85 (s, 2H), 8.50 (s, 1H), 7.34 (m, 8H), 7.25-7.11 (m, 1H), 7.11-6.99 (m, 3H) , 6.88 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 5.32 (m, 1H), 5.01 - 4.95 (m, 1H), 4.87 (s, 1H), 4.48 ( s, 2H), 4.42 (s, 3H), 3.54 (m, 7H), 2.75 (m, 9H), 2.30 (s, 2H), 2.00 (m, 1H), 1.74 (s, 2H), 1.54 (s) , 2H), 1.30–1.19 (s, 8H).

Example 31: [(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quine)啉-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 31)

[(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

First step: (Z/E)-3-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]prop-2-enoic acid tert-butyl ester (31A)

Tert-butyl(Z/E)-3-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H -cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]prop-2-enoate

[(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Intermediate 2) (2.87 g, 8.9 mmol) and (Z/E)-3-(4-formylphenoxy)prop-2-enoic acid tert-butyl ester (Intermediate 8) (2.2 g, 8.9 mmol) was placed in a 50 mL round bottom flask, methanol (30 mL) was added, dichloromethane (30 mL) was added, and the mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (5.6 g, 26.7 mmol) was added. Continue to react for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12), (Z/E)-3-[4-[[(3aR,5s,6aS)-5-[(2-benzene) Phenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]propane tert-Butyl-2-enoate (31A) (2.4 g, yield: 49%).

Second step: 3-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]propanoic acid tert-butyl ester (31B)

Tert-butyl3-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol- 2-yl]methyl]phenoxy]propanoate

(Z/E)-3-[4-[[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6, 6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]methyl]phenoxy]prop-2-enoic acid tert-butyl ester (31A) (2.4 g, 4.3 mmol) dissolved in methanol Palladium carbon (0.25 g) was added to (20 mL), and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The filtrate filtered through celite was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) = 1:12) to give 3-[4-[[( 3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] tert-Butyl pyrrol-2-yl]methyl]phenoxy]propanoate (31B) (0.9 g, yield 38%).

The third step: [(3aR, 5s, 6aS)-2-[[4-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]benzene Methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (31C)

[(3aR,5s,6aS)-2-[[4-[3-[2,2-dimethoxyethyl(methyl)amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6 ,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

3-[4-[[(3aR,5s,6aS)-5-[(2-Phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro-1H - tert-Butylcyclopenta[c]pyrrol-2-yl]methyl]phenoxy]propanoate (31B) (0.90 g, 1.6 mmol) in a 50 mL round bottom flask at 0 ° C Dichloromethane (10 mL) was added, and trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was evaporated. The mixture was concentrated at room temperature for 1 hour, then concentrated under reduced pressure. Toluene (20 mL) was then evaporated. Dichloromethane (15 mL) and triethylamine (1.1 mL, 8.1 mmol) were added to the residue sequentially at 0 ° C under nitrogen, and then stirred, and then N-(2,2-dimethoxyethyl) 1-Ammonia (0.21 g, 1.8 mmol) and HATU (0.92 g, 2.4 mmol) were allowed to react to room temperature for 1 hour. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1: 20) gave [(3aR,5s,6aS)-2-[[4-[3-[2,2-dimethoxy] as a yellow liquid. Ethyl (methyl)amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (31C) (0.93 g, yield: 96%).

Fourth step: [(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (31D)

[(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo -1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c ]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[[4-[3-[2,2-Dimethoxyethyl(methyl)amino]-3-oxo-propoxy]phenyl]- -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (31C (0.93 g, 1.6 mmol) was dissolved in tetrahydrofuran (15 mL), and p-toluenesulfonic acid monohydrate (1.47 g, 7.8 mmol) was added thereto, and the mixture was stirred at 40 ° C for 1 hour, and then a saturated aqueous solution of sodium hydrogencarbonate was added dropwise. The reaction was quenched with EtOAc (EtOAc (EtOAc) In a mixed solvent. To which 5-[2-amino-1-(tert-butyl) Methyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.52 g, 1.6 mmol), stirred at room temperature for 30 min, then sodium triacetoxyborohydride (0.99 g, 4.7 mmol), the reaction was stirred at room temperature for 3 hours and then terminated! The reaction mixture was quenched with EtOAc (EtOAc m. :methanol (v/v) = 1:0 to 8:1) gave [(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-) [tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]- 3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-( 2-phenylphenyl)carbamate (31D) (0.84 g, yield 62%)

Step 5: [(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quine啉-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 31)

[(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl) Ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[[4-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-) Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propoxy]phenyl]methyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (31D) (0.84 g, 1.0 mmol) Dissolved in tetrahydrofuran (10 mL), triethylamine trihydrofluoric acid (1.98 g, 12.3 mmol) was added to the reaction mixture and stirred at room temperature for 12 hours. A saturated aqueous solution of sodium hydrogencarbonate (50 mL), EtOAc (5 mL) Chromatography (dichloromethane:methanol (v/v) = 1:0 to 8:1) to give [(3aR,5s,6aS)-2-[[4-[3-[2-[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-methyl-amino]-3-oxo-propyl Oxy]phenyl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl Carbamate (Compound 31) (0.21 g, yield 29%).

^{1 H NMR (400MHz, DMSO-} d6) δ10.17 (s, 1H), 8.49 (s, 1H), 8.18 (dd, J = 9.9,1.5Hz, 1H), 7.44-7.26 (m, 9H), 7.16 (dd, J = 8.6, 2.5 Hz, 2H), 7.06 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 8.6, 2.5 Hz, 2H) , 6.48 (d, J = 9.9 Hz, 1H), 4.94 - 5.05 (m, 2H), 4.16 (t, J = 6.2 Hz, 2H), 3.45 - 3.09 (m, 7H), 2.90 - 2.56 (m, 8H) ), 2.33 (d, J = 8.9 Hz, 2H), 2.18-2.28 (m, 2H), 1.65-1.77 (m, 2H), 1.47-1.58 (m, 2H).

LCMS m/z = 761.4 [M+2].

Example 32: [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxy) -1H-quinolin-5-yl)ethyl]amino]ethyl-propyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 32)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-propyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

First step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(propyl)amino)-3-oxo- Propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (32A)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(propyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (11A) (0.57 g, 0.95 mmol) placed in a 50 mL round bottom In the flask, dichloromethane (15 mL) was added at 0 ° C, trifluoroacetic acid (8 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was added to continue to reduce. Concentrated by pressure. Dichloromethane (20 mL) and triethylamine (0.42 g, 4.2 mmol) were successively added to the residue under a nitrogen atmosphere at 0 ° C, and then stirred and then added with propylaminoacetal dimethylacetal (prepared by CN102526808) (0.18) g, 1.2 mmol) and HATU (0.54 g, 1.5 mmol) were allowed to react to room temperature for 10 min. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2- Methoxyethyl (propyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentyl Dienyl[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (32A), colorless liquid (0.51 g, yield 79%).

Second step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-propyl-amino]-3-oxo-propoxy]ethyl] Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (32B)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-propyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(propyl)amino)-3-oxo-propoxy) ]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (32A) (0.51 g, 0.76 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.72 g, 3.8 mmol) were added and reacted at 40 ° C. After 30 minutes, cool to room temperature and add sodium bicarbonate (0.5 g, 6 mmol) The aqueous solution (10 mL) was stirred for 10 min. EtOAc EtOAc (EtOAc) 5-[2-Amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.25 g, 0.76 mmol), methanol (8 mL) and dichloromethane (8 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.63 g, 3 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2) )-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-propyl -amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole- 5-N-(2-phenylphenyl)carbamate (32B), yellow solid (0.35 g, yield: 49%).

LCMS m/z = 472.8 [M/2+1].

The third step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-propyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 32)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-propyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate

Taking [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-propyl-amino]-3-oxo-propoxy]ethyl]phenyl] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( 32B) (0.35 g, 0.37 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added thereto, and after stirring, triethylamine trihydrofluoride (0.4 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) and then purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water containing 0.1% trifluoroacetic acid ( A), acetonitrile (B), gradient elution B content 5% ~ 50%, elution time 15min, flow rate 12mL / min, column temperature: 30 ° C) to get the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]ethyl-propyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6, 6a-Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 32), white solid (0.07 g, yield: 20%).

LCMS m/z = 415.8 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.47 (s, 2H), 9.70 (s, 1H), 8.78 (s, 1H), 8.56 (s, 1H), 8.16 (s, 1H), 7.53-7.07 (m, 10H), 6.98 (d, J = 8.1 Hz, 1H), 6.58 (t, J = 8.5 Hz, 1H), 6.17 (s, 1H), 5.28 (d, J = 8.7 Hz, 1H), 5.06 (s, 1H), 4.71 (s, 1H), 3.93 (d, J = 73.7 Hz, 12H), 3.61 (m, 4H), 3.41 (s, 1H), 3.33 - 2.97 (m, 6H), 2.79 ( m,5H), 2.74–2.54 (m, 3H), 2.13 (s, 1H), 1.86 (s, 1H), 1.65 (d, J = 14.9 Hz, 1H), 1.60–1.39 (m, 2H), 1.24 (s, 1H).

Example 33: [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxy) -1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 33 )

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

First step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(cyclopropylmethyl)amino]-3-oxyl -Phenoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-( 2-phenylphenyl)carbamate (33A)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(cyclopropylmethyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl] N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (11A) (0.57 g, 0.95 mmol) placed in a 50 mL round bottom In the flask, dichloromethane (15 mL) was added at 0 ° C, trifluoroacetic acid (8 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was added to continue to reduce. Concentrated by pressure. Dichloromethane (20 mL) and triethylamine (0.42 g, 4.2 mmol) were successively added to the residue under a nitrogen atmosphere at 0 ° C, and then stirred and then added to the mixture of propyl propylamino acetal dimethyl acetal (refer to CN102526808) (0.18 g, 1.1 mmol) and HATU (0.54 g, 1.5 mmol) were allowed to react to room temperature for 10 min. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2- Methoxyethyl (cyclopropylmethyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (33A), colorless liquid (0.54 g, yield 82%).

Second step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]B Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (33B)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(cyclopropylmethyl)amino]-3-oxo-propane Oxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (33B) (0.54 g, 0.79 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate (0.76 g, 4 mmol) were added, and reacted at 40 ° C for 30 minutes, and cooled to room temperature. After adding an aqueous solution (10 mL) of sodium hydrogencarbonate (0.5 g, 6 mmol), and stirring for 10 minutes, a saturated sodium hydrogen carbonate solution (20 mL), ethyl acetate (30 mL × 2) Filtration, concentration of the filtrate under reduced pressure, and 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinoline- 2-ketone (1E) (0.27 g, 0.79 mmol), methanol (8 mL) and dichloromethane (8 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.42 g, 2 mmol) was added to continue the reaction 3 hour. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2) -2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropane Methyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (33B), yellow solid (0.36 g, yield: 49%).

LCMS m/z = 478.9 [M/2+1].

The third step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 33 )

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

Taking [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]benzene Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid The ester (31B) (0.36 g, 0.39 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.4 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (dichloromethane/methanol (v/v) = 1:10) and then purified by liquid phase preparative column (liquid phase preparation Preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water (A) containing 0.1% trifluoroacetic acid, acetonitrile (B), gradient elution B content 5% ~ 50%, elution time 15min, flow rate 12mL /min, column temperature: 30 ° C) to give the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropylmethyl-amino]-3-oxo-propoxy]ethyl]phenyl] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate II Trifluoroacetate (Compound 31), white solid (0.13 g, yield: 32%).

LCMS m/z = 421.8 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.47 (s, 2H), 9.76 (s, 1H), 8.78 (s, 1H), 8.56 (s, 1H), 8.16 (s, 1H), 7.52-7.07 (m, 10H), 6.99 (s, 1H), 6.67 - 6.51 (m, 1H), 6.17 (s, 1H), 5.29 (d, J = 9.1 Hz, 1H), 5.06 (s, 1H), 4.72 ( s, 1H), 4.02–3.48 (m, 15H), 3.41 (s, 1H), 3.18 (m, 7H), 2.79 (m, 5H), 2.60 (m, 3H), 2.13 (s, 1H), 1.99 (s, 1H), 1.87 (s, 1H), 1.65 (d, J = 14.1 Hz, 1H), 1.47 (s, 1H), 1.20 (s, 1H).

Example 34: [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 32)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

First step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino)-3-oxo -propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -phenylphenyl)carbamate (34A)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino]-3-oxo-propoxy]ethy l]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take 3-[2-[4-[2-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a - hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propanoic acid tert-butyl ester (11A) (0.57 g, 0.95 mmol) placed in a 50 mL round bottom In the flask, dichloromethane (15 mL) was added at 0 ° C, trifluoroacetic acid (8 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was added to continue to reduce. Concentrated by pressure. Dichloromethane (20 mL) and triethylamine (0.42 g, 4.2 mmol) were successively added to the residue under a nitrogen atmosphere at 0 ° C, and then stirred and then added with cyclopentylaminoacetal dimethylacetal (prepared by CN102526808) 0.19 g, 1.1 mmol) and HATU (0.54 g, 1.5 mmol) were allowed to react to room temperature for 10 min. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1 : 80) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2- Methoxyethyl (cyclopentyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (34A), colorless liquid (0.48 g, yield 76%).

Second step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (34B)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2,2-dimethoxyethyl(cyclopentyl)amino)-3-oxo-propoxy Ethyl]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (34A) (0.48 g, 0.73 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (15 mL) and p-toluenesulfonic acid monohydrate were added. The compound (0.67 g, 3.5 mmol) was reacted at 40 ° C for 30 minutes, cooled to room temperature, and aqueous sodium hydrogen carbonate (0.5 g, 6 mmol) (10 mL) was added and stirred for 10 min. 20 mL), ethyl acetate (30 mL×2) was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-[2-amino-1-(tert-butyl) Methyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (1E) (0.24 g, 0.72 mmol), methanol (8 mL) and dichloromethane (8 mL) After 1 hour, sodium triacetoxyborohydride (0.42 g, 2 mmol) was added and the reaction was continued for 3 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2) -2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopentyl -amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole -5-yl]N-(2-phenylphenyl)carbamate (34B), yellow solid (0.27 g, yield: 40%).

LCMS m/z = 485.8 [M/2+1].

The third step: [(3aR, 5r, 6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 34)

[(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

Taking [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]ethyl]phenyl ]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (34B) (0.27 g, 0.28 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) was added. After stirring, triethylamine trihydrofluoride (0.3 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) and then purified by liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water containing 0.1% trifluoroacetic acid ( A), acetonitrile (B), gradient elution B content 5% to 50%, when eluting Between 15 min, flow rate 12 mL/min, column temperature: 30 ° C) gave the title compound [(3aR,5r,6aS)-2-[2-[4-[2-[3-[2-[[(2)) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopentyl-amino]-3-oxo-propoxy]B Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate ditrifluoroacetate (Compound 34), white solid (0.09 g, yield: 30%).

LCMS m/z = 428.8 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.47 (s, 2H), 9.78 (s, 1H), 8.78 (s, 1H), 8.59 (s, 2H), 8.18 (d, J = 10.0Hz, 1H ), 7.50–7.06 (m, 11H), 6.98 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 10.0 Hz, 1H), 6.17 (s, 1H), 5.31 (d, J = 6.9 Hz) , 2H), 5.06 (s, 1H), 4.71 (s, 1H), 4.42 (s, 1H), 4.17 (d, J = 8.0 Hz, 1H), 3.83 (s, 2H), 3.71 - 3.53 (m, 4H), 3.45 (s, 2H), 3.13 (m, 5H), 2.80 (m, 4H), 2.65 (m, 3H), 2.11 (s, 1H), 2.00 (m, 1H), 1.86 (d, J) = 6.5 Hz, 1H), 1.79 (s, 1H), 1.65 (d, J = 13.1 Hz, 3H), 1.49 (s, 4H), 1.24 (s, 3H).

Example 35: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]-ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 35)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

First step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(ethyl)amino]-3-oxo-propyl Oxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-benzene Phenyl)carbamate (35A)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(ethyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking tert-butyl 3-[2-[3-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propionate (6A) (0.48 g, 0.8 mmol) in 50 mL round In a bottom flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was added. Concentrate under reduced pressure. Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were added successively to the residue under nitrogen at 0 ° C, and then stirred and then added with ethylaminoacetal dimethylacetal (prepared by CN102526808) (0.14 g) , 1 mmol) and HATU (0.38 g, 1 mmol), and allowed to react to room temperature for 10 minutes. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1: 60) gave the title compound [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2- Methoxyethyl (ethyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (35A), colorless liquid (0.48 g, yield: 92%).

Second step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]-ethyl-ethyl-amino]-3-oxo-propoxy]ethyl Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (35B)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(ethyl)amino]-3-oxo-propoxy]] Ethyl]phenyl] Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ( 35A) (0.48 g, 0.73 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.68 g, 3.6 mmol) were added and reacted at 40 ° C for 30 minutes, and cooled to room temperature. After adding an aqueous solution (10 mL) of sodium hydrogencarbonate (0.5 g, 6 mmol), and the mixture was stirred for 10 minutes, then brine (20 mL), ethyl acetate (30 mL×2) The filtrate was concentrated under reduced pressure, and 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinoline-2- was added to the residue. Ketone (1E) (0.24 g, 0.73 mmol), methanol (10 mL) and dichloromethane (10 mL), EtOAc (EtOAc) After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15), [[3aR,5s,6aS)-2-[2-[3-[2-[3-[3-[2-[[(2R)-) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]-ethyl-ethyl- Amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5 N-(2-phenylphenyl)carbamate (35B), yellow solid (0.25 g, yield: 37%).

LCMS m/z = 466.0 [M/2+1].

The third step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]-ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 35)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]-ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl ]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (35B) (0.25 g, 0.27 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (10 mL) was added and stirred, and then triethylamine trihydrofluoric acid salt (0.4 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) and then purified by liquid phase preparative column (liquid phase preparation conditions: C18 reversed phase The column was prepared. The mobile phase was deionized water (A) containing 0.1% trifluoroacetic acid, acetonitrile (B), gradient elution, B content 5% to 50%, elution time 15 min, flow rate 12 mL/min, column temperature: 30 ° C) to give [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]-ethyl-ethyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate trifluoroacetate (compound 35), White solid (0.12 g, yield: 43%).

LCMS m/z = 816.5 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.47 (s, 2H), 9.86 (s, 1H), 8.62 (m, 3H), 8.18 (d, J = 10.0Hz, 1H), 7.51-7.23 (m , 8H), 7.23 - 7.05 (m, 4H), 6.98 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 9.6 Hz, 1H), 6.16 (s, 1H), 5.41 - 5.23 (m, 1H), 5.08 (d, J = 5.7 Hz, 1H), 4.99 (s, 1H), 3.78 (s, 4H), 3.38 (m, 5H), 3.14 (m, 4H), 2.90 (s, 3H), 2.77 (m, 3H), 2.57 (t, J = 6.7 Hz, 2H), 2.00 (m, 1H), 1.88 (s, 1H), 1.76 (s, 1H), 1.69 (s, 2H), 1.24 (s) , 3H), 1.09 (s, 2H).

Example 36: [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]-ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 36 )

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

First step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopropyl)amino]-3-oxo -propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -phenylphenyl)carbamate (36A)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopropyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Taking tert-butyl 3-[2-[3-[2-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]ethyl]phenyl]ethoxy]propionate (6A) (0.48 g, 0.8 mmol) in 50 mL round In a bottom flask, dichloromethane (10 mL) was added at 0 ° C, trifluoroacetic acid (5 mL) was added dropwise to the system, and the mixture was added dropwise. After reacting at room temperature for 1 hour, the system was concentrated under reduced pressure, and then toluene (20 mL) was added. Concentrate under reduced pressure. Dichloromethane (15 mL) and triethylamine (0.3 g, 3 mmol) were added to the residue under nitrogen at 0 ° C, and then stirred and then added with cyclopropylaminoacetaldehyde dimethylacetal (prepared by CN102526808) (0.15) g, 1 mmol) and HATU (0.38 g, 1 mmol) were allowed to react to room temperature for 10 min. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated. Purification (dichloromethane/methanol (v/v) = 1:60) gave [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxy] Ethyl ethyl (cyclopropyl)amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Alkeno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (36A), colorless liquid (0.38 g, yield: 72%).

Second step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]] Oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]-ethyl-cyclopropyl-amino]-3-oxo-propoxy]B Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (36B)

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2,2-dimethoxyethyl(cyclopropyl)amino)-3-oxo-propoxy Ethyl]ethyl] Phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate The acid ester (36A) (0.38 g, 0.57 mmol) was placed in a 50 mL round bottom flask, and tetrahydrofuran (20 mL) and p-toluenesulfonic acid monohydrate (0.57 g, 3 mmol) were added and reacted at 40 ° C for 30 minutes, cooled to After adding an aqueous solution (10 mL) of sodium hydrogencarbonate (0.42 g, 5 mmol), and stirring for 10 minutes, the mixture was added with saturated brine (20 mL), ethyl acetate (30 mL×2) Filtration, concentration of the filtrate under reduced pressure, and 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinoline- 2-ketone (1E) (0.19 g, 0.57 mmol), methanol (10 mL) and dichloromethane (10 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.42 g, 2 mmol) hour. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:15), [[3aR,5s,6aS)-2-[2-[3-[2-[3-[3-[2-[[(2R)-) 2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]-ethyl-cyclopropyl -amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole- 5-Methoxy]N-(2-phenylphenyl)carbamate (36B), yellow solid (0.16 g, yield: 30%).

LCMS m/z = 471.9 [M/2+1].

The third step: [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]-ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a, 4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 36 )

[(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin) -5-yl)ethyl]amino]ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol -5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

Take [(3aR,5s,6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy)- 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]-ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]benzene Ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid The ester (36B) (0.16 g, 0.17 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (10 mL) was added. After stirring, triethylamine trihydrofluoride (0.3 mL) was added to the system, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (dichloromethane/methanol (v/v) = 1:10) and then purified by liquid phase preparative column (liquid Phase preparation conditions: C18 reverse phase preparative column, mobile phase is deionized water (A) containing 0.1% trifluoroacetic acid, acetonitrile (B), gradient elution, B content 5% to 50%, elution time 15 min, flow rate 12 mL/min, column temperature: 30 ° C) gave [(3aR, 5s, 6aS)-2-[2-[3-[2-[3-[2-[[(2R)-2-hydroxy-2-) 8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]-ethyl-cyclopropyl-amino]-3-oxo-propoxy]ethyl]phenyl]B -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Fluoroacetate (Compound 36), white solid (0.05 g, yield: 28%).

LCMS m/z = 828.5 [M + 1].

Biological test case

Test Example 1: Inhibitory activity against human muscarinic M3 receptor

CHO cells (PerkinElmer, ES-212-AF) stably expressing human muscarinic receptor 3 (hM3) and apo-Aequorin were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141), 400 μg/mL G418 (sigma G5013) and 250 μg/mL Zeocin (invivogen ant-zn-5p) in Ham'S F12 medium (Invitrogen 12500-062), cultured at 37 ° C, 5% CO ₂ to achieve 90-100% confluence. The cells were washed with PBS/5 mM EDTA, collected by centrifugation, resuspended in 0.1% BSA (BOVOGEN BSAS 100) phenol red-free Ham's F12 medium (Invitrogen 11039-021) and counted, and the cell concentration was adjusted to 1×10 ⁶ cells/mL. . 15 ml of the cell suspension was added to a 50 mL centrifuge tube and Coelenterazine-h (promega S2011) was added to a final concentration of 5 μM. It was wrapped in tin foil and protected from light and incubated for 4 hours at 20 ° C in a rotary shaker. The cells were diluted with 0.1% BSA/phenol red-free Ham's F12 medium to a final concentration of 5.0×10 ⁵ cells/mL, and the cells were placed on a rotary shaker at low speed and incubated at room temperature for at least 1 hour. The compound of the example was prepared as a 10 mM mother liquor in DMSO, diluted with 0.1% BSA/phenol red free Ham's F12 medium (log (M): -7, -8, -9, -10, -11), and added to a 96-well plate. 50 μL per well. An additional 50 μL of cell suspension (25,000 cells/well) was added to each well and incubated for 15 minutes at room temperature. The 96-well plate was placed in a microplate reader (Perkin Elmer, Envision), and 50 μL of acetylcholine chloride (Sigma A6625) solution was added to each well of the microplate reader at a concentration of 112.92 nM (hM3), and the luminescence was recorded for 20 seconds. The IC _{50 was} calculated and analyzed using origin 7.5. The inhibitory activity of the muscarinic receptor of the compound of the present invention was measured by the above experiment, and the measured IC ₅₀ values are shown in Table 1 below.

Table 1 Results of inhibitory activity of test compounds on human muscarinic M3 receptor

Compound number	hM3 receptor IC 50 (nM)	Compound number	hM3 receptor IC 50 (nM)
1	13.64	18	2.4
2	8.54	19	6.08
3	1.09	twenty one	2.83

4	4.33	twenty two	3.96
5	23.84	twenty three	6.02
6	28.27	25	1.69
9	21.31	26	0.99
10	0.87	27	15.51
11	0.96	29	12.24
12	0.64	30	4.71
13	1.77	31	10.67
14	2.44	32	3.33
15	1.79	33	14.77
16	27.94	34	10.43
17	1.52	-	-

Conclusion: The compounds of the present invention have significant inhibitory activity against the human muscarinic M3 receptor.

Test Example 2: Agonistic activity on human adrenergic β2 receptor

The agonistic activity of the example compounds on human adrenergic receptors was determined by LANCE Ultra cAMP Assay.

CHO cells (PerkinElmer, ES-034-CF) stably expressing human adrenergic receptor (hβ2) were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141) and 250 μg/mL Zeocin (InvivoGen ant-zn) -5p) MEM-alpha medium (Invitrogen 12561-056), cultured at 37 ° C, 5% CO ₂ , 90-100% confluence, and assayed with LANCE Ultra cAMP Assay kit (PerkinElmer TRF0263) The agonistic effect of cAMP. The cells were detached with PBS/5 mM EDTA, collected by centrifugation, and resuspended in a Stimulation Buffer (1 x HBSS, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4) to adjust the cell concentration to 6 × 10 ⁵ cells/ml. . The compound of the Example was prepared as a 10 mM stock solution in DMSO, diluted with a Stimulation Buffer gradient, and added to a 384-well plate at 5 μl per well. Add 5 μL of cell suspension (3000 cells/well) to each well, incubate for 30 minutes at room temperature, add 5 μl of 4 x Eu-cAMP tracer working solution to each well, and then add 5 μl of 4 x Ulight-anti-cAMP working solution to each well. Incubate for 1 hour at room temperature. TR-FRET detection plate 384 using a plate reader (Perkin Elmer, Envision), calculated and analyzed using origin7.5 EC _50. The agonistic activity of the compounds of the present invention on human adrenergic receptors was determined by the above experiment, and the measured EC ₅₀ values are shown in Table 2:

Table 2 Results of agonistic activity of test compounds on human adrenergic β2 receptor

Compound number	Hβ2 receptor EC 50 (nM)	Compound number	Hβ2 receptor EC 50 (nM)
1	3.15	17	1.9
2	13.82	18	0.8
3	3.35	16	2.17
4	2.53	17	1.9
5	17.1	18	0.8
6	16.1	twenty one	0.75
7	10.65	twenty two	2.01
8	3.65	twenty three	2.57
9	11.2	25	9.0
11	0.93	26	0.15
12	0.15	30	1.15
13	1.41	31	3.4
14	4.81	32	0.55
16	2.17	-	-

Conclusion: The compounds of the invention have significant agonistic activity on the β2 adrenergic receptor.

Test Example 3: Methotrexate-induced inhibition of bronchial contraction in guinea pigs

Eight-week old male guinea pigs were purchased in Vitalivic, and the experiment was started after 3 days of adaptation. The test compound was formulated into a 0.6 mM stock solution using 83% absolute ethanol + 17% Tween 80. Dilute to the desired concentration with water prior to administration. Prior to administration, the animals were anesthetized with 5% isoflurane using a small animal anesthesia machine (Matrx; VME2) for an anesthesia time of 1.5 to 2 minutes. After guinea pig anesthesia, the guinea pigs were fixed on an tracheal intubation operating platform and intratracheally administered using a rat liquid aerosol administration kit (penn-century; MSA-250-R), and each guinea pig was administered with a volume of 250 μl. After administration, the guinea pig enhanced exhalation pause (PenH) value was measured using a full volume oximeter (DSI; GS220A12-R7B) at 4 hours and 24 hours. 3 mg/ml methacholine (Mch) was administered by nebulization, the atomization time was 36 seconds, and the recording time was 7 minutes. Calculate the PenH average. (Reference J Pharmacol Exp Ther 345: 260-270.). The experimental results are shown in Table 3.

PenH calculation formula: PenH=PEP/PIP*Pause; Pause=(Te-Tr)/Tr

Te: expiratory time (s)

Tr: relaxed phase time (s)

PEP: peak expiratory flow rate (ml/s)

PIP: Inspiratory peak flow rate (ml/s)

Table 3 results of inhibition of methacholine-induced bronchial contraction in guinea pigs

Conclusion: The compound of the present invention has obvious inhibitory effect on methacholine-induced bronchial contraction in guinea pigs, and some compounds still have good bronchoconstriction inhibition effect after 24 hours of administration.

Claims (14)

1. A compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof:

   

   among them:

   R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3- 6} cycloalkyl, -OR ^1a , -C(O)OR ^1b , -SR ^1c , -S(=O)R ^1d , -S(=O) ₂ R ^1e or -NR ^1f R ^1g ;

   R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ^1f and R ^1g are each independently selected from H or C _1-4 alkyl;

   W is selected from -O-, -NH- or -NC _1-4 alkyl-;

   R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

   R ³ and R ⁴ are each independently selected from H or C _1-4 alkyl;

   R ^{5 is} selected from H or OH;

   a is 0, 1, 2, 3 or 4;

   b is 0, 1, 2, 3, 4 or 5;

   c or d is independently selected from 0, 1, 2, 3 or 4;

   B is selected from

   

   

   Q is selected from -CH=CH-, -CH ₂ CH ₂ -, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH ₃ ) ₂ -;

   L is selected from

   

   The condition is that the number of connected atoms of the L shortest chain is in the range of 6 to 26;

   R ^3a , R ^3c , and R ^3d are each independently selected from a C _1-6 alkylene group, and the alkylene group is optionally further substituted with 0 to 5 R ^3e ;

   R ^{3b is} selected from C _1-6 alkylene, phenylene or 5- to 6-membered heteroarylene, and the alkylene, phenylene or heteroarylene is optionally further 0 to 4 selected from F Substituted with a substituent of Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

   R ^{3e is} selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

   Alternatively, the two R ^3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C _1-4 alkyl group or a C _1-4 alkoxy group;

   A ₁ and A ₂ are each independently selected from a C _3-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC _3-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, and a C _3-11 carbocyclic ring-O-. Or a 5- to 11-membered heterocyclic ring-O-, said carbocyclic or heterocyclic ring optionally further substituted by 0 to 5 R ⁶ , and said heterocyclic ring containing 1 to 3 selected from N, O or S Hetero atom

   X ₁ and X ₂ are each independently selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -S-, -S(=O). )-, -S(=O) ₂ -, -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O) O-, -NR ^x C(=O)NR ^x -, -NR ^x S(=O) ₂ -, -S(=O) ₂ NR ^x -, -NR ^x S(=O) ₂ NR ^x - or -NR ^x -;

   R ^{x is} each independently selected from H, C _1-6 alkyl or C _3-8 cycloalkyl, and the alkyl or cycloalkyl group is further further selected from 0 to 5 selected from F, Cl, Br, I, Substituted with a substituent of a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a C _1-4 alkoxy group;

   R ^{6 is} each independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , =0, carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(=O)-C _1-4 alkyl, -S (=O) ₂ -C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OC _1-4 alkyl, -OC(=O)-C _{1- 4-} alkyl, -C(=O)NH ₂ or 5- to 6-membered heteroaryl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, NH ₂ , -C(=O)NH ₂ or a heteroaryl group optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(=O)-C ₁ Substituted with a _-4 alkyl substituent;

   Alternatively, R ⁶ and R ^{x are} directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , = Substituted with a substituent of O, C _1-4 alkyl or C _1-4 alkoxy;

   m, n, p or q are each independently selected from 0 or 1.
2. A compound according to claim 1 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof:

   R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , NH ₂ , OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio , -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

   A ₁ and A ₂ are each independently selected from a C _5-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC _5-11 carbocyclic ring, a -O-5 to 11 membered heterocyclic ring, and a C _5-11 carbocyclic ring-O-. Or a 5- to 11-membered heterocyclic ring-O-, wherein said carbocyclic or heterocyclic ring is optionally further substituted with 0 to 5 R ⁶ and said heterocyclic ring contains 1 to 3 selected from N, O or S Hetero atom

   R ^{6 is} each independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , =0, carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _3-6 naphthenic , C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(=O)-C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OC _1-4 alkyl or 5- to 6-membered heteroaryl, said alkyl, alkynyl, alkane The oxy, cycloalkyl, NH ₂ or heteroaryl group is further optionally from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or - Substituted by a C(=O)-C _1-4 alkyl group;

   Alternatively, R ⁶ and R ^{x are} directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , = Substituted by a substituent of O, C _1-4 alkyl or C _1-4 alkoxy.
3. The compound according to claim 2, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein said compound is selected from the group consisting of formula (III) compound of:

   

   The condition is that the number of linking atoms of the shortest chain of R ^3a to R ^3d is in the range of 6 to 26.
4. A compound according to claim 3, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof:

   R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , NH ₂ , OH, cyano, methyl, ethyl, methoxy, ethoxy, -NHCH ₃ or -N (CH) ₃ ) ₂ ;

   W is selected from -O-, -NH- or -NCH ₃ -;

   R' and R" are each selected from the group consisting of F, Cl, Br, I, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;

   R ³ and R ⁴ are each independently selected from H, methyl or ethyl;

   B is selected from

   

   

   R ^{3a is} selected from methylene, ethylene, propylene, butylene, pentylene or

   

   The methylene, ethylene, propylene, butylene, pentylene or

   

   Optionally further substituted with 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

   R ^{3b is} selected from the group consisting of methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene, Methylene, ethylene, propylene, butylene, pentylene, phenylene, thienylene, furanyl, thiazolyl, oxazolyl or pyridylene optionally further 0 to 4 Substituted by a substituent selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

   R ^{3d is} selected from methylene, ethylene, propylene, butylene or pentylene, and the methylene, ethylene, propylene, butylene or pentylene group is optionally further 0 to Substituted by five substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy;

   A _{2 is} selected from the group consisting of a benzene ring-O-, a -O-benzene ring, a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, said benzene ring-O-, -O-benzene ring, a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring is optionally further substituted with 0 to 4 R ⁶ ;

   R ^{6 is} selected from the group consisting of F, Cl, Br, OH, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, propynyl, CHF ₂ , CF ₃ , methoxy, ethoxy, - OCHF ₂ , -OCF ₃ , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl;

   X _{1 is} selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR ^x -, -NR ^x C( =O)-, -OC(=O)NR ^x -, -NR ^x C(=O)O- or -NR ^x -;

   R ^{x is} selected from H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, said methyl, ethyl, propyl Base, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl are optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, methyl, ethyl, Substituted by cyclopropyl, cyclobutyl, cyclopentyl, methoxy or ethoxy;

   Alternatively, R ⁶ and R ^{x are} directly bonded to form a 4 to 6 membered nitrogen-containing heterocyclic ring, which is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , = Substituted by a substituent of O, methyl, ethyl, methoxy or ethoxy;

   a is 0 or 1;

   b is 0, 1 or 2;

   c or d are each independently selected from 0, 1, 2 or 3.
5. A compound according to claim 4, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein:

   R ^{3a is} selected from the group consisting of methylene, ethylene, propylene, -CH ₂ CH(CH ₃ )-, -CH(CH ₃ )CH ₂ -, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, n-n-butyl, -CH(CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -,

   

   Or pentylene;

   R ^{3b is} selected from a methylene group, an ethylene group, a propylene group, a butylene group or a pentylene group;

   R ^3c and R ^3d are each independently selected from the group consisting of methylene, ethylene, propylene, -CH ₂ CH(CH ₃ )-, -CH(CH ₃ )CH ₂ -, n-butylene, -CH ( CH ₃ )CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ - or pentylene;

   A _{2 is} selected from the group consisting of a benzene ring-O-, a -O-benzene ring, a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, said benzene ring-O-, -O-benzene ring, a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring is optionally further substituted with 0 to 4 R ⁶ ;

   R ^{6 is} selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, CHF ₂ , CF ₃ , methoxy, ethoxy, -OCHF ₂ or -OCF ₃ ;

   Alternatively, R ⁶ and R ^{x are} directly bonded to form a 4 to 6 membered nitrogen-containing heterocyclic ring, which is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , = Substituted by a substituent of O, methyl, ethyl, methoxy or ethoxy;

   a, b, c, and d are all 0.
6. The compound according to any one of claims 1 to 5, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of:

   

   

   
7. A pharmaceutical composition, which comprises a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable Accepted salts, eutectic or prodrugs, and pharmaceutically acceptable carriers, diluents, adjuvants, vehicles or excipients; said compositions may further comprise one or more additional therapeutic agents.
8. The pharmaceutical composition according to claim 7, wherein said other therapeutic agent is selected from the group consisting of PDE4 inhibitors, M One or more of a receptor antagonist, a corticosteroid, and a β-adrenergic receptor agonist.
9. The compound of any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, or the drug of claim 7 or A composition for use in the manufacture of a medicament for the treatment of an airway obstructive disease.
10. The compound of any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, or the drug of claim 7 or A composition for use in the manufacture of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.
11. A method of treating an airway obstructive disease, the method comprising administering a compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically acceptable a salt, eutectic or prodrug, or a pharmaceutical composition according to claim 7 or 8.
12. A method of treating asthma, chronic obstructive pulmonary disease or bronchitis, the method comprising administering a compound according to any one of claims 1 to 6, or a stereoisomer, hydrate, metabolite, solvate thereof A pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition according to claim 7 or 8.
13. An intermediate for the preparation of a compound of the formula (III) or a stereoisomer thereof, which is selected from the group consisting of a compound of the formula (IV) or a stereoisomer thereof:

    

    M is selected from the group consisting of a carboxyl group, -C(=O)OC(CH ₃ ) ₃ , -X ₁ -R ^3f -CHO, -X ₁ -R ^3f -C(OC _1-4 alkyl) ₂ ;

    R ^{3f is} selected from a methylene group, an ethylene group or a propylene group;

    R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , NH ₂ , OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio , -NHC _1-4 alkyl or -N(C _1-4 alkyl) ₂ ;

    W is selected from -O-, -NH- or -NC _1-4 alkyl-;

    R' and R" are each independently selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy;

    R ^3c , R ^3d are each independently selected from a C _1-6 alkylene group, and the alkylene group is optionally further substituted with 0 to 5 R ^3e ;

    R ^{3b is} selected from C _1-6 alkylene, phenylene or 5- to 6-membered heteroarylene, and the alkylene, phenylene or heteroarylene is optionally further 0 to 4 selected from F Substituted with a substituent of Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy;

    R ^{3e is} selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene;

    Alternatively, the two R ^3e may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Substituted by a substituent of a C _1-4 alkyl group or a C _1-4 alkoxy group;

    A _{2 is} selected from a C _5-11 carbocyclic ring, a 5 to 11 membered heterocyclic ring, a -OC _5-11 carbon ring, a -O-5 to 11 membered heterocyclic ring, a C _5-11 carbon ring-O- or a 5 to 11 member a heterocyclic ring-O- wherein said carbocyclic or heterocyclic ring is optionally further substituted with 0 to 5 R ⁶ and said heterocyclic ring contains 1 to 3 heteroatoms selected from N, O or S;

    X ₁ and X ₂ are each independently selected from the group consisting of a bond, -O-, -C(=O)-, -C(=O)O-, -OC(=O)-, -S-, -S(=O). )-, -S(=O) ₂ -, -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x -, -NR ^x C(=O) O-, -NR ^x C(=O)NR ^x -, -NR ^x S(=O) ₂ -, -S(=O) ₂ NR ^x -, -NR ^x S(=O) ₂ NR ^x - or -NR ^x -;

    R ^{x is} each independently selected from H, C _1-6 alkyl or C _3-8 cycloalkyl, and the alkyl or cycloalkyl group is further further selected from 0 to 5 selected from F, Cl, Br, I, Substituted with a substituent of a C _1-4 alkyl group, a C _3-6 cycloalkyl group or a C _1-4 alkoxy group;

    R ^{6 is} each independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , =0, carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _3-6 naphthenic , C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, -S(=O)-C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OC _1-4 alkyl or 5- to 6-membered heteroaryl, said alkyl, alkynyl, alkane The oxy, cycloalkyl, NH ₂ or heteroaryl group is further optionally from 0 to 4 selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or - Substituted by a C(=O)-C _1-4 alkyl group;

    Alternatively, R ⁶ and R ^{x are} directly bonded to form a 4 to 7 membered nitrogen-containing heterocyclic ring, which is optionally further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , = Substituted with a substituent of O, C _1-4 alkyl or C _1-4 alkoxy;

    a is 0, 1, 2, 3 or 4;

    b is 0, 1, 2, 3, 4 or 5;

    c or d is independently selected from 0, 1, 2, 3 or 4.
14. The intermediate according to claim 13, which is optionally selected from one of the following compounds: