WO2017063564A1 - 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 a β ₂ -adrenal gland A novel octahydrocyclopenta[c]pyrrole derivative stimulating by a receptor receptor, or a stereoisomer, hydrate, solvate, metabolite, pharmaceutically acceptable salt, eutectic or anterior Medicine, 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:

其中：

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;

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷或R¹⁸各自独立的选自H、F、Cl、Br、I、CF₃、OH、-CH₂OH、氰基、羧基、C_1-4烷基、C_1-4烷氧基、-C(＝O)C_1-4烷基、-C(＝O)OC_1-4烷基、-NHC(＝O)H、-NHS(＝O)₂-C_1-4烷基、-NHS(＝O)₂-NH₂或-NHS(＝O)₂-NHC_1-4烷基，Q选自-CR^q1＝CR^q2-、-CR^q1R^q2CR^q3R^q4-、-O-、-S-、-OCR^q1R^q2-、-CR^q1R^q2O-、-SCR^q1R^q2-、-CR^q1R^q2S-，所述R^q1、R^q2、R^q3或R^q4各自独立的选自选自H、F、Cl、Br、I或C_1-4烷基； 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

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

条件是L最短链的连接原子数目在6至26范围内；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

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 preferred

条件是L最短链的连接原子数目在6至26范围内；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 (II) 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;

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷或R¹⁸各自独立的选自H、F、Cl、Br、I、CF₃、OH、-CH₂OH、氰基、羧基、C_1-4烷基、C_1-4烷氧基、-C(＝O)C_1-4烷基、-C(＝O)OC_1-4烷基、-NHC(＝O)H、-NHS(＝O)₂-C_1-4烷基、-NHS(＝O)₂-NH₂或-NHS(＝O)₂-NHC_1-4烷基，Q选自-CR^q1＝CR^q2-、-CR^q1R^q2CR^q3R^q4-、-O-、-S-、-OCR^q1R^q2-、-CR^q1R^q2O-、-SCR^q1R^q2-、-CR^q1R^q2S-，所述R^q1、R^q2、R^q3或R^q4各自独立的选自选自H、F、Cl、Br、I或C_1-4烷基；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

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 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. The 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 _1-4 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 _{1 is} 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, a C _5-11 carbon ring-O- or a 5 to 11 member. Heterocyclic ring-O-, preferably C _5-11 carbocyclic or 5- to 11-membered heterocyclic ring, more preferably benzene ring or 5- to 6-membered heterocyclic ring, further preferably benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring Or a pyridine ring, said carbocyclic, heterocyclic, benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring optionally further substituted by 0, 1, 2, 3, 4 or 5 R ⁶ And the heterocyclic ring contains 1 to 3 hetero atoms 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 ^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 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 (II): 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

所述的亚甲基、亚乙基、亚丙基、亚丁基、亚戊基或

任选进一步被0、1、2、3、4或5个选自F、Cl、Br、I、氰基、OH、甲基、乙基、甲氧基或乙氧基的取代基所取代；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 ^{3d is} selected from methylene, ethylene, propylene, butylene or pentylene, and the methylene, ethylene, propylene, butylene or pentylene group is further further 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 _{1 is} selected from a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, and the benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring is optionally further 0. 1, 2, 3 or 4 R ⁶ substitutions;

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 (II) 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

或亚戊基； 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 ^{3d is} 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 _{1 is} selected from a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, and the benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring is optionally further 0. 1, 2, 3, 4 or 5 R ⁶ substitutions;

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 ;

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;

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 (II) or a stereoisomer, hydrate or metabolite thereof. a solvate, a pharmaceutically acceptable salt, a co-crystal or a prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; said composition may further comprise one or A variety of other therapeutic agents; preferably, wherein the additional therapeutic agent is selected from one or more of a PDE4 inhibitor, a M receptor antagonist, a corticosteroid, and a beta-adrenoreceptor agonist.

The present invention also relates to providing a compound of the formula (I) or (II) 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 (II) 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 (II) or a stereoisomer thereof or a hydrate thereof. , metabolites, solvates, A pharmaceutically acceptable salt, eutectic or prodrug, or a pharmaceutical composition as described above.

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

M is selected from a carboxyl group, -COOC _1-4 alkyl, -X ₁ -A ₁ -CH ₂ OH, -X ₁ -A ₁ -CHO or -X ₁ -A1-1,3-dioxolan-2- base;

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 ^{3d is} selected from a C _1-6 alkylene group, and the alkylene 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, 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 is} 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, a C _5-11 carbon ring-O- or a 5 to 11 member. Heterocyclic-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 selected from N, O Or a hetero atom of 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 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.

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 The reagent (such as saturated sodium bicarbonate solution or saturated sodium carbonate solution) adjusts the pH to alkaline, and after stirring, it is extracted with an organic solvent (such as dichloromethane, ethyl acetate, etc.), and the organic phase is concentrated under reduced pressure to obtain the corresponding compound. Free base form.

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 ), tritium (T, also known as tritium), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, comprising sulfur, ³² S, ³³ S, ³⁴ S and ³⁶ S, the nitrogen isotopes ¹⁴ N and ¹⁵ comprising 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 Wait.

"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.

所述的碳环基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、-CH₂F、-CHF₂、-CF₃、-OCH₂F、-OCHF₂、-OCF₃、羟基、-SR¹⁹、硝基、氰基、异氰基、烷基、羟基烷基、烷氧基、碳环基、杂环基、C_2-8烯基、C_2-8炔基、-(CH₂)_k-C(＝O)-R¹⁹、-(CH₂)_k-C(＝O)-O-R¹⁹、-(CH₂)_k-C(＝O)-NR¹⁹R^19a、-(CH₂)_k-S(＝O)_j-R¹⁹、-O-C(＝O)-O-R¹⁹或者-NR¹⁹R^19a的取代基所取代。本文中出现的碳环基，其定义如上所述。"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.

R³、R⁴各自独立的选自H或C_1-4烷基，R⁵选自H或OH，B选自

其中Q选自-CH＝CH-、-CH₂CH₂-、-O-、-S-、-CH₂O-、-OCH₂-、-C(CH₃)₂O-或-OC(CH₃)₂-。"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 can be removed by conventional procedures or in vivo to provide 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 description

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). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) NMR instrument 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 special description in the examples, and M is mol/L.

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: N-(2-chloro-4-carbaldehydel-5-methoxy-phenyl)-4-methylamino-butanamide trifluoroacetate

N-(2-chloro-4-formyl-5-methoxy-phenyl)-4-methylamino-butanamide trifluoroacetic acid

First step: tert-butyl N-[4-[(2-chloro-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate (3c )

Tert-butyl N-[4-[(2-chloro-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate

5-(tert-Butoxycarbonyl(methyl)amino)butyric acid (3a) (prepared by reference to WO2010123766A1) (5A) (4.0 g, 18 mmol) was dissolved in dichloromethane (200 mL). 2-Chloro-5-methoxy-aniline (3b) (2.9 g, 18 mmol), triethylamine (5.6 g, 55 mmol), The reaction was quenched with EtOAc EtOAc (EtOAc m. Column chromatography (dichloromethane/methanol (v/v) = 15:1) gave t-butyl N-[4-[(2-chloro-5-methoxy-phenyl)amino] as a yellow liquid. 4-Oxo-butyl]-N-methyl-carbamate (3c) (5.3 g, yield 81%).

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

Second step: tert-butyl N-[4-[(4-bromo-2-chloro-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamic acid Ester (3d)

Tert-butyl N-[4-[(4-bromo-2-chloro-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate

tert-Butyl N-[4-[(2-chloro-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate (3c) (5.3 g, 15 mmol) was dissolved in dichloromethane (100 mL). N-Bromosuccinimide (2.8 g, 16 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc m. After column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give tert-butyl N-[4-[(4-bromo-2-chloro-5-methoxy) as a yellow liquid. -Phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate (3d) (6.5 g, yield 100%).

LCMS m/z = 457.0 [M+Na].

The third step: tert-butyl N-[4-[[2-chloro-4-(hydroxymethyl)-5-methoxy-phenyl]amino]-4-oxo-butyl]-N- Carbamate (3e)

Tert-butyl N-[4-[[2-chloro-4-(hydroxymethyl)-5-methoxy-phenyl]amino]-4-oxo-butyl]-N-methyl-carbamate

tert-Butyl N-[4-[(4-bromo-2-chloro-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate (3d (6.66g, 15.3mmol) dissolved in tetrahydrofuran (100ml), reduced to -20 ° C conditions, slowly added (15.3mL, 1M) chloroisopropyl format reagent, stirred for 1 hour, cooled to -78 ° C Butyllithium (21.4 mL, 53.5 mmol) was slowly added, then stirred for half an hour, N,N-dimethylformamide (5.59 g, 76.4 mmol) was added, and the mixture was allowed to react to room temperature for 4 hours. After cooling to -10 ° C, water (50 mL) was added to quench the reaction mixture, then the solvent was evaporated, then ethyl acetate (100 mL × 3) was added, and the combined organic phases dried over anhydrous sodium sulfate After concentration and column chromatography (petroleum ether / ethyl acetate (v / v) = 2: 1) to give tert-butyl N-[4-[[2-chloro-4-(hydroxymethyl)- 5-methoxy-phenyl]amino]-4-oxo-butyl]-N-methyl-carbamate (3e) (2.66 g, yield 45%).

LCMS m/z = 409.1 [M+Na].

Fourth step: tert-butyl N-[4-[(2-chloro-4-carbaldehyde-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-amino Formate (3f)

Tert-butyl N-[4-[(2-chloro-4-formyl-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate

tert-Butyl N-[4-[[2-chloro-4-(hydroxymethyl)-5-methoxy-phenyl]amino]-4-oxo-butyl]-N-methyl-amino A The ester (3e) (2.66 g, 6.88 mmol) was dissolved in dichloromethane (50 mL). Dess Martin oxidizing agent (5.83 g, 13.75 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc m. After column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1), tert-butyl N-[4-[(2-chloro-4-carbaldehyde-5-methoxy) as a yellow liquid Base-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate (3f) (5.5 g, yield 80%).

LCMS m/z = 407.1 [M+Na].

Step 5: N-(2-Chloro-4-carbaldehydel-5-methoxy-phenyl)-4-methylamino-butanamide trifluoroacetate (Intermediate 3)

N-(2-chloro-4-formyl-5-methoxy-phenyl)-4-methylamino-butanamide trifluoroacetic acid

tert-Butyl N-[4-[(2-chloro-4-carbaldehyde-5-methoxy-phenyl)amino]-4-oxo-butyl]-N-methyl-carbamate (3f) (4.0 g, 10 mmol) was dissolved in dichloromethane (20 mL). Trifluoroacetic acid (4 mL) was added and stirred at room temperature for 2 hr. The reaction solvent was concentrated under reduced pressure. EtOAc (EtOAc m. Methylamino-butyramide trifluoroacetate (Intermediate 3) (3.0 g, yield 100%).

LCMS m/z = 285.1 [M + 1].

Intermediate 4: N-(2-chloro-4-formyl-5-methoxy-phenyl)-5-(methyl(acryloyl)amino)pentanamide

N-(2-chloro-4-formyl-5-methoxy-phenyl)-5-(methyl(prop-2-enoyl)amino)pentanamide

First step: tert-butyl N-[5-[(2-chloro-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate (4b )

Tert-butyl N-[5-[(2-chloro-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate

5-(tert-Butoxycarbonyl(methyl)amino)propanoic acid (4a) (prepared by reference to WO2008076259A1) (8.68 g, 36 mmol) was dissolved in dichloromethane (200 mL). 2-Chloro-5-methoxy-aniline (5.8 g, 36 mmol), triethylamine (11.2 g, 110 mmol), HATU (16.8 g, 44 mmol), and then stirred at room temperature for 2 hr. The reaction was quenched with EtOAc EtOAc (EtOAc) The filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane/methanol (v/v) = 15:1) to give tert-butyl N-[5-[(2-chloro-5-) Oxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate (4b) (11.1 g, yield 81%).

LCMS m/z = 393.2 [M+Na].

Second step: tert-butyl N-[5-[(4-bromo-2-chloro-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate Acid ester (4c)

Tert-butyl N-[5-[(4-bromo-2-chloro-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate

tert-Butyl N-[5-[(2-chloro-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate (4b) (6.85 g, 18.5 mmol) was dissolved in dichloromethane (100 mL). N-bromosuccinimide (3.45 g, 19.4 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction was quenched with aq. EtOAc (EtOAc (EtOAc) After concentration and column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give tert-butyl N-[5-[(4-bromo-2-chloro-5-methoxy) as a yellow liquid. (Phenyl-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate (4c), (7.89 g, yield 95%).

LCMS m/z = 471.1 [M+Na].

The third step: tert-butyl N-[5-[(2-chloro-4-(hydroxymethyl)5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl -carbamate (4d)

Tert-butyl N-[5-[[2-chloro-4-(hydroxymethyl)-5-methoxy-phenyl]amino]-5-oxo-pentyl]-N-methyl-carbamate

tert-Butyl N-[5-[(4-bromo-2-chloro-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate ( 4c) (7.89g, 17.6mmol) dissolved in tetrahydrofuran (100ml), reduced to -20 ° C conditions, slowly added (9mL, 1M) chloroisopropyl format reagent, stirred for 1 hour, then cooled to -78 ° C, Butyllithium (26.6 mL, 66.5 mmol) was slowly added, and after stirring for half an hour, N,N-dimethylformamide (6.94 g, 95 mmol) was added, and the mixture was further reacted to room temperature for 4 hours. After cooling to -10 ° C, the reaction mixture was quenched by adding an appropriate amount of water (50 mL), then the solvent was evaporated, then ethyl acetate (100 mL×3) was added and the organic phase was dried over anhydrous sodium sulfate and filtered. After pressure concentration and column chromatography (petroleum ether / ethyl acetate (v / v) = 2:1) to give tert-butyl N-[5-[(2-chloro-4-(hydroxymethyl)) as a yellow liquid. 5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate (4d) (4d) (2.8 g, yield 37%).

LCMS m/z = 423.1 [M+Na].

The fourth step: tert-butyl N-[5-[(2-chloro-4-carbaldehyde-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate Acid ester (4e)

Tert-butyl N-[5-[(2-chloro-4-formyl-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate

tert-Butyl N-[5-[(2-chloro-4-(hydroxymethyl)5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate The ester (4d) (1.8 g, 4.49 mmol) was dissolved in dichloromethane (50 mL). Dess Martin oxidant (3.808 g, 8.98 mmol) was added at room temperature and stirred at room temperature for 2 hours. The reaction was quenched with EtOAc EtOAc (EtOAc) The filtrate was concentrated under reduced pressure and purified by column chromatography ( petroleum ether / ethyl acetate (v/v) = 4:1) to give tert-butyl N-[5-[(2-chloro-4-carbaldehyde) as a yellow liquid. 5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate (4e) (1.43 g, yield 80%).

LCMS m/z = 421.1 [M+Na].

The fifth step: N-(2-chloro-4-carbaldehyde-5-methoxy-phenyl)-5-methylamino-pentanamide. Trifluoroacetate (4f)

N-(2-chloro-4-formyl-5-methoxy-phenyl)-5-methylamino-pentanamide trifluoroaceticacid

Weighing tert-butyl N-[5-[(2-chloro-4-carbaldehyde-5-methoxy-phenyl)amino]-5-oxo-pentyl]-N-methyl-carbamate (4e) (3.7 g, 1.77 mmol), m. Trifluoroacetic acid (4 mL) was added and stirred at room temperature for 2 hr. The reaction solvent was concentrated under reduced pressure. EtOAc (EtOAc m. Methylamino-pentanamide. Trifluoroacetate (4f) (2.78 g, yield 100%).

LCMS m/z = 299.1 [M + 1].

Step 6: N-(2-Chloro-4-formyl-5-methoxy-phenyl)-5(methyl(acryloyl)amino)-pentanamide (Intermediate 4)

N-(2-chloro-4-formyl-5-methoxy-phenyl)-5-(methyl(prop-2-enoyl)amino)pentanamide

Dissolving N-(2-chloro-4-carbaldehyde-5-methoxy-phenyl)-5-methylamino-pentanamide. Trifluoroacetate (4f) (2.78 g, 9.30 mmol) in dichloro In methane (50 mL). Triethylamine (4.71 g, 46.5 mmol) and acryloyl chloride (1.01 g, 11.2 mmol) were added sequentially at room temperature and stirred at room temperature for 2 hr. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. After concentration under reduced pressure, the residue was purified (jjjjjjjjjjj -5 (methyl(acryloyl)amino)-pentanamide (Intermediate 4) (0.96 g, yield 29%).

LCMS m/z = 353.1 [M + 1].

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

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

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

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

Taking [(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (1B) (1.3 g, 4 mmol) and 5-[methyl(prop-2-enoyl)amino]pentanoic acid (0.72 g, 4 mmol) in 50 mL In a round bottom flask, tetrahydrofuran (20 mL) and triethylamine (0.81 g, 8 mmol) were added, and the mixture was heated to 50 ° C for 16 h. After completion of the reaction, the system was concentrated under reduced pressure to give 5-[3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4 ,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]propanoyl-methyl-amino]pentanoic acid (1A), (2.02 g, yield: 100%) .

LCMS m/z = 508.4 [M + 1].

The second step: [(3aR, 5s, 6aS)-2-[3-[[5-[4-(1,3-dioxolan-2-yl)anilino]-5-oxo-pentyl -Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N -(2-phenylphenyl)carbamate (1B)

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

5-[3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6 at 0 ° C under nitrogen , 6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]propanoyl-methyl-amino]pentanoic acid (1A) (2.02 g, 4.0 mmol) was placed in a 50 mL round bottom flask. Dichloromethane (20 mL) and triethylamine (0.91 g, 9 mmol) were added successively, and then stirred, and then 4-(1,3-dioxolan-2-yl)phenylamine (0.8 g, 4.8 mmol) was added sequentially. Prepared with reference to WO2012044825A1 and HATU (1.82 g, 4.8 mmol), and allowed to react to room temperature for 20 minutes. After completion of the reaction, water (30 mL) was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Purification by silica gel column chromatography (dichloromethane / methanol (v/v) = 1: 60) afforded as a brown oil as a brown oil [(3aR,5s,6aS)-2-[3-[[5-[4-( 1,3-dioxol-2-yl)anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5, 6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (1B), (2.2 g, yield: 85% ).

LCMS m/z = 655.4 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(5-Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl- Amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylbenzene Carbamate (1C)

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

[(3aR,5s,6aS)-2-[3-[[5-[4-(1,3-dioxolan-2-yl)anilinyl]-5-oxo-pentyl]- Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (1B) (0.66 g, 1 mmol) was placed in a 25 mL round bottom flask, and then acetonitrile (2 mL) was added to neutralize 1.0 M hydrochloric acid (2 mmol, 2 mL,) and heated to 50 ° C 2 hours. After the reaction, the system was concentrated under reduced pressure. EtOAc (EtOAc m. Add 8-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-5-hydroxy-4H-1,4-benzoxazine in order 3-ketone (1D) (0.34 g, 1.0 mmol) (prepared by the synthesis of intermediate 65 of WO2008149110A1), methanol (10 mL) and dichloromethane (10 mL), stirred at room temperature for 1 hour, then added triacetoxy boron Sodium hydride (0.62 g, 3.0 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) = 1:12) gave [(3aR,5s,6aS)-2-[3-[[5-[4-[[[(2)) -[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl Anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene And [c]pyrrole-5-yl N-(2-phenylphenyl)carbamate (1C), (0.49 g, yield: 53%).

LCMS m/z = 467.4 [M/2 + 1].

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

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

Take [(3aR,5s,6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5) -hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]- 3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)amino Formate (1C) (0.49 g, 0.53 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (10 mL) was added, and after stirring, triethylamine trihydrofluorate (0.5 mL) 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 [(3aR,5s,6aS)-2-[3-[[5-[4-[[[(2))) 2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl ]-Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-( 2-Phenylphenyl)carbamate (Compound 1), (0.31 g, Yield: 71%).

LCMS m/z = 410.4 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.78 (s, 2H), 8.49 (s, 1H), 7.50 (d, J = 8.4Hz, 2H), 7.41 (d, J = 7.6Hz, 2H), 7.38–7.31 (m, 5H), 7.28 (d, J = 1.8 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.48 (d, J) = 8.4 Hz, 1H), 5.75 (s, 2H), 5.02 (s, 1H), 4.95 (s, 1H), 4.86 (m, 1H), 4.43 (s, 2H), 3.17 (s, 1H), 2.93 (s, 2H), 2.77 (s, 2H), 2.30 (m, 3H), 2.22 (m, 3H), 2.07 - 1.93 (m, 1H), 1.73 (m, 3H), 1.51 (m, 7H), 1.24(s, 3H).

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

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

First step: [(3aR, 5s, 6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (2A)

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

[(3aR,5s,6aS)-2-[3-[[5-[4-(1,3-dioxolan-2-yl)anilinyl]-5-oxo-pentyl]- Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (1B) (0.66 g, 1 mmol) was placed in a 25 mL round bottom flask, and then acetonitrile (2 mL) was added to neutralize 1.0 M hydrochloric acid (2 mmol, 2 mL) and heated to 50 ° C. hour. After the reaction, the system was concentrated under reduced pressure. EtOAc (EtOAc m. Add 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (2B) (0.34 g) After stirring at room temperature for 1 hour, methanol (10 mmol), methanol (10 mL), m. 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-[[5-[4-[[[[ Tert-Butyl (dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo De-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5- N-(2-phenylphenyl)carbamate (2A), yellow Solid (0.44 g, yield: 47%).

LCMS m/z = 465.4 [M/2+1].

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

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

Take [(3aR,5s,6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propan -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (2A (0.44 g, 0.48 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (10 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), the title compound [(3aR,5s,6aS)-2-[3-[[5-[4-[[[[2] Hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]- 3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (Compound 2), yellow solid (0.17 g, yield: 39%).

LCMS m/z = 408.4 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.26 (s, 2H), 9.81 (d, J = 15.3Hz, 1H), 8.50 (s, 1H), 8.09 (dd, J = 9.9,2.3Hz, 1H ), 7.51 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 7.0 Hz, 2H), 7.36 (m, 4H), 7.29 (s, 2H), 7.22 (d, J = 8.4 Hz, 2H) ), 7.05 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.46 (dd, J = 9.8, 1.9 Hz, 1H), 5.76 (s, 2H), 5.32 (m, 1H), 5.05 (m, 1H), 4.95 (m, 1H), 3.69 (s, 2H), 2.94 (s, 1H), 2.78 (s, 1H), 2.66 (m, 2H), 2.45 - 2.37 (m, 4H), 2.33 (m, 2H), 2.23 (m, 2H), 2.06 - 1.94 (m, 1H), 1.91 (s, 1H), 1.70 (m, 2H), 1.52 (m, 6H), 1.36 (s, 1H) , 1.24 (s, 3H).

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

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

First step: 5-[3-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrol-2-yl]propanoyl-methyl-amino]pentanoic acid (3A)

5-[3-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl ]propanoyl-methyl-amino]pentanoic acid

Taking [(3aR,5r,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Intermediate 1) (1.3 g, 4 mmol) and 5-[methyl(prop-2-enoyl)amino]pentanoic acid (Kelly Blue, Shanghai) (0.72 g, 4 mmol) In a 50 mL round bottom flask, tetrahydrofuran (20 mL) and triethylamine (0.81 g, 8 mmol) were added, and the mixture was heated to 50 ° C for 16 hours. After completion of the reaction, the system was concentrated under reduced pressure to give the title compound 5-[3-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4, 5,6,6a-Hexahydro-1H-cyclopenta[c]pyrrol-2-yl]propanoyl-methyl-amino]pentanoic acid (3A), brown oil (2.02 g, yield: 100 %).

LCMS m/z = 508.4 [M + 1].

Second step: [(3aR,5r,6aS)-2-[3-[[5-[4-(1,3-dioxolan-2-yl)anilino]-5-oxo-pentyl -Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N -(2-phenylphenyl)carbamate (3B)

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

5-[3-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6 at 0 ° C under nitrogen , 6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]propanoyl-methyl-amino]pentanoic acid (3A) (2.02 g, 4.0 mmol) was placed in a 50 mL round bottom flask. Dichloromethane (20 mL) and triethylamine (0.91 g, 9 mmol) were added successively, and then stirred, and then 4-(1,3-dioxolan-2-yl)phenylamine (0.8 g, 4.8 mmol) was added sequentially. Prepared with reference to WO2012044825) and HATU (2.28 g, 6.0 mmol), and allowed to react to room temperature for 20 minutes. After completion of the reaction, 30 mL of water and 30 ml of water were added, and the mixture was combined with methylene chloride (30 mL × 2). Purification by chromatography (dichloromethane/methanol (v/v) = 1:60) to give the title compound [(3aR,5r,6aS)-2-[3-[[5-[4-(1,3-) Oxacyclo-2-yl)anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (3B), brownish yellow oil (1.2 g, yield: 46%).

LCMS m/z = 655.4 [M + 1].

The third step: [(3aR, 5r, 6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]aniline]-5-oxo-pentyl]-methyl-amino ]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (3C)

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

[(3aR,5r,6aS)-2-[3-[[5-[4-(1,3-dioxolan-2-yl)anilinyl]-5-oxo-pentyl]- Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (3B) (0.60 g, 0.92 mmol) was placed in a 25 mL round bottom flask, and then acetonitrile (2 mL) was added to neutralize 1.0 M hydrochloric acid (2 mmol, 2 mL) and heated to 50 ° C 2 hours. After the reaction, the system was concentrated under reduced pressure. EtOAc (EtOAc m. Add 8-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-5-hydroxy-4H-1,4-benzoxazine in order 3-ketone (1D) (0.34 g, 1.0 mmol), methanol (10 mL) and dichloromethane (10 mL). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.62 g, 3.0 mmol) 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,5r,6aS)-2-[3-[[5-[4-[[[[ Tert-Butyl (dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]aniline 5-[Oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[ c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (3C), white solid (0.25 g, yield: 29%).

LCMS m/z = 467.5 [M/2+1].

The fourth step: [(3aR, 5r, 6aS)-2-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 3)

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

Taking [(3aR,5r,6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5) -hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]- 3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (3C) (0.25g, 0.27mmol) was placed in a 25mL round bottom flask, tetrahydrofuran (10mL) was added, and after stirring, triethylamine trihydrofluorate (0.25mL) was added to the system and reacted at room temperature. 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10), the crude product was obtained, and the crude product was separated and purified by a liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase containing 0.1%) Deionized water (A) of trifluoroacetic acid, acetonitrile (B) containing 0.1% trifluoroacetic acid, gradient elution A: B = 95% to 80%, elution time 15 min, flow rate 12 mL/min, column temperature: 30 °C)[[3aR,5r,6aS)-2-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1) , 4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3, 3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate ( Compound 3), white solid (0.08 g, yield: 37%).

LCMS m/z = 410.4 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.07 (s, 1H), 9.95 (d, J = 12.7Hz, 2H), 9.56 (s, 1H), 9.12 (s, 1H), 8.98 (s, 1H ), 8.84 (s, 2H), 8.58 (s, 1H), 7.73 - 7.54 (m, 2H), 7.52 - 7.27 (m, 11H), 7.05 (d, J = 51.0 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.54 (d, J=8.5 Hz, 1H), 5.92 (s, 1H), 5.03 (s, 2H), 4.46 (s, 2H), 4.11 (s, 2H), 3.80 ( s, 1H), 3.27 (m, 2H), 3.16 (s, 1H), 2.95 (m, 3H), 2.90 - 2.57 (m, 6H), 2.42 - 2.30 (m, 2H), 2.24 (s, 1H) , 2.13 - 1.96 (m, 1H), 1.82 (m, 1H), 1.56 (m, 4H), 1.41 (s, 1H), 1.24 (s, 1H).

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

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

First step: [(3aR,5r,6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (4A)

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

[(3aR,5r,6aS)-2-[3-[[5-[4-(1,3-dioxolan-2-yl)anilinyl]-5-oxo-pentyl]- Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (3B) (0.66 g, 1.0 mmol) was placed in a 25 mL round bottom flask, EtOAc (2 mL) and EtOAc (2 <RTIgt; Reaction for 2 hours. After the reaction, the system was concentrated under reduced pressure. EtOAc (EtOAc m. In the middle, 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxyl was added sequentially -1H-quinolin-2-one (2B) (0.34 g, 1.0 mmol), methanol (10 mL) and dichloromethane (10 mL). 3.0 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 [(3aR,5r,6aS)-2-[3-[[5-[4-[[[(2)) -[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5 -oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole- 5-Based]N-(2-phenylphenyl)carbamate (4A) (0.53 g, yield: 57%).

LCMS m/z = 465.4 [M/2+1].

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

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

Take [(3aR,5r,6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propan -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (4A (0.53 g, 0.56 mmol) was placed in a 25 mL round bottom flask, and tetrahydrofuran (10 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 [(3aR,5r,6aS)-2-[3-[[5-[4-[[[(2))) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino ]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Compound 4) (0.33 g, yield: 72%).

LCMS m/z = 408.4 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.80 (d, J = 14.7Hz, 1H), 8.45 (s, 1H), 8.10 (dd, J = 9.9,1.7Hz, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.46 - 7.24 (m, 10H), 7.21 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H) ), 6.46 (d, J = 9.9 Hz, 1H), 5.76 (s, 2H), 5.11 - 4.99 (m, 1H), 4.68 (m, 1H), 3.67 (s, 2H), 2.94 (s, 2H) , 2.79 (s, 2H), 2.65 (m, 2H), 2.40 - 2.27 (m, 8H), 2.03 - 1.88 (m, 3H), 1.53 (m, 5H), 1.26 (m, 3H).

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

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

First step: 3-[methyl(2-acryloyl)amino]propionic acid tert-butyl ester (5B)

Tert-butyl 3-[methyl(prop-2-enoyl)amino]propanoate

tert-Butyl 3-(methylammonium)propionate (5A) (1.3 g, 8.2 mmol) was placed in a 50 mL round bottom flask at 0 ° C under nitrogen, and dichloromethane (30 mL) and acrylic acid were added sequentially. (0.72g, 10mmol), stir evenly and then add three Ethylamine (2.02 g, 20 mmol) and HATU (5.7 g, 15 mmol) were warmed to room temperature for 20 min. After the reaction was completed, water (30 mL), EtOAc (EtOAc (EtOAc) Purification by silica gel column chromatography (dichloromethane /methanol (v/v) = 1 : 100) g, yield: 72%).

Second step: N-[4-(hydroxymethyl)phenyl]-3-[methyl(2-acryloyl)amino]propanamide (5C)

N-[4-(hydroxymethyl)phenyl]-3-[methyl(prop-2-enoyl)amino]propanamide

3-[Methyl(2-acryloyl)amino]propanoic acid tert-butyl ester (5B) (0.85 g, 4.0 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) was added at 0 ° C. Trifluoroacetic acid (7 mL) was added dropwise to the system, and the mixture was diluted. After 1 hour at room temperature, the system was concentrated under reduced pressure, and dichloromethane (15 mL) and triethylamine were added to the residue under 0 ° C under nitrogen. After stirring 1.04 g, 10 mmol), isobutyl chloroformate (0.85 g, 4.0 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 30 minutes, then p-aminobenzyl alcohol (0.5 g, 4.0 mmol) was added and the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification by silica gel column chromatography (dichloromethane /methanol (v/v) = 1:60) to afford N-[4-(hydroxymethyl)phenyl]-3-[methyl(2-propene) Acyl)amino]propanamide (5C), (0.53 g, yield: 50%).

LCMS m/z = 263.1 [M + 1].

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

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

Taking [(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Intermediate 2) (0.63 g, 2 mmol) and N-[4-(hydroxymethyl)phenyl]-3-[methyl(2-acryloyl)amino]propanamide (5C) (0.53 g, 2 mmol) was placed in a 50 mL round bottom flask, tetrahydrofuran (20 mL) and triethylamine (0.4 g, 4 mmol) were added, and the system was heated to 50 ° C for 36 hours. After completion of the reaction, the system was evaporated to dryness. -2-[3-[[3-[4-(hydroxymethyl)) Anilino]-3-oxo-propyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene [c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (5D), (0.45 g, yield: 39%).

LCMS m/z = 585.3 [M + 1].

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

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

Taking [(3aR,5s,6aS)-2-[3-[[3-[4-(hydroxymethyl)anilinyl]-3-oxo-propyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (5D) (0.45 g, 0.77 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin oxidant (0.64 g, 1.5 mmol) were added to the system at 0 ° C, and reacted at room temperature for 30 minutes. Add saturated sodium thiosulfate solution (10 mL) and saturated sodium hydrogen carbonate solution (10 mL) to the system, stir for 10 minutes, extract with dichloromethane (30 mL × 2), and combine the organic phase with saturated sodium hydrogen carbonate solution (30 mL × 1), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy- -8-hydroxy-1H-quinolin-2-one (2B) (0.26 g, 0.78 mmol), methanol (15 mL), dichloromethane (15 mL) and anhydrous sodium sulfate (2.84 g, 20 mmol) After stirring for 4 hours, sodium borohydride (76 mg, 2 mmol) was added and the reaction was continued for 10 min. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjjjjjjjj Purification by chromatography (dichloromethane/methanol (v/v) = 1:12), [(3aR,5s,6aS)-2-[3-[[3-[4-[[[[ [tert-Butyl (dimethylsilyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxo代-propyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5- N-(2-phenylphenyl)carbamate (5E), yellow solid (0.48 g, yield: 69%).

LCMS m/z = 451.3 [M/2+1].

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

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

Take [(3aR,5s,6aS)-2-[3-[[3-[4-[[[(2R)-2-[tert-butyl(dimethylsilyl)oxy-2-(8-) Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxo-propyl]-methyl-amino]-3-oxo-propyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (5E) (0.48 g, 0.53 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (10 mL) was added, and after stirring, triethylamine trihydrofluoride (0.5 mL) was added to the system, and the reaction was carried out for 16 hours at room temperature. The reaction was quenched with EtOAc EtOAc (EtOAc (EtOAc) /methanol (v/v) = 1:10) to give [(3aR,5s,6aS)-2-[3-[[3-[4-[[[(2)) 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-3-oxo-propyl]-methyl-amino]-3- Oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (Compound 5) (0.22 g, yield: 52%).

LCMS m/z = 394.2 [M/2 + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.35-10.08 (s, 1H), 9.94 (d, J = 15.8Hz, 2H), 8.49 (s, 1H), 8.09 (d, J = 3.8Hz, 1H ), 7.48 (m, 2H), 7.40 (m, 2H), 7.38 - 7.30 (m, 5H), 7.27 (m, 3H), 7.22 (m, 2H), 7.05 (d, J = 8.2 Hz, 1H) , 6.90 (m, 1H), 6.45 (d, J = 9.9 Hz, 1H), 5.75 (s, 1H), 5.03 (m, 1H), 4.94 (m, 1H), 4.46 (s, 1H), 3.67 ( m, 2H), 3.61 (m, 1H), 3.53 (m, 1H), 2.98 (s, 2H), 2.79 (s, 2H), 2.62 (m, 3H), 2.21 (m, 3H), 2.06–1.92 (m, 1H), 1.73 (m, 2H), 1.51 (m, 2H), 1.23 (m, 5H).

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

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

First step: 4-[methyl(prop-2-enoyl)amino]butyric acid methyl ester (6B)

Methyl 4-[methyl(prop-2-enoyl)amino]butanoate

Methyl 4-(methylammonium)butanoate (6A) (prepared by reference to WO2015028850) (0.66 g, 5 mmol) was placed in a 50 mL round bottom flask at 0 ° C under nitrogen and dichloromethane (30 mL) And acrylic acid (0.36 g, 5 mmol), and after stirring, triethylamine (1.01 g, 10 mmol) and HATU (2.28 g, 6 mmol) were successively added, and the mixture was allowed to react at room temperature for 20 minutes. After the reaction was completed, water (30 mL), EtOAc (EtOAc (EtOAc) Purified by silica gel column chromatography (dichloroform) Methyl 4-[methyl(prop-2-enoyl)amino]butanoate (6B) (0.73 g, yield: 79%) ).

Second step: 4-[3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro -1H-cyclopentadienyl[c]pyrrol-2-yl]propionyl-methyl-amino]butyric acid methyl ester (6C)

Methyl 4-[3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2- Yl]propanoyl-methyl-amino]butanoate

Taking [(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Intermediate 2) (0.63 g, 2 mmol) and methyl 4-[methyl(prop-2-enoyl)amino]butanoate (6B) (0.37 g, 2 mmol) in 50 mL round In the bottom flask, tetrahydrofuran (20 mL) and triethylamine (0.4 g, 4 mmol) were added, and the mixture was heated to 50 ° C for 24 hours. After completion of the reaction, the system was evaporated to dryness. ,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole Methyl-2-phenyl]propanoyl-methyl-amino]butanoate (6C) (0.49 g, yield: 48%).

LCMS m/z = 508.3 [M + 1].

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

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

4-[3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro-1H- Methyl cyclopenta[c]pyrrol-2-yl]propanoyl-methyl-amino]butanoate (6C) (0.49 g, 0.97 mmol) was placed in a 50 mL round bottom flask and tert-butanol (10 mL) And water (10 mL), after stirring, add lithium hydroxide (84 mg, 2 mmol), and react at room temperature for 1 hour, then adjust the system to pH=2 with hydrochloric acid (1M), and add water (30 mL) with dichloromethane ( 30mL × 2) extraction, combined with The organic layer was washed with brine (40 mL×1), dried over anhydrous sodium sulfate After stirring uniformly, isobutyl chloroformate (0.14 g, 1 mmol) was added dropwise at 0 ° C under nitrogen. After completion of the dropwise addition, stirring at 0 ° C for 30 minutes, p-aminobenzyl alcohol (0.13 g, 1 mmol) was added, and the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:30) afforded [(3aR,5s,6aS)-2-[3-[[4-[4-(hydroxymethyl)aniline 4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[ c] Pyrrol-5-yl N-(2-phenylphenyl)carbamate (6D) as a colorless oil (0.25 g, yield: 44%).

LCMS m/z = 599.3 [M + 1].

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

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

Taking [(3aR,5s,6aS)-2-[3-[[4-[4-(hydroxymethyl)anilino]-4-oxo-butyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)carbamate ( 6D) (0.25 g, 0.42 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin oxidant (0.42 g, 1 mmol) were added to the system at 0 ° C, and reacted at room temperature for 30 minutes. Add saturated sodium thiosulfate solution (10 mL) and saturated sodium hydrogen carbonate solution (10 mL), stir for 10 minutes, then extract with dichloromethane (30 mL×2), and combine the organic phase with saturated sodium hydrogen carbonate solution (30 mL) ×1) Washing, drying over anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure, and adding 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl] -8-Hydroxy-1H-quinolin-2-one (2B) (0.15 g, 0.45 mmol), methanol (15 mL), dichloromethane (15 mL) and anhydrous sodium sulfate (2.84 g, 20 mmol) After an hour, sodium borohydride (41 mg, 1.1 mmol) was added and the reaction was continued for 10 min. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjjjjjjjj Purification by chromatography (dichloromethane/methanol (v/v) = 1:12), The target compound [(3aR,5s,6aS)-2-[3-[[4-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) (8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (6E), yellow solid (0.32 g, yield: 78%).

LCMS m/z = 458.4 [M/2+1].

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

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

Take [(3aR,5s,6aS)-2-[3-[[4-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (6E (0.32 g, 0.35 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (10 mL) was added, 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), the crude product was obtained, and the crude product was separated and purified by a liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase containing 0.1%) Deionized water (A) of trifluoroacetic acid, acetonitrile (B), gradient elution B content 5% to 50%, elution time 15 min, flow rate 12 mL/min, column temperature: 30 ° C) [[3aR, 5s ,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl) Amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H -cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 6), white solid (80 mg, yield: 20% ).

LCMS m/z = 401.4 [M/2+1].

^{1 H NMR (400MHz, DMSO)} δ10.45 (d, J = 13.1Hz, 1H), 10.04 (d, J = 24.4Hz, 1H), 9.43 (s, 1H), 8.94 (s, 1H), 8.61 ( d, J = 12.0 Hz, 1H), 8.02 (dd, J = 10.0, 5.5 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.48 - 7.25 (m, 7H), 7.11 (d, J = 8.1 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 9.9 Hz, 1H), 6.14 (s, 1H), 5.31 (m, 2H), 5.09 (s, 1H) ), 4.97 (s, 1H), 4.40 (s, 5H), 4.16 (s, 2H), 3.73 (s, 1H), 2.97 (s, 3H), 2.86 (s, 2H), 2.74 (m, 3H) , 2.38 (m, 1H), 2.31 (m, 1H), 2.00 (m, 1H), 1.85 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.46 (m, 1H), 1.24 (m, 5H).

Example 7: [(3aR,5s,6aS)-2-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]-N-methyl-anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 7)

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

First step: N-[4-(hydroxymethyl)phenyl]-N-methyl-5-[methyl(prop-2-enoyl)amino]pentanamide (7B)

N-[4-(hydroxymethyl)phenyl]-N-methyl-5-[methyl(prop-2-enoyl)amino]pentanamide

5-[Methyl(prop-2-enoyl)amino]pentanoic acid (7A) (0.22 g, 1.2 mmol) was placed in a 50 mL round bottom flask at 0 ° C under nitrogen. 15 mL), isobutyl chloroformate (0.16 g, 1.2 mmol) was added dropwise to the system, then triethylamine (0.14 g, 1.4 mmol) was added, and stirred at 0 ° C for 30 min, then [4-(methylamino)phenyl]methanol was added. (0.16 g, 1.2 mmol), and allowed to react to room temperature for 6 hours. After completion of the reaction, 30 mL of water and 30 ml of water were added, and the mixture was combined with methylene chloride (30 mL × 2). Purification by chromatography (dichloromethane/methanol (v/v) = 1: 60) afforded N-[4-(hydroxymethyl)phenyl]-N-methyl-5-[ (C2--2-enoyl)amino]pentanamide (7B) (0.3 g, yield: 80%).

LCMS m/z = 305.2 [M + 1].

Second step: [(3aR,5s,6aS)-2-[3-[[5-[4-(hydroxymethyl)-N-methyl-anilino]-5-oxo-pentyl]-A -amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (7C)

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

Taking [(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (Intermediate 2) (0.32 g, 1 mmol) and N-[4-(hydroxymethyl)phenyl]-N-methyl-5-[methyl(prop-2-enoyl) Amino]pentanamide (7B) (0.3 g, 1 mmol) was placed in a 50 mL round bottom flask, tetrahydrofuran (20 mL) and triethylamine (0.2 g, 2 mmol) were added, and the system was heated to 50 ° C for 24 hours. After completion of the reaction, the system was evaporated to dryness. -2-[3-[[5-[4-(hydroxymethyl)-N-methyl-anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl ]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (7C) (0.25 g, yield: 40%).

LCMS m/z = 627.3 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-N-methyl-anilino]-5-oxo-pentyl]-methyl- Amino]-3-oxo-propyl -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (7D )

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

Taking [(3aR,5s,6aS)-2-[3-[[5-[4-(hydroxymethyl))-N-methyl-anilino]-5-oxo-pentyl]-methyl-amino ]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (7C) (0.25 g, 0.4 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin oxidant (0.42 g, 1 mmol) were added to the system at 0 °C. After reacting for 30 minutes at room temperature, a saturated sodium thiosulfate solution (10 mL) and a saturated sodium hydrogen carbonate solution (10 mL) were added to the system, stirred for 10 minutes, and then extracted with dichloromethane (30 mL×2). The mixture was washed with a saturated aqueous solution of sodium bicarbonate (30 mL×1), 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 (2B) (0.15 g, 0.45 mmol), methanol (15 mL), dichloromethane (15 mL) and anhydrous sodium sulfate (2.84 g) After stirring at room temperature for 4 hours, sodium borohydride (41 mg, 1.1 mmol) was added and the reaction was continued for 10 min. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjjjjjjjj Chromatography (dichloromethane/methanol (v/v) = 1 : 12) to afford [(3aR,5s,6aS)-2-[3-[[5-[4-[[[ 2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- N-methyl-anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (7D) (0.38 g, yield: 90%).

The fourth step: [(3aR, 5s, 6aS)-2-[3-[[5-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]-N-methyl-anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 7)

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

Take [(3aR,5s,6aS)-2-[3-[[5-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-N-methyl-anilino]-5-oxo-pentyl]-methyl-amino]- 3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (7D) (0.38g, 0.4mmol) was placed in a 25mL round bottom flask, tetrahydrofuran (10mL) was added, and after stirring, triethylamine trihydrofluorate (0.4mL) was added to the system and reacted at room temperature. 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10) gave [(3aR,5s,6aS)-2-[3-[[5-[4-[[[(2) 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-N-methyl-anilino]-5-oxo-pentyl ]-Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N- (2-Phenylphenyl)carbamate (Compound 7) (0.13 g, Yield: 39%).

LCMS m/z = 415.3 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.26 (s, 1H), 8.50 (s, 1H), 8.12 (dd, J = 9.9,6.7Hz, 1H), 7.49-7.16 (m, 9H), 7.06 (s, 1H), 6.94–6.87 (m, 1H), 6.46 (dd, J=9.9, 2.9 Hz, 1H), 5.32 (m, 1H), 5.06 (m, 1H), 5.02–4.86 (m, 1H) ), 3.76 (s, 2H), 3.13 (s, 3H), 2.86 (s, 1H), 2.70 (m, 2H), 2.38 (m, 4H), 2.23 (m, 2H), 2.01 (m, 2H) , 1.74 (m, 2H), 1.51 (m, 2H), 1.36 (m, 3H), 1.24 (s, 3H), 0.96 (m, 7H).

Example 8: [(3aR,5s,6aS)-2-[3-[[5-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine)- 8-yl)ethylamino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 8)

[(3aR,5s,6aS)-2-[3-[[5-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethylamino]methyl]] Anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

[(3aR,5s,6aS)-2-[3-[[5-[4-(1,3-dioxolan-2-yl)anilinyl]-5-oxo-pentyl]- Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (1B) (0.66 g, 1 mmol) was placed in a 25 mL round bottom flask, and then acetonitrile (2 mL) was added to neutralize 1.0 M hydrochloric acid (2 mmol, 2 mL) and heated to 50 ° C. hour. After the reaction, the system was concentrated under reduced pressure. EtOAc (EtOAc m. In the above, 8-(2-aminoethyl)-5-hydroxy-4H-1,4-benzoxazin-3-one acetate (8A) (0.27 g, 1.0 mmol) was added in sequence (refer to WO2008075025 A1). Obtained, methanol (10 mL), N-methylpyrrolidone (10 mL), acetic acid (0.12 g, 2 mmol). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.62 g, 3.0 mmol) was added and the reaction was continued for 5 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave [(3aR,5s,6aS)-2-[3-[[5-[4-[[2-(5-hydroxy) 3-oxo-4H-1,4-benzoxazine-8-yl)ethylamino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (Compound 8) (86 mg, yield: 16%).

LCMS m/z = 402.3 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.77 (s, 2H), 9.59 (s, 1H), 8.50 (s, 2H), 7.50 (d, J = 8.4Hz, 2H), 7.45-7.24 (m , 8H), 7.20 (d, J = 8.4 Hz, 2H), 6.60 (dd, J = 8.3, 2.1 Hz, 2H), 6.42 (d, J = 8.3 Hz, 1H), 5.76 (s, 1H), 4.95 (s, 1H), 4.45 (s, 3H), 3.63 (s, 2H), 2.94 (s, 2H), 2.77 (s, 1H), 2.60 (s, 3H), 2.38 - 2.27 (m, 3H), 2.22 (m, 2H), 2.01 (m, 1H), 1.74 (m, 2H), 1.52 (m, 6H), 1.24 (s, 4H).

Example 9: [(3aR,5s,6aS)-2-[3-[[5-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-) Oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]amino]-5-oxo-phenyl]-methyl-amino]-3- Oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrolyl-5-yl]N-(2-phenylphenyl)amino Formate (compound 9)

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

First step: [(3aR, 5s, 6aS)-2-[3-[[5-[(2-chloro-4-carbaldehyde-5-methoxy-phenyl)amino]-5-oxo- Amyl]methylamino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N- (2-phenylphenyl)carbamate (9A)

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

[(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Amino group The formate (intermediate 2) (0.877 g, 2.72 mmol) was taken in 2-methyltetrahydrofuran (25 mL). N-(2-Chloro-4-formyl-5-methoxy-phenyl)-5(methyl(acryloyl)amino)-pentanamide (Intermediate 4) (0.96 g, .2.7) was added thereto in that order. Methyl), triethylamine (0.55 g, 5.4 mmol). The reaction was stirred at 60 ° C for 4 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated. After column chromatography (dichloromethane/methanol (v/v) = 15:1) to give a yellow liquid [(3aR,5s,6aS)-2-[3-[[5-[(2-chloro-4) -formaldehyde-5-methoxy-phenyl)amino]-5-oxo-pentyl]methylamino]-3-oxo-propyl]-3,3a,4,5,6,6a- Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (9A) (1.26 g, yield 69%).

LCMS m/z = 675.8 [M + 1].

The second step: [(3aR, 5s, 6aS)-2-[3-[[5-[[4-[[[(2)]-(2-tert-butyl(dimethyl)silyl)oxy) )-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]amino-5-oxo De-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5- N-(2-phenylene)carbamate (9B)

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

[(3aR,5s,6aS)-2-[3-[[5-[(2-Chloro-4-carbamoyl-5-methoxy-phenyl)amino]-5-oxo-pentyl] Methylamino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2- Phenylphenyl)carbamate (9A) (0.338 g, 0.50 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and methanol (5 mL). To this was added 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (2B) (0.167 g, After adding 0.5 g of anhydrous sodium sulfate and stirring at room temperature for 3 hours, sodium borohydride (0.057 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc (EtOAc) Separation and separation (dichloromethane:methanol (v/v) = 1:0 to 8:1) gave [(3aR,5s,6aS)-2-[3-[[5-[[4-[[ [[(2R)-(2-tert-butyl(dimethyl)silyl)oxy)-2-(8-hydroxy-2-oxo-1H-- Quinoline-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]amino-5-oxo-pentyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (9B) (0.28 g, yield 56%).

LCMS m/z = 497.4 [M/2 + 1].

The third step: [(3aR, 5s, 6aS)-2-[3-[[5-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-) Oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]amino]-5-oxo-phenyl]-methyl-amino]-3- Oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrolyl-5-yl]N-(2-phenylphenyl)amino Formate (compound 9)

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

[(3aR,5s,6aS)-2-[3-[[5-[[4-[[[(2)] -(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]amino-5-oxo-pentyl -Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c]pyrrole-5-yl]N -(2-biphenyl)carbamate (9B) (0.28 g, 0.28 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoric acid (0.12 g, 0.56 mmol). . A saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added dropwise, and the mixture was evaporated. After concentration under reduced pressure, the residue was purified (jjjjjjjjjjjjjjjjjj -[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-phenyl]amino]-5-oxo-phenyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro -1H-cyclopenta[c]pyrrolyl-5-yl]N-(2-phenylphenyl)carbamate (Compound 9) (0.11 g, yield 44%).

LCMS m/z = 880.4 [M + 1].

Example 10: [(3aR,5r,6aS)-2-[3-[[5-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine)- 8-yl)ethylamino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 10)

[(3aR,5r,6aS)-2-[3-[[5-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethylamino]methyl]] Anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclope Nta[c]pyrrol-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetic acid

[(3aR,5r,6aS)-2-[3-[[5-[4-(1,3-dioxolan-2-yl)anilinyl]-5-oxo-pentyl]- Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (3B) (0.66 g, 1 mmol) was placed in a 25 mL round bottom flask, and then acetonitrile (2 mL) was added to neutralize 1.0 M hydrochloric acid (2 mmol, 2 mL) and heated to 50 ° C. hour. After the reaction, the system was concentrated under reduced pressure. EtOAc (EtOAc m. Add 8-(2-aminoethyl)-5-hydroxy-4H-1,4-benzoxazin-3-one acetate (8A) (0.27 g, 1.0 mmol), methanol (10 mL) After stirring with N-methylpyrrolidone (10 mL) at room temperature for 1 hour, sodium triacetoxyborohydride (0.62 g, 3.0 mmol) was added and the reaction was continued for 5 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane / methanol (v / v) = 1: 12) to obtain a crude product, the crude product was separated and purified by a liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase containing 0.1% three Defluorinated water of fluoroacetic acid (A), acetonitrile (B), gradient elution B content 5% to 50%, elution time 15 min, flow rate 12 mL / min, column temperature: 30 ° C) to obtain a white solid [ 3aR,5r,6aS)-2-[3-[[5-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl) Amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 10) (104 mg, yield: 10%).

LCMS m/z = 402.3 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.03 (d, J = 16.1Hz, 1H), 9.92 (s, 1H), 9.84 (s, 1H), 9.41 (s, 1H), 8.76 (s, 2H ), 7.63 (dd, J = 5.8, 2.8 Hz, 2H), 7.37 (m, 9H), 6.64 (d, J = 8.4 Hz, 1H), 6.48 (s, 1H), 5.32 (t, J = 4.5 Hz) , 1H), 5.03 (s, 1H), 4.50 (m, 2H), 4.10 (m, 2H), 3.80 (m, 1H), 3.34 (m, 1H), 3.25 (m, 1H), 3.15 (m, 1H), 2.97 (m, 2H), 2.85 (s, 5H), 2.34 (m, 2H), 2.24 (m, 1H), 2.00 (m, 3H), 1.83 (m, 2H), 1.57 (m, 4H) ), 1.40 (s, 1H), 1.24 (s, 6H).

Example 11: [(3aR,5s,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 11)

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

First step: [(3aR, 5s, 6aS)-2-[3-[[4-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(5-Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl- Amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (11A)

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

Taking [(3aR,5s,6aS)-2-[3-[[4-[4-(hydroxymethyl)anilino]-4-oxo-butyl]-methyl-amino]-3-oxo -C -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)carbamate (6D) (0.22 g, 0.37 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin oxidant (0.42 g, 1 mmol) were added to the system at 0 ° C, and reacted at room temperature for 30 minutes, then added to the system. Saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL). After stirring for 10 min, dichloromethane (30 mL×2), and the organic phase was combined with saturated sodium hydrogen carbonate solution (30 mL×1) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 8-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl 5-amino-4-H-1,4-benzoxazin-3-one (1D) (0.17 g, 0.5 mmol), methanol (15 mL), dichloromethane (15 mL) and anhydrous sodium sulfate After stirring at room temperature for 4 hours, sodium borohydride (41 mg, 1.1 mmol) was added and the reaction was continued for 10 min. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjjjjjjjj Chromatography (dichloromethane/methanol (v/v) = 1 : 12) to give [(3aR,5s,6aS)-2-[3-[[4-[4-[[[ 2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl] Amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (11A) (0.32 g, yield: 78%).

LCMS m/z = 460.4 [M/2+1].

The second step: [(3aR, 5s, 6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 11)

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

Take [(3aR,5s,6aS)-2-[3-[[4-[4-[[[(2R)-2-[t-butyl(dimethyl)silyl]oxy-2-(5) -hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]- 3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (11A) (0.32 g, 0.35 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 and reacted at room temperature. 16 hours. After the reaction, the saturated sodium bicarbonate solution (30 mL) was quenched. The reaction was quenched with EtOAc (EtOAc) (EtOAc). 1:10), [(3aR,5s,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3)) -oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 11) (0.11 g, Yield: 39%).

LCMS m/z = 403.3 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.87 (s, 1H), 9.81 (s, 1H), 8.49 (s, 1H), 7.57-7.46 (m, 2H), 7.46-7.24 (m, 9H) , 7.20 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.75 (s, 1H), 5.02 (s, 1H) , 4.98 - 4.90 (m, 1H), 4.86 (m, 1H), 4.42 (m, 2H), 3.65 (m, 2H), 3.51 (s, 1H), 2.95 (s, 2H), 2.79 (s, 2H) ), 2.22 (m, 3H), 2.07 - 1.92 (m, 1H), 1.87 - 1.61 (m, 5H), 1.49 (m, 3H), 1.31 - 1.16 (m, 6H).

Example 12: [(3aR,5s,6aS)-2-[3-[[4-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine)- 8-yl)ethylamino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a -Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 12)

[(3aR,5s,6aS)-2-[3-[[4-[4-[[2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethylamino]methyl]] Anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]N- (2-phenylphenyl)carbamate

Taking [(3aR,5s,6aS)-2-[3-[[4-[4-(hydroxymethyl)anilino]-4-oxo-butyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)carbamate ( 6D) (0.22 g, 0.37 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin oxidant (0.42 g, 1 mmol) were added to the system at 0 ° C, and reacted at room temperature for 30 minutes. Add saturated sodium thiosulfate solution (10 mL) and saturated sodium hydrogen carbonate solution (10 mL), stir for 10 minutes, then extract with dichloromethane (30 mL×2), and combine the organic phase with saturated sodium hydrogen carbonate solution (30 mL) ×1) Washing, drying with anhydrous sodium sulfate, filtration, decompression of filtrate Concentrated, and added 8-(2-aminoethyl)-5-hydroxy-4H-1,4-benzoxazin-3-one acetate (0.13 g, 0.5 mmol) (8A), methanol (15 mL), N-methylpyrrolidone (15 mL) and acetic acid (0.06 g, 1 mmol). After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (0.25 g, 1.2 mmol) was added and the reaction was continued for 4 hours. After completion of the reaction, the mixture was applied to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:12) gave [(3aR,5s,6aS)-2-[3-[[4-[4-[[2-(5-) Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethylamino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3- Oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (Compound 12) (98 mg, yield: 34%).

LCMS m/z = 789.3 [M + 1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.85 (s, 1H), 9.78 (d, J = 10.9Hz, 1H), 8.48 (d, J = 4.1Hz, 1H), 7.49 (d, J = 7.0 Hz, 2H), 7.45 - 7.23 (m, 7H), 7.19 (d, J = 8.4 Hz, 2H), 6.59 (dd, J = 8.2, 5.1 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H) ), 5.75 (s, 1H), 5.31 (s, 1H), 4.93 (s, 1H), 4.43 (s, 2H), 3.63 (s, 2H), 2.94 (s, 2H), 2.78 (s, 1H) , 2.60 (m, 3H), 2.46 - 2.27 (m, 6H), 2.21 (m, 3H), 2.09 - 1.92 (m, 1H), 1.75 (s, 4H), 1.47 (m, 2H), 1.23 (s , 5H), 0.84 (m, 1H).

Example 13: [(3aR,5r,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate

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

First step: 4-[3-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro -1H-cyclopentadienyl[c]pyrrol-2-yl]propionyl-methyl-amino]butyric acid methyl ester (13A)

Methyl 4-[3-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2- Yl]propanoyl-methyl-amino]butanoate

Taking [(3aR,5r,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene Carbamate (3B) (0.63 g, 2 mmol) and methyl 4-[methyl(prop-2-enoyl)amino]butyrate (6D) (0.37 g, 2 mmol) in 50 mL round bottom In the flask, tetrahydrofuran (20 mL) and triethylamine (0.4 g, 4 mmol) were added, and the mixture was heated to 50 ° C for 24 hours. After the completion of the reaction, the system was evaporated under reduced pressure. mjjjjjjjjjjjjjjjjj ,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2 -yl]propionyl-methyl-amino]butyrate (13A), colorless viscous (0.54 g, yield: 53%).

LCMS m/z = 508.3 [M + 1].

Second step: [(3aR,5r,6aS)-2-[3-[[4-[4-(hydroxymethyl)anilino]-4-oxo-butyl]-methyl-amino]-3 -oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)carbamate Acid ester (13B)

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

Take methyl 4-[3-[(3aR,5r,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro- 1H-Cyclopenta[c]pyrrol-2-yl]propanoyl-methyl-amino]butyrate (13A) (0.78 g, 1.5 mmol) was placed in a 50 mL round bottom flask and tert-butanol was added ( 10mL) and water (10mL), after stirring, add lithium hydroxide (0.19g, 4.5mmol), react at room temperature for 1 hour, then adjust the system to pH=2 with hydrochloric acid (1M), add water (30mL), dichloride The organic phase was extracted with EtOAc (3 mL, EtOAc) After stirring with ethylamine (0.4 g, 4 mmol), isobutyl chloroformate (0.22 g, 1.6 mmol) was added dropwise at 0 ° C under nitrogen. After completion of the dropwise addition, stirring at 0 ° C for 30 minutes, p-aminobenzyl alcohol (0.26 g, 2 mmol) was added, and the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Purification by silica gel column chromatography (dichloromethane/methanol (v/v) = 1:30) afforded [(3aR,5r,6aS)-2-[3-[[4-[4-(hydroxy) Methyl)anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentyl Dienyl[c]pyrrole-5-yl N-(2-phenylphenyl)carbamate (13B) (0.4 g, yield: 40%).

LCMS m/z = 599.3 [M + 1].

The third step: [(3aR, 5r, 6aS)-2-[3-[[4-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (13C)

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

Taking [(3aR,5r,6aS)-2-[3-[[4-[4-(hydroxymethyl)anilino]-4-oxo-butyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)carbamate ( 13B) (0.2 g, 0.33 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin were added to the system at 0 °C. The oxidizing agent (0.28 g, 0.66 mmol) was reacted at room temperature for 30 minutes, then a saturated sodium thiosulfate solution (10 mL) and a saturated sodium hydrogen carbonate solution (10 mL) were added to the system, and stirred for 10 minutes, dichloromethane (30 mL×2) The organic phase was combined and washed with a saturated sodium hydrogen carbonate solution (30 mL×1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Butyl (dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (2B) (0.11 g, 0.33 mmol), methanol (15 mL), dichloromethane (15 mL After stirring with anhydrous sodium sulfate (2.84 g, 20 mmol) at room temperature for 4 hours, sodium borohydride (38 mg, 1 mmol) was added and the reaction was continued for 10 minutes. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjjjjjjjj Chromatography (dichloromethane/methanol (v/v) = 1 : 12) to give [(3aR,5r,6aS)-2-[3-[[4-[4-[[[ 2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]aniline 4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[ c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (13C), (0.28 g, yield: 90%).

LCMS m/z = 915.5 [M + 1].

The fourth step: [(3aR, 5r, 6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 13)

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

Take [(3aR,5r,6aS)-2-[3-[[4-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (13C (0.28 g, 0.35 mmol) was placed in a 25 mL round bottom flask, tetrahydrofuran (10 mL) was added, 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) = 1:8) gave [(3aR,5r,6aS)-2-[3-[[4-[4-[[[[ 2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl] Anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene [c] Pyrrol-5-yl]N-(2-phenylphenyl)carbamate (Compound 13) (100 mg, yield: 40%).

LCMS m/z = 401.3 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.29 (s, 1H), 9.90 (d, J = 24.3Hz, 1H), 8.48 (s, 1H), 8.09 (dd, J = 9.9,4.3Hz, 1H ), 7.65 - 7.48 (m, 2H), 7.46 - 7.18 (m, 10H), 7.06 (dd, J = 8.1, 2.1 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.47 (dd, J=9.9, 3.3 Hz, 1H), 5.75 (s, 1H), 5.10 (s, 1H), 4.70 (s, 1H), 3.77 (s, 2H), 3.51 (s, 1H), 2.96 (s, 1H) ), 2.80 (s, 2H), 2.71 (s, 2H), 2.57 (s, 2H), 2.46 - 2.21 (m, 7H), 2.05 - 1.89 (m, 2H), 1.79 (m, 2H), 1.40 - 1.15 (m, 7H), 1.07 (m, 2H).

Example 14: [(3aR,5r,6aS)-2-[3-[[4-[4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 14)

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

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

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

Taking [(3aR,5r,6aS)-2-[3-[[4-[4-(hydroxymethyl)anilino]-4-oxo-butyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)carbamate ( 13B) (0.2 g, 0.433 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin oxidant (0.28 g, 0.66 mmol) were added to the system at 0 ° C, and reacted at room temperature for 30 minutes. Saturated sodium thiosulfate solution (10 mL) and saturated sodium hydrogen carbonate solution (10 mL) were added to the system, and stirred for 10 min, then extracted with dichloromethane (30 mL×2). Washed with 30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 8-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxyl -ethyl]-5-hydroxy-4H-1,4-benzoxazin-3-one (1D) (0.14 g, 0.4 mmol), methanol (15 mL), dichloromethane (15 mL) Sodium (2.84 g, 20 mmol) was stirred at room temperature for 4 hr then sodium borohydride (38 mg, 1 mmol). After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjjjjjjjj Purification by chromatography (dichloromethane/methanol (v/v) = 1: 12) gave the title compound [(3aR,5r,6aS)-2-[3-[[4-[4-[[[[ -2-[tert-Butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino] Methyl]anilino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentyl Dieno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (14A), yellow solid (0.26 g, yield: 80%).

LCMS m/z = 460.3 [M/2+1].

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

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

Taking [(3aR,5r,6aS)-2-[3-[[4-[4-[[[(2R)-2-[t-butyl(dimethyl)silyl]oxy-2-(5) -hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]-methyl-amino]- 3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl) Carbamate (14A) (0.26g, 0.28mmol) was placed in a 25mL round bottom flask, tetrahydrofuran (10mL) was added, and after stirring, triethylamine trihydrofluorate (0.4mL) was added to the system and reacted at room temperature. 16 hours. After completion of the reaction, the reaction mixture was evaporated to m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (Dichloromethane/methanol (v/v) = 1:10), the title compound [(3aR,5r,6aS)-2-[3-[[4-[4-[[[[ Hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]anilino]-4-oxo-butyl]- Methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (Compound 14), white solid (80 mg, yield: 40%).

LCMS m/z = 403.3 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.86 (s, 1H), 9.81 (s, 1H), 8.44 (s, 1H), 7.50 (dd, J = 8.4,2.7Hz, 2H), 7.32 (m , 10H), 6.84 (d, J = 8.5 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.75 (s, 1H), 5.01 (s, 1H), 4.86 (d, J = 4.9 Hz) , 1H), 4.66 (d, J = 5.5 Hz, 1H), 4.43 (s, 2H), 3.65 (m, 2H), 3.51 (s, 1H), 2.95 (s, 2H), 2.80 (s, 2H) , 2.40–2.20 (m, 8H), 2.06–1.87 (m, 3H), 1.76 (m, 2H), 1.33–1.16 (m, 6H).

Example 15: [(3aR,5s,6aS)-2-[3-[[4-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-) Oxo-1hydroquinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]amino]-4-oxo-butyl]-methyl-amino]-3- Oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (compound 15)

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

First step: tert-butyl 3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrol-2-yl]propionate (15B)

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

[(3aR,5s,6aS)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-5-yl]N-(2-phenylbenzene The carbamate (Intermediate 2) (3.224 g, 10.0 mmol) was taken in 2-methyltetrahydrofuran (25 mL). Tert-butyl acrylate (1.41 g, 11.0 mmol), potassium carbonate (2.76 g, 20 mmol) was added thereto in that order. The reaction was stirred at 60 ° C for 4 hours. After the reaction was cooled to room temperature, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Separation (dichloromethane/methanol (v/v) = 15:1) afforded as a yellow liquid, tert-butyl 3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy Base-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]propanoate (15B) (4.51 g, yield 100%).

LCMS m/z = 451.3 [M + 1].

Second step: 3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H- Cyclopentane Oxo[c]pyrrol-2-yl]propionic acid (15C)

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

tert-Butyl 3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrol-2-yl]propanoate (15B) (4.5 g, 10 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (5 mL) was added dropwise to the reaction at room temperature and stirred for 4 hours. The reaction solvent was concentrated under reduced pressure. EtOAc (EtOAc m.) Acyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]propionic acid (15C) (3.9 g, yield 100%) .

LCMS m/z = 395.2 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[3-[[4-[(2-chloro-4-carbaldehyde-5-methoxy-phenyl)amino]-4-oxo-butyl -Methyl-amino]-3-oxo-propyl l]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N -(2-phenylphenyl)carbamate (15D)

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

3-[(3aR,5s,6aS)-5-[(2-Phenylphenyl)carbamoyloxy]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentane Iso[c]pyrrol-2-yl]propanoic acid (15C) (2.08 g, 5.27 mmol) in dichloromethane (20 mL). At room temperature, N-(2-chloro-4-carbaldehyde-1-amine-phenyl)-4-methylamino-butanamide trifluoroacetate (intermediate 3) (1.5 g, 5.27 mmol), triethylamine (1.07 g, 10.5 mmol), EtOAc (EtOAc) The reaction was quenched with EtOAc EtOAc (EtOAc m. After column chromatography (dichloromethane/methanol (v/v) = 15:1) to give a yellow liquid [(3aR,5s,6aS)-2-[3-[[4-[(2-) -formaldehyde-5-methoxy-phenyl) Amino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl l]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c Pyrrrol-5-yl]N-(2-phenylphenyl)carbamate (15D) (0.37 g, yield 10.6%).

LCMS m/z = 661.3 [M + 1].

Fourth step: [(3aR, 5s, 6aS)-2-[3-[[4-[[4-[[[(2)))]] 2-(8-Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]amino]-4-oxo- Butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N -(2-phenylphenyl)carbamate (15E)

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

[(3aR,5s,6aS)-2-[3-[[4-[(2-chloro-4-carbazinyl-5-methoxy-phenyl)amino]-4-oxo-butyl]- Methyl-amino]-3-oxo-propyl l]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (15D) (0.37 g, 0.56 mmol) was dissolved in a mixed solvent of dichloromethane (5 mL) and methanol (5 mL). To this was added 5-[2-amino-1-(tert-butyl(dimethyl)silyl)oxy-ethyl]-8-hydroxy-1H-quinolin-2-one (2B) (0.19 g, After adding 0.5 g of anhydrous sodium sulfate and stirring at room temperature for 3 h, sodium borohydride (0.064 g, 1.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with aq. EtOAc (EtOAc) Methyl chloride:methanol (v/v) = 1:0 to 8:1) to give [(3aR,5s,6aS)-2-[3-[[4-[[4-[[[[ )-2-(tert-butyl(dimethyl)silyl)oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2- Chloro-5-methoxy-phenyl]amino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-six Hydrogen-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (15E) (0.28 g, yield 51%).

LCMS m/z = 490.3 [M/2 + 1].

The fifth step: [(3aR, 5s, 6aS)-2-[3-[[4-[[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-) Oxo-1hydroquinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]amino]-4-oxo-butyl]-methyl-amino]-3- Oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate Acid ester (compound 15)

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

[(3aR,5s,6aS)-2-[3-[[4-[[4-[[[(2R)-2-(tert-butyl(dimethyl)silyl)oxy-2-) 8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]amino]-4-oxo-butyl] -methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2 -Phenylphenyl)carbamate (15E) (0.28 g, 0.29 mmol) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoric acid (0.12 g, 0.56 mmol). A saturated aqueous solution of sodium hydrogencarbonate (50 mL), EtOAc (5 mL) After column chromatography (dichloromethane:methanol (v/v) = 1:0 to 8:1), [(3aR,5s,6aS)-2-[3-[[4-[[ 2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1hydroquinolin-5-yl)ethyl]amino]methyl]-5-A Oxy-phenyl]amino]-4-oxo-butyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclo Pentio[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (Compound 15) (0.07 g, yield 30%).

LCMS m/z = 865.3 [M + 1].

¹ H NMR (400 MHz, CD ₃ OD) δ 8.23 (dd, J = 9.8, 6.1 Hz, 1H), 7.53 (d, J = 6.3 Hz, 2H), 7.46 - 7.19 (m, 9H), 7.12 (dd , J=8.1, 3.2 Hz, 1H), 6.99–6.86 (m, 1H), 6.57 (dd, J=9.7, 6.9 Hz, 1H), 5.15–5.08 (m, 1H), 5.04 (dd, J=11.6) , 4.1 Hz, 1H), 3.73 (d, J = 7.9 Hz, 5H), 3.56 - 3.40 (m, 2H), 3.07 (s, 2H), 2.93 (s, 2H), 2.73 - 2.41 (m, 11H) , 2.37 (d, J = 8.9 Hz, 2H), 1.93 (ddd, J = 38.2, 25.6, 19.3 Hz, 5H), 1.69 - 1.47 (m, 2H), 1.40 - 1.23 (m, 4H).

Example 16: [(3aR,5s,6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3 ,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 16)

[(3aR,6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8 -yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-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-[3-[[5-[3-(hydroxymethyl)anilino]-5-oxo-pentyl]-methyl-amino]-3 -oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)amino Formate (16A)

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

5-[3-[(3aR,5s,6aS)-5-[(2-phenylphenyl)carbamoyloxy)-3,3a,4,5,6,6a-hexahydro-1H- Cyclopenta[c]pyrrol-2-yl]propanoyl-methyl-amino]pentanoic acid (1A) (2.5 g, 4.9 mmol) was placed in a 50 mL round bottom flask, dichloromethane (30 mL) and Triethylamine (0.61 g, 6 mmol) was stirred, and then isobutyl chloroformate (0.84 g, 6.4 mmol) was added dropwise at 0 ° C under nitrogen. After completion of the dropwise addition, stirring at 0 ° C for 30 minutes, m-aminobenzyl alcohol (0.75 g, 6.1 mmol) was added, and the mixture was allowed to react at room temperature for 4 hours. After completion of the reaction, water (30 mL), EtOAc (3 mL, EtOAc) Silica gel column Chromatography (dichloromethane/methanol (v/v) = 1 : 30) to give [(3aR,5s,6aS)-2-[3-[[5-[3-(hydroxymethyl) Anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadiene And [c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16A) (1.7 g, yield: 56%).

LCMS m/z = 613.4 [M + 1].

Second step: [(3aR, 5s, 6aS)-2-[3-[[5-[3-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(5-Hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl- Amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenyl Phenyl)carbamate (16B)

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

Taking [(3aR,5s,6aS)-2-[3-[[5-[3-(hydroxymethyl)anilinyl]-5-oxo-pentyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16A) (0.56 g, 0.92 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin oxidant (0.85 g, 2 mmol) were added to the system at 0 ° C, and reacted at room temperature for 30 minutes. Saturated sodium thiosulfate solution (10 mL) and saturated sodium hydrogen carbonate solution (10 mL) were added to the system, and stirred for 10 min, then extracted with dichloromethane (30 mL×2). Washed with 30 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To the residue was added 8-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxyl -ethyl]-5-hydroxy-4H-1,4-benzoxazin-3-one (1D) (0.34 g, 1.0 mmol), methanol (15 mL), dichloromethane (15 mL) Sodium (4.26 g, 30 mmol) was stirred at room temperature for 4 hr then sodium borohydride (0.11 g, 3 mmol). After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjjjjjjjj Chromatography (dichloromethane/methanol (v/v) = 1 : 12) to give [(3aR,5s,6aS)-2-[3-[[5-[3-[[[ (2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl Amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H -cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16B) (0.48 g, yield: 56%).

LCMS m/z = 933.5 [M + 1].

The third step: [(3aR, 5s, 6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-) 1,4-benzoxazine-8- Ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a- Hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 16)

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

Take [(3aR,5s,6aS)-2-[3-[[5-[3-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5) -hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]- 3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl N-(2-phenylphenyl)amino Formate (16B) (0.48g, 0.52mmol) was placed in a 25mL round bottom flask, tetrahydrofuran (10mL) was added, and after stirring, triethylamine trihydrofluorate (0.6mL) 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) = 1:8), the crude product was obtained, and the crude product was separated and purified by a liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase containing 0.1%) Deionized water (A) of 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 obtain a white solid [ (3aR,5s,6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzene) And oxazin-8-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4, 5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (compound 16) 80 mg, yield: 10%).

LCMS m/z = 410.4 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ9.98 (m, 2H), 9.55 (s, 1H), 9.03 (s, 1H), 8.91 (s, 1H), 8.62 (d, J = 14.2Hz, 1H ), 7.84 (s, 1H), 7.70 - 7.25 (m, 10H), 7.19 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 8.5 Hz) , 1H), 5.92 (s, 1H), 5.06 (m, 1H), 4.45 (s, 2H), 4.14 (s, 2H), 3.74 (s, 5H), 3.20 (s, 2H), 2.95 (m, 2H), 2.93–2.68 (m, 6H), 2.43–2.27 (m, 2H), 2.00 (m, 1H), 1.85 (s, 1H), 1.74 (s, 1H), 1.67 (s, 2H), 1.62 – 1.44 (m, 4H), 1.24 (s, 4H).

Example 17: [(3aR,5s,6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5 ,6,6a-hexahydro-1H-ring Pentadieno[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 17)

[(3aR,6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl ]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-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-[3-[[5-[3-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2) -(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamic acid Ester (17A)

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

Taking [(3aR,5s,6aS)-2-[3-[[5-[3-(hydroxymethyl)anilinyl]-5-oxo-pentyl]-methyl-amino]-3-oxo -propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (16A) (0.56 g, 0.92 mmol) was placed in a 50 mL round bottom flask, and dichloromethane (15 mL) and Dess-Martin oxidant (0.85 g, 2 mmol) were added to the system at 0 ° C, and reacted at room temperature for 30 minutes. Saturated sodium thiosulfate solution (10 mL) and saturated sodium hydrogen carbonate solution (10 mL) were added to the system, and stirred for 10 min, then extracted with dichloromethane (30 mL×2). Washed with 30 mL × 1), 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 8-8-Hydroxy-1H-quinolin-2-one (0.34 g, 1.0 mmol) (2B), methanol (15 mL), dichloromethane (15 mL) and anhydrous sodium sulfate (4.26 g, 30 mmol) After 4 hours, sodium borohydride (0.11 g, 3 mmol) was added and the reaction was continued for 10 min. After completion of the reaction, the mixture was filtered. EtOAcjjjjjjjjjjjjjjjjj Purification by chromatography (dichloromethane/methanol (v/v) = 1: 12) gave the title compound [(3aR,5s,6aS)-2-[3-[[5-[3-[[[[ -2-[tert-Butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino] -5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopentadienyl[c] Pyrrole-5-yl]N-(2-phenylphenyl)carbamate (17A), pale yellow solid (0.45 g, yield: 53%).

LCMS m/z = 929.4 [M + 1].

The second step: [(3aR, 5s, 6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5 ,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 17)

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

Taking [(3aR,5s,6aS)-2-[3-[[5-[3-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-) -hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propan -3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate (17A (0.45g, 0.49mmol) was placed in a 25mL round bottom flask, tetrahydrofuran (10mL) was added, stirred evenly, to the system Triethylamine trihydrofluoride (0.6 mL) was added 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) = 1:8), the crude product was obtained, and the crude product was separated and purified by a liquid phase preparative column (liquid phase preparation conditions: C18 reverse phase preparative column, mobile phase containing 0.1%) Deionized water (A) of trifluoroacetic acid, acetonitrile (B), gradient elution B content 5% to 50%, elution time 15 min, flow rate 12 mL/min, column temperature: 30 ° C), [[3aR, 5s,6aS)-2-[3-[[5-[3-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)) Amino]methyl]anilino]-5-oxo-pentyl]-methyl-amino]-3-oxo-propyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-5-yl]N-(2-phenylphenyl)carbamate ditrifluoroacetate (Compound 17), white solid (70 mg, yield: 10 %).

LCMS m/z = 408.4 [M/2+1].

^{1 H NMR (400MHz, DMSO-} d6) δ10.47 (s, 2H), 10.00 (s, 1H), 9.50 (s, 1H), 9.02 (s, 2H), 8.64 (s, 1H), 8.05 (d , J = 10.0 Hz, 1H), 7.86 (d, J = 12.0 Hz, 1H), 7.35 m, 9H), 7.20 (m, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 9.9 Hz, 1H), 6.16 (s, 1H), 5.75 (s, 1H), 5.32 (m, 1H), 5.09 (s, 1H), 4.96 ( s, 1H), 4.20 (s, 2H), 3.57 (m, 4H), 3.17 (m, 1H), 3.06 (m, 1H), 2.94 (m, 2H), 2.88 (m, 1H), 2.79 (m) , 4H), 2.34 (m, 2H), 2.00 (m, 1H), 1.85 (m, 1H), 1.74 (m, 1H), 1.66 (m, 1H), 1.60 - 1.41 (m, 4H), 1.40 ( s, 1H), 1.24 (s, 4H).

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 0.74 10 8.65 2 0.67 11 0.69 3 4.43 12 0.76 4 4.40 13 4.6 5 1.08 14 4.01 6 0.72 15 0.99 7 2.49 16 0.69 8 1.36 17 1.13 9 1.17

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 separated by PBS/5 mM EDTA, collected by centrifugation, and the cells were resuspended with Stimulation Buffer (1 x HBSS, 5 mM HEPES, 0.5 mM IBMX, 0.1% BSA, pH 7.4), and the cell concentration was adjusted 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 4x Eu-cAMP tracer working solution to each well, then add 5 μl of 4x Ulight-anti-cAMP working solution per well and at room temperature. Incubate for 1 hour. 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 0.26 9 0.69 2 0.25 11 0.16 3 0.31 13 2.07 4 1.11 14 0.31 5 6.7 15 0.76 6 5.02 16 3.11 7 3.34

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 inhibitory effects of compounds on methacholine-induced bronchial contraction in guinea pigs

Conclusion: The compounds of the present invention have significant inhibition of methacholine-induced bronchial contraction in guinea pigs, and some compounds still have good bronchoconstriction inhibition effects after 24 hours of administration.

Claims (14)

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. 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. 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 (II) 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. 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 -NC _1-4 alkyl-; 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 _{1 is} selected from a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, and the benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring is optionally further 0 to 4 R ⁶ substitutions; 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 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 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. 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 ^{3d is} each selected from the group consisting of methylene, ethylene, propylene, -CH ₂ CH(CH ₃ )-, -CH(CH ₃ )CH ₂ -, 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 _{1 is} selected from a benzene ring, a thiophene ring, a furan ring, a thiazole ring, an oxazole ring or a pyridine ring, and the benzene ring, thiophene ring, furan ring, thiazole ring, oxazole ring or pyridine ring is optionally further 0 to 5 R ⁶ substitutions; 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. 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:

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. The pharmaceutical composition according to claim 7, wherein the other therapeutic agent is selected from one or more of a PDE4 inhibitor, a M receptor antagonist, a corticosteroid, and a β-adrenoreceptor agonist. 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. 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. 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. The method of treatment according to claim 11, wherein the airway obstructive disease comprises asthma, chronic obstructive pulmonary disease or bronchitis. An intermediate for the preparation of a compound of the formula (II) or a stereoisomer thereof, which is selected from the group consisting of a compound of the formula (III) or a stereoisomer thereof:

M is selected from a carboxyl group, -COOC _1-4 alkyl, -X ₁ -A ₁ -CH ₂ OH, -X ₁ -A ₁ -CHO or -X ₁ -A1-1,3-dioxolan-2- base; The definitions of a, b, c, d, X ₁ , X ₂ , A ₁ , R ¹ , R ² , R', R", R ^3b , R ^3d , W are as defined in claim 3. The intermediate according to claim 13, which is optionally selected from one of the following compounds: